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Muto, T., S. Wakui, H. Takahashi, S. Maekawa, T. Masaoka, S. Ushigome, and M. Furusato. "p53 Gene Mutations Occurring in Spontaneous Benign and Malignant Mammary Tumors of the Dog." Veterinary Pathology 37, no. 3 (May 2000): 248–53. http://dx.doi.org/10.1354/vp.37-3-248.
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Sixty-three cases of benign and malignant canine mammary tumors were analyzed to define the alteration of exons 5–8 for the p53 tumor suppressor gene using polymerase chain reaction direct sequence analysis with paraffin-embedded tissues. Four missense mutations were found in 38 benign mammary tumors (11%), and five missense (one tumor had two missense mutations) and one nonsense mutations were found in 25 mammary carcinomas (20%). These data suggest that the p53 gene alterations might be initiated at an early stage of canine mammary carcinogenesis and p53 mutations might be associated with malignancy. However, there was no evidence of any relationship between the p53 alterations and the histologic types of tumors or breeds of dogs.
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Sun, Woo, Jina Lee, Bong Kim, Jong Kim, and Joonhong Park. "Distinct Somatic Alteration Features Identified by Gene Panel Sequencing in Korean Triple-Negative Breast Cancer with High Ki67 Expression." Diagnostics 11, no. 3 (March 1, 2021): 416. http://dx.doi.org/10.3390/diagnostics11030416.
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This study aimed to clarify the genetic difference between Korean triple-negative breast cancer (TNBC) and other breast cancer (BC) subtypes. TNBC was defined as the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) amplification. DNA panel of the Ion Torrent Oncomine Comprehensive Assay (OCA) v3 was performed to identify somatic alteration in 48 specimens. In a total of 102 alterations (37 nonsense, 35 missense, 8 frameshift and 22 amplifications), 30 nucleotide alterations (24 nonsense, 1 missense, and 5 frameshift) were newly identified. The eight most commonly altered genes were PIK3CA, TP53, ERBB2, BRCA2, FANCD2, AKT1, BRCA1, and FANCA. TNBC had significantly lower mutation frequency in PIK3CA (TNBC vs. hormone receptor-positive and HER2-negative BC [HRPBC], p = 0.009), but higher mutation frequency in TP53 (TNBC vs. HRPBC, p = 0.036; TNBC vs. hormone receptor-positive and HER2- positive BC [HHPBC], p = 0.004). TNBC showed frequently higher Ki-67 expression than any positive BC (p = 0.004) due to HRPBC (p < 0.001). TNBC with high Ki-67/unmutated PIK3CA/mutated TP53 appears at a younger age (52.2 ± 7.6 years), compared to other subtypes (63.7 ± 11.0 years). TNBC with high Ki-67/unmutated PIK3CA/mutated TP53 may be related to relatively early onset BC. These findings demonstrate the genomic heterogeneity between TNBC and other BC subtypes and could present a new approach for molecular targeted therapy in TNBC patients.
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Huang, Minqi, Ellen B. Jaeger, Sydney Caputo, William Fleming, Malcolm Light, Charlotte Manogue, Isabelle P. Sussman, et al. "Longitudinal ctDNA alterations in germline positive CRPC patients." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): 275. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.275.
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275 Background: Circulating tumor-derived DNA (ctDNA) is an accessible method for characterizing somatic alterations. We report longitudinal ctDNA screenings of mCRPC patients (pts) who have had germline testing. Methods: Patients with both germline testing and ctDNA assessment were included. Germline testing was performed with a multi-gene cancer panel from Invitae (50-83 genes) and somatic alterations in ctDNA were identified by testing with Guardant 360 (70-83 genes). ctDNA alterations were characterized as deletions, frameshift, missense, nonsense, and other mutations. A total of 177 patients in various stages of therapy had both ctDNA and germline DNA tested. Results: From 2015-2021, 177 mCRPC patients were included and had an average of 3 ctDNA tests. 11.3% (20/177) had pathogenic or likely-pathogenic germline mutations. The common pathogenic germline mutations were in BRCA2 (25%; 5/20), ATM (10%; 2/20), and MSH2 (10%; 2/20). In ctDNA, missense mutations were the most prevalent type of gene alteration in germline negative (n = 539/790, 68%) and germline positive (n = 124/218, 57%) followed by frameshift mutations at 22% (n = 48/218) in germline positive and 10% (n = 80/790) in germline negative patients. Germline positive patients were more likely to have somatic frameshift mutations (OR = 2.09, 95% C.I. (1.3792, 3.1618), p = 0.001) and less likely to have missense mutations (OR = 0.61, 95% C.I. (0.4519, 0.8351), p = 0.002). Other alterations including deletions, nonsense, and other mutations were not significantly different. Of the germline positive pts, BRCA2 mutation was associated with the highest number of somatic alterations. Conclusions: Germline positive CRPC patients were more likely to have frameshift mutations and less likely to missense mutations compared to germline negative CRPC patients. Patients with germline mutations in BRCA2 and TP53 had the highest number of somatic alterations detected in ctDNA over the course of ctDNA evaluation.
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Zhang, Longfeng, Weijin Xiao, Fangjun Wu, Ran Peng, Jialong Shi, Chao Li, and Gen Lin. "SMARCA4-mutated lung adenocarcinoma, a distinctive non-small cell lung cancer with worse prognosis." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e20548-e20548. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e20548.
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e20548 Background: SMARCA4 gene is one of the catalytic subunits of the SWI/SNF chromosomal remodeling complex, which can regulate important cellular processes and functions and is closely associated to tumors. The clinical features, therapeutic efficacy, prognosis and pathological features of lung adenocarcinoma with this genetic variation are still unknown and controversial. Methods: The study recruited 274 patients (pts) with lung adenocarcinoma whose samples were sent to perform parallel hybridization-based next-generation sequencing. Two categories of SMARCA4 mutations were divided into Type1 mutations (frameshift mutations, nonsense mutations, splice-3 mutations, copy number amplification) and Type2 mutations (missense mutations and copy number loss) based on whether the mutation may result in defective protein. Furthermore, comparative analysis by using the clinical outcome data, the genomic and pathological characteristics were be performed in SMARCA4 Type 1 alterations corhort and Type 2 alterations corhort. Results: Among 274 pts were recruited, the mutation rate of SMARCA4 gene in lung adenocarcinoma was 9.1%. Furthermore, the presence of SMARCA4 alteration was associated with smoking (P＜0.05). Missense, nonsense, frameshift and splice were the most common types of mutations (92%). The pts with SMARCA4 Type1 alterations which probably lead to defective protein expression, had a worse prognosis compared with pts with SMARCA4 Type1 alterations (The role leading to defective protein expression is uncertain) and SMARCA4 Wild groups (P＜0.05). In addition, EGFR alterations were strongly associated with SMARCA4 Wild corhort compared to SMARCA4 Type1 alterations corhort (67% vs. 31% ), and SMARCA4 Type1 alterations was more associated with the absence of TP53, RB1, and Robo3 alterations. GO enrichment analysis suggested that the differentiated mutated genes between SMARCA4 Type1 alterations corhort and SMARCA4 Wild corhort were mainly enriched in cell cycle regulation. Pathologically, The SMARCA4 Type1 alterations was mostly poorly or moderately differentiated and strongly accompanied by the loss of expression of TTF-1(83.3%) and BRG1(80%) in immunohistochemistry. Conclusions: SMARCA4 Type1 alterations which probably lead to abnormality of protein was associated with poor prognosis and having different the genomic and pathological characteristics.
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Gagny, Bénédicte, and Philippe Silar. "Identification of the Genes Encoding the Cytosolic Translation Release Factors from Podospora anserina and Analysis of Their Role During the Life Cycle." Genetics 149, no. 4 (August 1, 1998): 1763–75. http://dx.doi.org/10.1093/genetics/149.4.1763.
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Abstract In an attempt to decipher their role in the life history and senescence process of the filamentous fungus Podospora anserina, we have cloned the su1 and su2 genes, previously identified as implicated in cytosolic translation fidelity. We show that these genes are the equivalents of the SUP35 and SUP45 genes of Saccharomyces cerevisiae, which encode the cytosolic translation termination factors eRF3 and eRF1, respectively. Mutations in these genes that suppress nonsense mutations may lead to drastic mycelium morphology changes and sexual impairment but have little effect on life span. Deletion of su1, coding for the P. anserina eRF3, is lethal. Diminution of its expression leads to a nonsense suppressor phenotype whereas its overexpression leads to an antisuppressor phenotype. P. anserina eRF3 presents an N-terminal region structurally related to the yeast eRF3 one. Deletion of the N-terminal region of P. anserina eRF3 does not cause any vegetative alteration; especially life span is not changed. However, it promotes a reproductive impairment. Contrary to what happens in S. cerevisiae, deletion of the N terminus of the protein promotes a nonsense suppressor phenotype. Genetic analysis suggests that this domain of eRF3 acts in P. anserina as a cis-activator of the C-terminal portion and is required for proper reproduction.
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Louie, Raymond J., Michael J. Friez, Cindy Skinner, Michael Baraitser, Robin D. Clark, Charles E. Schwartz, and Roger E. Stevenson. "Clark‐Baraitser syndrome is associated with a nonsense alteration in the autosomal gene TRIP12." American Journal of Medical Genetics Part A 182, no. 3 (December 8, 2019): 595–96. http://dx.doi.org/10.1002/ajmg.a.61443.
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Ohara, O., Y. Gahara, T. Miyake, H. Teraoka, and T. Kitamura. "Neurofilament deficiency in quail caused by nonsense mutation in neurofilament-L gene." Journal of Cell Biology 121, no. 2 (April 15, 1993): 387–95. http://dx.doi.org/10.1083/jcb.121.2.387.
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The existence of a neurofilament-deficient mutant of Japanese quail was recently documented (Yamasaki, H., C. Itakura, and M. Mizutani. 1991. Acta Neuropathol. 82:427-434), but the genetic events leading to the neurofilament deficiency have yet to be determined. Our molecular biological analyses revealed that the expression of neurofilament-L (NF-L) gene was specifically repressed in neurons of this mutant. To search for mutation(s) responsible for the shutdown of this gene expression, we cloned and sequenced the NF-L genes in the wild-type and mutant quails. It is eventually found that the NF-L gene in the mutant includes a nonsense mutation at the deduced amino acid residue 114, indicating that the mutant is incapable of producing even a trace amount of polymerization-competent NF-L protein at any situation. The identification of this nonsense mutation provides us with a solid basis on which molecular mechanisms underlying the alteration in the neuronal cytoskeletal architecture in the mutant should be interpreted.
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Qin, Wei, Huina Lu, Jianfei Fu, and Aibin Liang. "Alteration of SOCS Is a Possible Pathogenetic Mechanism of Myeloproliferative Neoplasm." Blood 116, no. 21 (November 19, 2010): 4121. http://dx.doi.org/10.1182/blood.v116.21.4121.4121.
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Abstract Abstract 4121 The activation of the JAK/STAT pathway caused by the JAK2 gene mutations is an important pathogenetic mechanism of myeloproliferative neoplasm(MPN). Recently, many evidences suggest that there are factors besides the mutations of JAK2 gene participate in the pathogenesis of MPN. Suppressors of cytokine signaling (SOCS) proteins are potent inhibitors of JAK/STAT pathway, therefore we hypothesized that the down regulation of SOCS protein system may be a possible pathogenetic mechanism of MPN through the activation of the JAK/STAT pathway. In order to testify our hypothesis, we investigated mutated points, the expression and methylation status of the SOCS1, SOCS2 and SOCS3 gene in 100 MPN patients(44 polycythemia vera (PV), 38 essential thrombocythemia (ET) and 18 idiopathic myelofibrosis(MF)). We obtained some interesting results: (1) By using DNA sequence analysis, two mutations of SOCS3 were identified with in the coding region in 1 of PV patients and 1 of ET patients (2%), respectively, and both of these 2 patients are with JAK2V617F mutation.(wide type ACG, coding Threonine, alterering to mutant type AAG, coding Lysine). Furthermore, three types of nonsense mutations were identified in SOCS3:Firstly,38 (38%) mutations of SOCS3 were identified with in the coding region in 19 of PV patients,17 of ET patients and 2 of MF respectively, (wide type CCC, coding Proline, alterering to mutant type CCA, coding Proline); Secondly, 44 (44%) mutations of SOCS3 were identified with in the coding region in 21 of PV patients,18 of ET patients and 5 of MF respectively, (wide type GTA, coding Valine, alterering to mutant type GTG, coding Valine); At last, 35 (35%) mutations of SOCS3 were identified with in the coding region in 13 of PV patients,20 of ET patients and 2 of MF respectively, (wide type GAT, coding Aspartic acid, alterering to mutant type GAC, coding Aspartic acid).Five nonsense mutations were found in SOCS2: 2 of PV patients,3 of ET patients, (wide type AAT, coding Asparagine, alterering to mutant type AAC, coding Asparagine). On the contrary, the presence of JAK2V617F mutation did not affect the nonsense mutations of SOCS2 or SOCS3. (2) By using Methylation Specific PCR (MSP), SOCS1 hypermethylation was identified in 27 patients. Hypermethylation of the SOCS2 promoter was identified in 9 of 100 (9%) patients. Hypermethylation of the SOCS3 promoter was identified in 35 of 100 (35%) patients. There was no hypermethylation of the SOCS1, SOCS2 and SOCS3 gene in 173 normal controls. (3) By using semi-quantitative PCR, the RNA expression levels of SOCS1, SOCS2 and SOCS3 were also investigated. We observed hypermethylated patients had lower SOCS1 or SOCS3 mRNA levels than unmethylated MPN samples, also observed that among patients with unmethylated SOCS1 and SOCS3, mRNA expression was higher from patients carrying the JAK2V617F mutation as compared with JAK2 wild type patients. On the contrary, the presence of JAK2V617F mutation did not affect the expression of SOCS1 or SOCS3 mRNA in methylated patients. Moreover, SOCS3 transcript levels were highest in patients with polycythemia vera and other JAK2 V617F negative myeloproliferative neoplasm. (4) According to SOCS1, SOCS3 methylation was not significantly correlated with survival or other clinical variables. In conclusion, SOCS1 and SOCS3 hypermethylation can activate the JAK/STATsignaling pathway in alternative or together with JAK2 mutations. These alterations might represent a potential therapeutic target. Disclosures: No relevant conflicts of interest to declare.
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Vail, E., M. Gayhart, and M. Azimpouran. "Malignant Melanoma with Atypical Phenotype and RAC1 Mutation." American Journal of Clinical Pathology 160, Supplement_1 (November 1, 2023): S95. http://dx.doi.org/10.1093/ajcp/aqad150.210.
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Abstract Introduction/Objective Melanoma, a highly invasive form of skin cancer associated with high mortality rates, poses significant challenges in diagnosis and treatment. RAC1, a member of the RHO family of GTPases, plays a crucial role as a molecular switch in cellular processes. A specific mutation in RAC1, caused by C > T transition induced by UV radiation, leads to P29S alteration, activating the SRF/MRTF pathway and triggering a phenotypic switch towards a mesenchymal phenotype. Methods/Case Report We present a case of a 74-year-old male patient who presented with a six-week history of right neck swelling. Ultrasonography revealed an enlarged lymph node in the right posterior triangle of the neck. PET scan showed a well- defined, moderately metabolically active lesion measuring 1.4x1.7cm. Initial biopsy indicated a diagnosis of malignant metastatic sarcomatous neoplasm. To establish a definitive diagnosis and determine the appropriate treatment plan, excision of the lymph node was performed. Histological examination revealed lymph node involvement by large, highly atypical cells exhibiting prominent nucleoli and frequent mitotic figures. Immunohistochemical analysis demonstrated positive staining for SOX10 and S100, while Melan-A and HMB45 were negative. Epithelial markers were also negative, although focal keratin positivity was observed. Further investigations were conducted to identify a primary or extranodal site. Routine dermatology visits had previously shown no evidence of primary cutaneous melanoma. Results (if a Case Study enter NA) Genomic profiling through next-generation sequencing (NGS) identified multiple alterations, including BRAF (G469R- exon 11, missense alteration), TP53 (R248W, missense alteration in TP53), RAC1 (P29S, missense alteration), TERT (Promoter Site Variant; chr5:g.1295228G>A c.-124C>T), and NF1 (Q1815, nonsense alteration). The tumor exhibited a high tumor mutational burden (TMB) and an ultraviolet (UV) signature characterized by C > T transitions. Conclusion Diagnosing melanoma with RAC1 mutation poses significant challenges due to its potential to induce phenotypic switching. Understanding the role of RAC1 mutations in driving melanoma progression can help improve diagnostic accuracy and guide targeted therapeutic strategies.
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Zhang, Xingming, Junjie Zhao, Xiaoxue Yin, Jiayu Liang, Yongquan Wang, Linmao Zheng, Ping Tan, et al. "Multi-omics analyses and molecular subtypes to provide potential therapeutic implications in fumarate hydratase-deficient renal cell carcinoma." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 4522. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.4522.
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4522 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare yet highly lethal kidney cancer. To deepen our understanding of FH-deficient RCC, we conducted a comprehensive integrated genomic study. Methods: A total of 126 treatment naïve FH-deficient RCC tissue samples were extracted from our multi-center database. Whole-exome, RNA-seq, and DNA-methylation sequencing were performed. All cases were confirmed with both FH/2SC immunohistochemical staining and FH alterations analysis. Results: Through whole-exome sequencing, we found FH alteration patterns were associated with both tumor behavior and patient survival outcomes. Tumors harboring FH truncating alteration (including nonsense, frameshift and splice site mutations) and mutations near hinge regions (such as p.S419L), were predominantly associated with more aggressive tumor behavior and poorer prognosis. We further developed a CpG sites-specific methylation signature for precise identification of FH-deficient RCC. More importantly, transcriptomic analysis unveiled three distinctive molecular subtypes characterized by enrichment of immune/Angiogenic/Stromal (C1), WNT/Notch/MAPK (C2), and proliferation/stemness (C3) pathways, respectively. Tumors in C1 derived the most substantial survival benefit from a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy. Tumors in C2 displayed moderate response to this therapeutic approach. In contrast, tumors in C3 exhibited an unfavorable response to anti-angiogenic monotherapy and its combination with ICB. Conclusions: These findings contribute to a profound understanding of the aggressive nature of FH-deficient RCC, offering insights into potential precision medicine approaches for disease management.
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Esakki, Amba, Anitha Pandi, Smiline A. S. Girija, and Vijayashree Priyadharsini Jayaseelan. "Correlating the genetic alterations and expression profile of the TRA2B gene in HNSCC and LUSC." Folia Medica 66, no. 5 (October 31, 2024): 673–81. http://dx.doi.org/10.3897/folmed.66.e117367.
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Introduction: Transformer (TRA2B) is a serine/arginine-rich (SR)-like protein family that regulates the alternative splicing of several genes in a concentration-dependent manner. Amplification of the TRA2B gene, which codes for TRA2B, occurs in several malignancies, including those of the lung, cervix, head and neck, ovary, stomach, and uterine. Materials and methods: The present study design follows a computational approach to predict the molecular mechanisms underlying TRA2B alterations in two cancer phenotypes, viz., lung and head and neck squamous cell carcinoma. The genetic alteration in the TRA2B gene was identified using the cBioportal database. The gene expression pattern in both the cancer types and their survival pattern concerning the expression profile was demonstrated using UALCAN. The microRNA targets of the TRA2B gene were identified using the miRDB database. Results: Genetic alteration was found to be 27% and 48% in HNSCC and LUSC datasets, respectively. The alterations included gene amplification, missense, nonsense, and splice site mutations. The gene expression profile of TRA2B correlated well with the gene amplification demonstrated by patients in both groups. However, the upregulation of TRA2B did not correlate well with the survival profile in LUSC patients. The downregulation of TRA2B markedly affected the survival of HNSCC patients, which can be attributed to the functions of microRNAs targeting TRA2B transcripts. Conclusion: Although TRA2B was found to be a potential diagnostic marker exhibiting a differential expression pattern for HNSCC, the employability of this gene as a prognostic marker needs more experimentation. Also, the influence of microRNAs on dysregulated gene expression should be considered to gain a better understanding of the underlying molecular mechanisms precipitating the disease.
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Borkar, Yashvanthi, Krishnananda Nayak, Ranjan K. Shetty, and Rajasekhar Moka. "A TBX5 NONSENSE MUTATION IN SIBLINGS WITH DIVERGENT PHENOTYPES ASSOCIATED WITH ISOLATED SEPTAL DEFECTS." Asian Journal of Pharmaceutical and Clinical Research 10, no. 9 (September 1, 2017): 126. http://dx.doi.org/10.22159/ajpcr.2017.v10i9.19628.
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Objective: Heart septal defects (HSD) account for 50% of the congenital heart malformations and are characterized by the hole in the wall of tissue which separates the heart chambers. The known causes of the SD are multifactorial and complex inheritance.Methods: Isolated 15 subjects with ostium secundum atrial SD (OS-ASD) and one subject with perimembranous ventricular SD (VSD) among 125 clinically diagnosed SD were included in the study. Sanger sequencing was performed for all the exons of TBX5 genes using genomic DNA of these patients.Results: Sequence variation c.444 G>A substitution, leads to the alteration of tryptophan residue into premature stop codon at codon 148. We observed a divergent phenotype within a family of four, where one sibling and the mother had OS-ASD, another sibling had phenotype of perimembranous VSD, and the father had normal genotype.Conclusion: We believe that this novel sequence variant in TBX5 gene is one of the factors in the SD and may hold a key determining the role of TBX5 gene in the heart development.
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Mayor, Paul, Laurie M. Gay, Erica Gornstein, Samantha Morley, Garrett Michael Frampton, Andreas Heilmann, James Sun, et al. "BRCA1/2 reversion mutations revealed in breast and gynecologic cancers sequenced during routine clinical care using tissue or liquid biopsy." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 5551. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5551.
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5551 Background: Tumors with genomic alteration (GA) of BRCA1 or BRCA2 ( BRCA) may be more sensitive to platinum (Pt) therapies and PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) can arise that may restore BRCA function and underlie reduced sensitivity to Pt compounds or PARPi. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for patients with predominantly relapsed, refractory or metastatic breast cancer (10967) or ovarian/peritoneal cancer (8352) was analyzed by hybrid-capture, next-generation sequencing for all classes of GA: base substitutions, indels, rearrangements, and copy number changes. RevGA were any GA that could restore the reading frame if in cis with a nonsense or frameshift (fs) GA. Results: 1900/19329 (9.8% ± 0.4%) tumors had ≥1 deleterious BRCA GA. 38 samples harbored potential revGA in BRCA1 (16) or BRCA2 (22): breast carcinoma (Ca) (21), ovarian or peritoneal serous Ca (10), ovarian or peritoneal adenocarcinoma (3), and ovarian epithelial Ca NOS (4). 35/38 sequenced samples were metastases. All potential revGA were somatic and fell into 3 classes: overlapping indel (21), compensatory fs (6), and missense mutation (11). One case harbored both an overlapping indel and a missense mutation with potential to revert a nonsense alteration. For 6 patients, testing of multiple tissue samples reveals the acquisition of revGA over time. RevGA are generally observed at allele frequencies lower than the deleterious GA they may revert. Clinical histories for patients with reversion mutations will be presented. Conclusions: Genomic profiling of breast and gynecological carcinomas, using either tissue or liquid biopsies, reveals potential revGA that may restore some level of BRCA function. RevGA, although rare, can be acquired during the course of treatment. We identified potentially compensatory missense, fs and indel mutations with CGP. Comparison of allele frequencies suggests that revGA often arise as subclones. The acquisition of a revGA over time can be observed through testing of multiple samples, either tissue or liquid biopsy.
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Rücker, Frank G., Lars Bullinger, Frank Stegelmann, Carmen Blersch, Peter Lichter, Jürgen Krauter, Brigitte Schlegelberger, et al. "NF1 Alterations Are Common In AML with Complex Karyotype and Correlate with Specific Genomic Imbalances." Blood 116, no. 21 (November 19, 2010): 4179. http://dx.doi.org/10.1182/blood.v116.21.4179.4179.
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Abstract Abstract 4179 In acute myeloid leukemia (AML), complex karyotype is defined as the presence of three or more chromosome abnormalities in the absence of one of the recurrent genetic abnormalities as defined by the recent WHO classification. AML with complex karyotype (CK-AML) account for approximately 10 to 15% of all cases and are associated with preceding myelodysplasia (MDS) or exposure to toxic agents; the prognosis of patients is very poor. So far, little is known about the molecular mechanisms underlying initiation or progression of CK-AML. To identify genomic regions of potential pathogenic relevance, we used microarray-based techniques [array-comparative genomic hybridization (CGH) and single-nucleotide polymorphism (SNP) analysis] for high-resolution genome-wide analysis in 242 cases, including 171 (71%) cases enrolled on clinical protocols using intensive chemotherapy. Among other genomic imbalances, we identified loss of chromosome band 17q11.2 encompassing the NF1 locus in 55 (23%) of the 242 cases. Interestingly, three of these cases exhibited homozygous loss of NF1. Based on these findings and the fact that NF1 is recurrently altered in myeloid malignancies, we further investigated its role in CK-AML. Therefore, we analyzed 11 cases with heterozygous microdeletions of NF1 for mutations in the remaining allele by direct sequencing of exons 1 to 60 and identified 5 mutations in 4 cases; all of these mutations resulted in a premature stop codon (3 frameshift mutations, 2 nonsense mutations); one frameshift mutation (c.2033dupC) was recurrent. Combining the findings from array-based and mutation analyses, we so far identified 7 patients with biallelic NF1 gene alterations, i.e. homozygous loss or loss of one allele and at least one mutation in the remaining allele. Since correlation of NF1 alteration with data from array-based genomic profiling revealed a significant correlation with loss of chromosome band 17p13 encompassing TP53 (P < .001), we correlated NF1 alteration with the TP53 status (mutation and/or loss), which was available for all 242 cases, and found a positive correlation with both TP53 alteration (mutation and/or loss) and TP53 mutation (P < .001 each). In addition, NF1 alteration was significantly correlated with biallelic TP53 alterations (loss and mutation or homozygous mutations) (P < .001). We than further investigated the two genotypes NF1alteration/TP53alteration (n=50) and NF1no alteration/TP53alteration (n=109) with regard to their association with other genomic imbalances. The genotype NF1alteration/TP53alteration was significantly correlated to the total number of deletions (median 9 vs 7; P = .025), the genomic complexity as measured by the total number of aberrations per case (median 13 vs 11; P = .039), and the presence of 16q loss (50% [25/50] vs 29% [32/109], P = .014) when compared with the NF1no alteration/TP53alteration genotype. Notably, in a recently published murine model deficiency of ICSBP, located on 16q24, was shown to synergize with NF1 haplo-insufficiency in leukemogenesis. In conclusion, the NF1 gene is found to be recurrently altered in CK-AML. Being associated with specific genomic aberrations, NF1 alteration is likely cooperating in myeloid leukemogenesis or disease progression. One important co-player might be TP53 that has an important role in genomic stability. The exact mechanism of interaction between NF1 and TP53 or other concurrent genetic alterations have to be further investigated. Disclosures: Döhner: Pfizer: Research Funding.
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Rifai, Kaoutar, Loubna Guissi, Nawal Moussaid, Lamyae Echchad, Hinde Iraqi, and Mohamed El Hassan Gharbi. "Simpson-Golabi-Behmel Syndrome and Pituitary Insufficiency: Genetic Predisposition or Coincidence." Saudi Journal of Medicine 8, no. 05 (May 6, 2023): 202–4. http://dx.doi.org/10.36348/sjm.2023.v08i05.002.
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Simpson-Golabi-Behmel syndrome (SGBS) is a rare genetic disorder that is characterized by the overgrowth of various parts of the body. We present a unique case of a young man with SGBS associated with pituitary insufficiency. This association has not been described yet in the literature. The patient was diagnosed with SGBS at 12 years, which was further confirmed through genetic testing (de novo nonsense mutation of the GPC3 gene). At the age of 18, the patient consulted for alteration of the general condition with asthenia. Laboratory evaluation revealed pituitary insufficiency consisting of central hypothyroidism associated with partial secondary adrenal insufficiency. The pituitary MRI was unremarkable. So far, Pituitary insufficiency has never been described in SGBS cases. To our knowledge, this is the first case reported in the literature.
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Li, Yan, Qingcong Li, Yaxuan Zhang, Yuqing Lai, Zhouchao Yang, Yueqin Li, Yuehan Liao, et al. "The landscape of ATM alteration in Chinese solid tumor patients." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e15147-e15147. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e15147.
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e15147 Background: The Ataxia-telangiectasia mutated (ATM) gene is an oncosuppressor, which plays an important role in the repair of DNA double-strand breaks (DSBs). The mutation profiles of ATM gene in Chinese solid tumor patients can help understand pathogenesis, prognosis, and identify targets for therapy. Methods: Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in normal-paired samples from 1351 patients with malignancies from January 2021 to October 2022, and alterations including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements. Results: ATM gene was altered in 6.8% (92 of 1351) of all solid tumors. The frequency of ATM variations was assessed in multiple cancer types, including non-small cell lung cancer 22% (35/159), endometrial carcinoma 15% (2/13), biliary tract tumor 12.1% (7/58), gastric cancer 10.7% (3/28), prostatic cancer 8.3% (1/12), breast cancer 6.7% (2/30), colorectal cancer 6.5% (11/168), thyroid cancer 6.2% (5/80), cervical carcinoma 5.7% (2/35), prostatic cancer 3.9% (2/51), liver cancer 3% (2/66). A total 102 genetic alterations were identified in 92 patients, including 70 missense mutations (69%), 14 nonsense (14%), 9 splicing (9%), 3 frameshift (3%), 2 deletion (2%), 2 copy number variation (2%). Among these patients, 2 had pathogenic germline ATM heterozygous mutations, including one lung adenocarcinoma and one pancreatic cancer. Furthermore, in our cohort, ATM mutation carriers also owned other actionable mutation, the most frequent one was TP53 (41%), followed by APC (29%), KRAS (23%), MLL3 (22%) and BRCA2 (20%). Conclusions: Our findings indicate that ATM alterations are widely mutated in Chinese multiple cancer types, with specific mutations differing largely among different tumor types. ATM alterations warrant further investigation as predictive biomarkers of response to PARP inhibitors or platinum-based therapy.
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Brown, Gary, De-Mao Chen, J. Scott Christianson, Ron Lee, and William S. Stark. "Receptor demise from alteration of glycosylation site in Drosophila opsin: Electrophysiology, microspectrophotometry, and electron microscopy." Visual Neuroscience 11, no. 3 (May 1994): 619–28. http://dx.doi.org/10.1017/s0952523800002509.
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AbstractIn the δAsn20 Drosophila stock, the N-linked glycosylation site of opsin in Rl-6 receptors (Rhl) is absent. We used electroretinography (ERG), microspectrophotometry (MSP), and electron microscopy (EM) to quantify visual cell defects. Positive controls, w9, had wild type Rhl. MSP revealed minimal photopigment in δAsn20 for 6 days posteclosion; w9 had near normal visual pigment. ERG sensitivity and prolonged depolarizing afterpotential (PDA) were compared for δAsn20 and w9. δAsn20's Rl-6 function is decreased 100–fold at eclosion and diminishes until only R7/8 functions at 11 days. What little rhodopsin is routed to the rhabdomere functions. Morphometry showed smaller Rl-6 rhabdomeres in δAsn20 for 8 days posteclosion. Rhabdomeres in w9 were normal. A negative control, ninaE0117, a deletion of the Rhl gene, also has small rhabdomeres. δAsn20 and ninaE0117 lack the extreme rhabdomere elimination of ora (outer rhabdomeres absent), a nonsense mutant interrupting Rhl's coding sequence. δAsn20 and ora have surplus membrane while ninaE0117 does not. Freeze fracture reveals that δAsn20's rhabdomeric P-face particle count is as low as for vitamin A deprivation, consistent with an opsin defect. High particle density, organized into rows, is present in adjacent plasmalemma where surplus membrane accumulates. In summary, δAsn20 interferes with either synthesis, deployment, or maintenance of opsin.
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Camacho, Emma, Luis Hernández, Silvia Hernández, Frederic Tort, Beatriz Bellosillo, Silvia Beà, Francesc Bosch, et al. "ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances." Blood 99, no. 1 (January 1, 2002): 238–44. http://dx.doi.org/10.1182/blood.v99.1.238.
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The ataxia–telangiectasia mutated (ATM) gene codifies for a protein critically involved in the cellular response to DNA damage. ATM alterations have been observed in some sporadic lymphoproliferative disorders. The recurrent 11q22-23 deletions found in mantle cell lymphoma (MCL) suggest that ATM could be inactivated in these lymphomas. In this study, ATM gene alterations and protein expression were examined in 20 and 17 MCL tumor specimens, respectively. Previously, these patients had been examined forp53 and p14ARF gene status and analyzed by comparative genomic hybridization. Nine patients had 11q22-23 losses. Eight ATM gene mutations were detected in 7 patients. These alterations were 3 missense mutations in the phosphatidylinositol-3 kinase (PI-3K) domain and 5 truncating mutations, including 3 frameshifts, a nonsense mutation, and a substitution of the initial methionine. All truncating mutations were associated with lack of protein expression. Somatic origin was demonstrated in 3 mutations, whereas one mutation was carried heterozygously in the patient germ line. Chromosomal imbalances were significantly higher in typical MCL with ATM inactivation (7.8 ± 1.3) than in tumors with the wild-type gene (3 ± 1.1) (P = .001). Moreover, tumors with bi-allelic ATM alteration were associated with 3q gains (P = .015) and frequent extranodal involvement (P = .049).ATM gene alterations were not related to the histologic variant of the tumors, p53/p14ARF gene status, survival, or other clinicopathologic features of the patients. These findings indicate that ATM gene mutations in MCL are mainly truncating or missense mutations involving the PI-3K domain, and that may play a role in the pathogenesis of a subset of these tumors with increased numbers of chromosomal imbalances.
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Basu, Gargi D., Tracey White, Janine R. LoBello, Kevin R. Lau, Michael Syring, Subha Krishnan, Laura Gonzalez, et al. "ARID1A alterations in gastrointestinal cancers as therapeutic opportunities." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 671. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.671.
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671 Background: The gene encoding the AT-rich interacting domain (ARID1A) is a tumor suppressor and a subunit of the Switch/Sucrose Non fermentable (SWI/SNF) chromatin remodeling complex that regulates gene expression. Additionally, ARID1A functions to maintain genomic integrity by interacting with ATR. Mutations in ARID1A have been observed in a number of cancers. Inactivation of ARID1A has been reported to lead to increased sensitivity to inhibitors of PARP and PI3K/AKT pathway. We evaluated ARID1A alterations in gastrointestinal (GI) cancers to identify new therapeutic options. Methods: Comprehensive genomic profiling was performed on 55 GI cancer samples with 28 metastatic and 27 primary samples. Targeted sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA samples. Results: ARID1A alterations were noted in 20% (11/55) of GI cancers. Alterations included frameshift and nonsense mutations, INDELs and structural breakpoints which are predicted to cause loss of ARID1A function. Tumor tissues harboring ARID1A alterations included 2/8 gastro-esophageal cancers, 2/2 duodenal cancers, 3/29 colorectal (CRC) cancers, 2/2 small bowel cancers, and 2/7 bile duct cancers. Mutations in the C-terminal half of ARID1A, known to interact with ATR and mediate its recruitment to double strand breakpoints was present in 2/11 samples. No pathogenic changes in the DNA repair genes (BRCA1/2, CHEK1/2, ATM, ATR or PALB2) or MMR genes were present in the tumors harboring ARID1A alterations. Interestingly, ARID1A mutations frequently coexisted with alterations leading to activation of the PI3K pathway. We found 45% (5/11) samples with mutated ARID1A had pathogenic alterations in PIK3CA, AKT, NF1, STK11, TSC1 and TSC2 genes which may increase sensitivity to PI3K pathway inhibitors. Conclusions: Targeted sequencing demonstrated that ARID1A is a frequent event in GI cancer. Our results suggest there may be a correlation between samples with ARID1A alteration and PI3K/AKT pathway activation which may lead to therapeutic opportunities with PI3K pathway inhibitors. The presence of ARID1A mutations especially those in the C-terminal half may predict clinical utility of PARP inhibitors in GI cancer.
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Murray, Nicole, Colton Leavitt, Noah Shepard, Zera Gonzales, Jiaming Li, Brock O'Neil, Christopher Dechet, et al. "Abstract 2559: Genotype-phenotype associations in von hippel-lindau syndrome: Implications for screening." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2559. http://dx.doi.org/10.1158/1538-7445.am2024-2559.
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Abstract Introduction and Objectives: Von Hippel-Lindau (VHL) is an autosomal dominant genetic disease. The type of VHL alteration has been shown to impact downstream VHL expression and clinical phenotype. However, current screening practices do not differ based on VHL genetic subtype. We aim to define the genotype-phenotype association among an institutional cohort of VHL patients. Methods: We conducted a retrospective cohort study of 69 patients (27 families) with von Hippel-Lindau at the Huntsman Cancer Institute from 1998-2023. 55% (38/69) patients have documented VHL variants for review. We evaluated the association of VHL type with risk of pheochromocytoma (Pheo), renal cancer (RCC), and hemangioblastoma (HB). t test and Fisher’s exact test were used to assess differences in clinicopathologic characteristics by VHL Type. P-value < 0.05 was considered significant. Results: We identified 24 unique VHL alterations among 38 patients. 66% (25/38) of patients had missense mutations, 10% (4/38) nonsense mutations, 21% (8/38) splice mutations, and 3% (1/38) deletion/duplication (Table 1). The median age at VHL diagnosis was 31 years old (range 4-76). VHL Type 2 was more common, 87% (33/38). All VHL Type 1 patients (5/5) developed RCC and HB. No patients with VHL Type 1 developed PheoPara. Of the VHL Type 2 patients, 39% (13/33) have not developed any VHL-associated clinical manifestations. Of the 33 patients diagnosed with VHL Type 2, 18% (6/33) were diagnosed with PheoPara, 30% (10/33) with RCC, and 48% (16/33) with HB. Conclusion: VHL type 2 comprised the majority of VHL diagnoses in our cohort with a notable absence of PheoPara phenotype. VHL Type 1 had higher penetrance and a higher prevalence for RCC and hemangioblastoma. With validation in larger cohorts, this cohort supports utilizing VHL genetic subtypes to personalize surveillance. Additional VHL testing for the remainder of the cohort is ongoing. Clinicopathologic characteristics of von Hippel-Lindau Syndrome cohort with known genetic mutations All (n=38) Type 1 (n=5) Type 2 (n=33) p-value AgeMean (Median) 33.1 (31) 42 (28) 31.7 (31) 0.38 White, n (%) 92% (n=35) 5 (100%) 30 (91%) 1 Hispanic, n (%) 8% (n=3) - 3 (9%) 1 VHL alteration, n (%) - Missense 25 (66%) - 25 (76%) Nonsense 4 (10%) 4 (80%) - Splice site 8 (21%) - 8 (24%) Deletion/Duplication 1 (3%) 1 (20%) - Penetrance, n (%) 25 (66%) 5 (100%) 20 (61%) 0.14 Phenotype, n (%) PheoPara 6 (16%) - 6 (18%) 0.57 RCC 15 (39%) 5 (100%) 10 (30%) 0.006 Hemangioblastoma 21 (55%) 5 (100%) 16 (48%) 0.26 Citation Format: Nicole Murray, Colton Leavitt, Noah Shepard, Zera Gonzales, Jiaming Li, Brock O'Neil, Christopher Dechet, Bogdana Schmidt, Benjamin L. Maughan, Kristen Pauley, Anne Naumer, Wendy Kohlmann, Alejandro Sanchez. Genotype-phenotype associations in von hippel-lindau syndrome: Implications for screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2559.
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Loret, Camille, Amandine Pauset, Pierre-Antoine Faye, Valérie Prouzet-Mauleon, Ioanna Pyromali, Angélique Nizou, Federica Miressi, et al. "CRISPR Base Editing to Create Potential Charcot–Marie–Tooth Disease Models with High Editing Efficiency: Human Induced Pluripotent Stem Cell Harboring SH3TC2 Variants." Biomedicines 12, no. 7 (July 12, 2024): 1550. http://dx.doi.org/10.3390/biomedicines12071550.
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Human induced pluripotent stem cells (hiPSCs) represent a powerful tool to investigate neuropathological disorders in which the cells of interest are inaccessible, such as in the Charcot–Marie–Tooth disease (CMT), the most common inherited peripheral neuropathy. Developing appropriate cellular models becomes crucial in order to both study the disease’s pathophysiology and test new therapeutic approaches. The generation of hiPS cellular models for disorders caused by a single nucleotide variation has been significantly improved following the development of CRISPR-based editing tools. In this study, we efficiently and quickly generated, by CRISPR editing, the two first hiPSCs cellular models carrying alterations involved in CMT4C, also called AR-CMTde-SH3TC2. This subtype of CMT is associated with alterations in the SH3TC2 gene and represents the most prevalent form of autosomal recessive demyelinating CMT. We aimed to develop models for two different SH3TC2 nonsense variants, c.211C>T, p.Gln71* and the most common AR-CMTde-SH3TC2 alteration, c.2860C>T, p.Arg954*. First, in order to determine the best CRISPR strategy to adopt on hiPSCs, we first tested a variety of sgRNAs combined with a selection of recent base editors using the conveniently cultivable and transfectable HEK-293T cell line. The chosen CRISPR base-editing strategy was then applied to hiPSCs derived from healthy individuals to generate isogenic CMT disease models with up to 93% editing efficiency. For point mutation generation, we first recommend to test your strategies on alternative cell line such as HEK-293T before hiPSCs to evaluate a variety of sgRNA-BE combinations, thus boosting the chance of achieving edited cellular clones with the hard-to-culture and to transfect hiPSCs.
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Jiang, Yong, Shiying Dang, Li Yang, Yin Han, Yongshen Zhang, Tianhao Mu, Shifu Chen, and Feng-Ming Kong. "Association between homologous recombination deficiency and tumor mutational burden in lung cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e21043-e21043. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e21043.
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e21043 Background: Homologous recombination (HR) is an important repair method for DNA double-strand damage. HR is involved with complex signaling pathways and multiple steps, including BRCA1/2. Homologous Recombination Deficiency (HRD) can be caused by the loss of function of BRCA1/2 proteins due to gene mutation. Tumor mutational burden (TMB) was indicated to involved with HRD, which is critical to the guidance of immunotherapy. Methods: Patients available with tumor specimen genomic testing for lung cancer were enrolled in this study. The sequencing library was captured using a 605-gene panel. Homologous recombination (HR)-related gene list included 102 genes. Genomic alterations of HR-related genes were assessed by next-generation sequencing assay, including nonsense, nonstop, frameshift, splice site, damaging missense mutations in somatic variants and pathogenic germline variants. Then, TMB was calculated by dividing the total number of mutations counted by the size of the coding region. Results: A total of 741 patients was enrolled and 182 of them (25.6%) had at least one genomic alteration of the HR genes. The top mutant HR genes included ATM (4.1%), DNMT3A (2.8%), ATR (1.8%), CHEK2 (1.5%), BRCA2 (1.5%), ABL1 (1.4%), FANCA (1.2%), RIF1 (1.1%), FANCI (1.1%), RAD50 (0.9%), BRCA1 (0.9%), and MRE11A (0.9%). The most common mutational type was missense mutation (69.2%), followed by frameshift (15.6%), and nonsense mutation (15.2%). The median age was 62 in the HRD group (age < 45:5.4%, 45-65:59.6%, > 65:34.9%) compared to 60 in the rest of the patients (age < 45:11.3%, 45-65:61.3%, > 65:27.4%). There were overall 57.5% males and 42.5% females in terms of gender. HRD group had a significantly higher rate than Non-HRD group in males (72.1% vs 52.8%, p < 0.01). The occurrence of HRD mutations was significantly correlated with a high level of TMB (p < 0.01). The median TMB of HRD group (7.9 muts/Mb, 95%CI:7.1-9.2 muts/Mb) was significantly higher than that of Non-HRD group (3.8 muts/Mb, 95%CI:3.3-4.2 muts/Mb). In addition, the upper quantile value (7.5 muts/Mb) was used to identify patients with high TMB. HRD group had a significantly higher rate of TMB-high patients than Non-HRD group (51.1% vs 17.0%, p < 0.01). Conclusions: Our study demonstrated genomic alterations of the HR genes in about one fourth’s lung cancer. Besides, there was a significant positive correlation between HRD mutations and TMB level. The significance of HRD genomic mutation on predicting the efficacy of immunotherapy deserves further study.
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Dupont, Marie Alice, Camille Humbert, Céline Huber, Quentin Siour, Ida Chiara Guerrera, Vincent Jung, Anni Christensen, et al. "Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion." Human Molecular Genetics 28, no. 16 (May 1, 2019): 2720–37. http://dx.doi.org/10.1093/hmg/ddz091.
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Abstract Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536–539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52−/− cells. Altogether, our findings allow a better comprehensive genotype–phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.
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Dai, Charles, Haley Barnes, Arielle Medford, Annika Putur, Jennifer Keenan, Beverly Moy, Seth Wander, Ryan Corcoran, and Aditya Bardia. "Abstract PO2-13-02: Detection of SPEN mutations in advanced breast cancer by circulating tumor cell-free DNA." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO2–13–02—PO2–13–02. http://dx.doi.org/10.1158/1538-7445.sabcs23-po2-13-02.
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Abstract Background: Alterations in the SPEN gene are rare in primary breast cancer (~3%, ref: TCGA). SPEN is a hormone-inducible transcriptional repressor with known functions in orchestrating X-inactivation in females. Additionally, SPEN has been implicated as a potential estrogen receptor co-repressor and molecular partner of NCOR2 as well as epigenetic modifiers such as KMT2D and HDACs via C-terminal interactions. SPEN loss-of-function is associated with tamoxifen resistance in preclinical models. However, the landscape of SPEN alterations in advanced breast cancer remains poorly described. The primary objective of this study was to evaluate the frequency and different types of SPEN alterations in metastatic breast cancer (MBC). Methods: A query was performed on all patients at an academic institution with available genomic testing from Guardant360, a next-generation sequencing cell-free DNA (cfDNA) assay, evaluating 500 genes in total. Patients with MBC were identified, and specific alterations in SPEN as well as co-alterations were extracted. Silent and germline mutations were excluded from analysis. Retrospective review was conducted to determine clinicopathologic characteristics such as age, hormone and HER2 receptor status, menopausal status, and therapy at time of the detected mutation. Results: Among 366 patients with MBC and available cfDNA, 8.5% (n=31) had an alteration detected in the SPEN gene. Median age of patients with SPEN mutations was 66 years (range 33-92). A majority of patients (90%) had HR+ disease (n=28/31), with HR-/HER2+ disease and TNBC additionally representing 3% (n=1/31) and 6% (n=2/31) of cases, respectively. SNVs were most frequent, comprising 89% (n=42/47) of all alterations. Indels were additionally identified in 11% (n=5/47), and no CNVs or fusions were noted. Nonsense and frameshift mutations represented 8/47 (17%) and 2/47 (4%) of all alterations respectively. No recurrent mutational hotspots were detected. The most common co-alterations in descending order were PIK3CA, TP53, ERBB2, ARID1A, MDM4, PPM1D, NF1, DNMT3A, ATM, and ESR1. Association between SPEN mutations and clinical outcomes will be presented at the meeting. Conclusions: SPEN mutations were detected mostly in patients with HR+/HER2- MBC and at a higher frequency than reported in primary disease via TCGA. SNVs were common, though it remains unclear whether these comprise driver versus passenger mutations. While no mutational hotspots were identified, several novel loss-of-function truncating mutations were identified, which warrant further validation of functional and clinical significance. SPEN alterations in metastatic breast cancer Alterations detected by cell-free DNA sequencing in patients with metastatic breast cancer and annotated by type of alteration and receptor subtype. Citation Format: Charles Dai, Haley Barnes, Arielle Medford, Annika Putur, Jennifer Keenan, Beverly Moy, Seth Wander, Ryan Corcoran, Aditya Bardia. Detection of SPEN mutations in advanced breast cancer by circulating tumor cell-free DNA [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-02.
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Murray, Nicole. "Genotype-phenotype associations in Von-Hippel Lindau Syndrome: implications for screening." Oncologist 29, Supplement_1 (August 5, 2024): S16. http://dx.doi.org/10.1093/oncolo/oyae181.024.
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Abstract Background Von Hippel-Lindau (VHL) is an autosomal dominant genetic disease with an estimated incidence of 1:36,000. The type of germline VHLI alteration has been shown to impact downstream VHL expression and clinical phenotype. However, current screening practices do not differ based on VHL genomic subtype. We aim to assess genotype-phenotype association among an institutional cohort of VHL patients. Methods We conducted a retrospective cohort study of 69 patients (27 families) at the University of Utah and Huntsman Cancer Institute from 1998- December 2023. 41 patients had documented germline testing in our system to define VHL type. VHL Type 1 was defined as those with nonsense mutations, deletions, and duplications and Type 2 as those with missense and splice mutations. Mean follow-up was 86- and 59-months for VHL type 1 and 2 respectively. We then evaluated the association of VHL type with risk of pheochromocytoma (Pheo), renal cancer (RCC), and hemangioblastoma (HB). Results We identified 24 unique VHL alterations among 41 patients. 83% (29/41) patients had missense mutations, 7.5% (3/41) had nonsense mutations, 17% (6/41) had splice mutations, and 3% (3/41) had a deletion. The median age at VHL diagnosis was 43 years old for type 1 (range 19-76) and 38 for VHL type 2 (range 4-67). VHL Type 2 was more common, 85% (35/41). All VHL Type 1 patients (6/6) developed RCC and HB. No patients with VHL Type 1 developed PheoPara. Of the 35 patients diagnosed with VHL Type 2, 20% (7/35) were diagnosed with PheoPara, 9% (3/35) with RCC, 31% (n = 11) with HB, and 37% (n = 13) were asymptomatic. No VHL Type 1 patients were asymptomatic. Conclusions VHL type 2 comprised the majority of VHL diagnoses in our cohort. Individuals diagnosed with VHL type 2 have the highest penetrance for: hemangioblastoma (hb), Pheo-Para, and renal cell carcinoma (RCC). In our study, 37% of VHL type 2 participants did not demonstrate any VHL manifestation. VHL type 1 had a high prevalence for RCC and HB, with a notable absence of PheoPara manifestation. However, majority of these patients (75%) were below the age of 20, and thus likely did not develop a manifestation yet. This cohort add to evidence supporting utilizing genetic VHL Types to personalize surveillance guidelines. Validation in larger cohorts with longer follow-up suggest that VHL type 1 patients could forgo pheo/para screening.
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Lobbous, Mina, ZacK Tucker, Elizabeth Coffee, and Louis Nabors. "PATH-35. RETROSPECTIVE ANALYSIS OF 145 PATIENTS WITH GLIOBLASTOMA; CORRELATING MOLECULAR ALTERATION INCIDENCE WITH DEMOGRAPHICS, TUMOR LOCATION, AND PROGNOSIS." Neuro-Oncology 21, Supplement_6 (November 2019): vi150—vi151. http://dx.doi.org/10.1093/neuonc/noz175.631.
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Abstract Glioblastoma is the most common and most aggressive primary brain tumor in adults. Glioblastoma was the first neoplasm to be systemically studied by The Cancer Genome Atlas and is one of the most molecularly well-characterized tumors in humans. Molecular profiling of glioblastoma is increasingly available and had led to the identifications of multiple prognostic factors as well as potential actionable targets for novel therapies. We identified 145 patients diagnosed with glioblastoma whose tumor tissue was analyzed using next generation sequencing (NGS). The NGS was performed using validated, commercially available panels. We studied somatic genetic alterations with a particular focus on TERT (which was altered in 55.9% of patients in the dataset), CDKN2A (44%), TP53 (39%), EGFR (38.6%), PTEN (31%), IDH1 (20%), and CDK4 (9%). These molecular alterations were analyzed in relation to the patients’ tumor locations, demographics, and outcomes. We used multiple binary logistic regressions to assess whether demographics and tumor location were predictive of the above alterations We also assessed the relationship between molecular alterations and outcomes when controlling for treatment and demographic variables. Among demographic variables, age predicted alterations in IDH1, EGFR, TERT, TP53, and PTEN. Frontal lobe tumors were more likely to be IDH1-mutated, irrespective of patient age. Sex and race did not predict the incidence of the molecular alterations of interest. Analysis of outcomes revealed that, when controlling for treatment and demographic variables, TERT promoter mutations, TP53 nonsense mutations, and EGFR A289V were predictive of a decreased progression-free survival, while CDKN2A deletion, PTEN missense mutations, and EGFR A289V were predictive of decreased overall survival. Our experience highlights the importance of incorporating routine NGS in the management of patients with glioblastoma. More studies are required to evaluate the predictive and/or prognostic values of different molecular alterations.
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Chang, Eric, Jill Tsai, and Bora Lim. "Abstract P5-05-03: Characterization of the genomic landscape of breast carcinoma patients with NF1 alterations using comprehensive cell-free tumor DNA next-generation sequencing." Cancer Research 83, no. 5_Supplement (March 1, 2023): P5–05–03—P5–05–03. http://dx.doi.org/10.1158/1538-7445.sabcs22-p5-05-03.
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Abstract Background: NF1 (neurofibromin type 1) encodes neurofibromin, and is commonly altered in many cancers, including breast cancer. NF1 suppresses breast cancer by not only negatively regulating RAS signaling but also by independently acting as a transcriptional co-repressor of the estrogen receptor (ER). In this study, we analyzed the genomic landscape of patients with NF1 alterations from a large genomic database to define what unique patient characteristics were associated with NF1 alterations. Methods: Retrospective analysis of the Guardant Health database based on samples from the commercially available Guardant360® plasma-based circulating tumor DNA (ctDNA) assay. Samples were queried between June 2020-June 2022 for patients with any detected NF1 alteration and breast cancer diagnosis. NF1 synonymous alterations were excluded from this study. Statistics were conducted using a two-sided Fisher’s exact test. Results: NF1 alterations were found in 895 patients with breast cancer over 1156 samples, typically in female patients (98.2%) diagnosed with breast carcinoma (99.4%). The average age of patients was 66 years old (23-93), with a median of 1.4 serial tests (1-19). The common nonsynonymous NF1 alterations are missense mutations (56.5%), nonsense mutations (23.5%), indels (22.3%), and aberrant splicing mutations (8.2%). There were significant differences in NF1 alteration frequency between younger (< 55 y/o) vs. older (≤55 y/o) patients, with older patients demonstrating an increase in NF1 alterations (p< 0.0001) across all mutation types except for splice mutations. There was also a significant difference in NF1 alterations between female vs. male patients, with male patients trending toward a higher frequency in NF1 missense alterations. Mutations affecting genes encoding the receptor tyrosine kinase (e.g., HER2) and the Ras-MAP kinase pathways (e.g., several RAS and RAF genes) co-occur with NF1 mutations. In contrast, there is no evidence of co-occurrence with mutations in the ESR1 gene, which encodes ER. The blood tumor mutational burden (bTMB) score was evaluable in 848 patients with an average score of 26.1 mut/Mb (range 1.16-447.7). In addition, mutations affecting genes controlling the cell cycle were also found to co-occur with NF1 mutations. Conclusions: Plasma-based liquid biopsy via G360 can efficiently identify NF1 alterations illustrating that such genetic alterations are common in this metastatic breast cancer cohort. Analysis of co-occurrent mutations supports our model that a key role of NF1 is to act as an ER transcriptional co-repressor, such that its loss is functionally redundant with acquiring ESR1 mutations. Oncogenic activation of the RTK-Ras pathways is needed for efficient progression to metastasis by additional mutations in this pathway. Mutational co-occurrence may also identify collaborating molecular events that collaborate with NF1 loss to promote treatment relapse and metastasis. Citation Format: Eric Chang, Jill Tsai, Bora Lim. Characterization of the genomic landscape of breast carcinoma patients with NF1 alterations using comprehensive cell-free tumor DNA next-generation sequencing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-03.
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Daniel, Sugganth, Erica Gornstein, Garrett Michael Frampton, James Sun, Samantha Morley, Andreas Heilmann, Prasanth Reddy, et al. "BRCA1/2 reversion mutations in prostate cancer identified from clinical tissue and liquid biopsy samples." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 5024. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5024.
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5024 Background: Prostate tumors with genomic alterations (GA) in BRCA1 or BRCA2 ( BRCA) may be sensitive to treatment with PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) can arise that may restore BRCA function and underlie reduced sensitivity to PARPi or platinum (Pt)-based therapy. Comprehensive genomic profiling (CGP), using either tissue or liquid biopsies, can detect the variety of clinically relevant revGA that can arise. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for 1911 patients with predominantly relapsed, refractory or metastatic prostate carcinoma was analyzed by hybrid-capture, next-generation sequencing for all classes of GA: base substitutions, indels, rearrangements, and copy number changes. RevGA were any GA that could restore the reading frame if in cis with a nonsense or frameshift (fs) GA. Results: 216/1911 (11.3% ± 1.4%) tumors had ≥1 deleterious BRCA GA. Of these, 7 samples harbored potential revGA in BRCA1 (1) or BRCA2 (6): prostate acinar adenocarcinoma (5), neuroendocrine carcinoma (1), or undifferentiated carcinoma (1). Of these, 2 samples were liquid biopsies (blood), 4 were FFPE tissue samples (liver), and 1 sample was a bone marrow core biopsy. All samples with revGA were metastases. Potential revGA were of 3 types: overlapping indel (4), compensatory fs (2), and missense (1). One case harbored 2 revGA, an overlapping indel and a compensatory fs. Alteration frequencies for TMPRSS2 (fusions), PTEN, and AR were similar with or without BRCA mutations; revGA-positive samples had a modest increase in PTEN alterations (42.9% vs 33.8%, NS). The frequency of CDK12 alterations was significantly reduced in BRCA-mutated tumors (0.9% vs 6.9%, p = 0.00002). Clinical histories for patients with reversion mutations will be presented. Conclusions: CGP of 1911 prostate carcinomas reveals ≥1 deleterious BRCA1/2 in 11.3% of samples. From these, a series of 7 cases, all metastases, with co-occurring potential revGA were identified. Although rare, revGA can be acquired during treatment and may underlie resistance to PARPi or Pt-based therapy. BRCA revGA can be detected from both tissue and liquid biopsies.
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Peng, Qiongling, Ying Cui, Jin Wu, Lianying Wu, Jiajia Liu, Yangyun Han, and Guanting Lu. "A c.726C>G (p.Tyr242Ter) nonsense mutation-associated with splicing alteration (NASA) of WDR45 gene underlies β-propeller protein-associated neurodegeneration (BPAN)." Heliyon 10, no. 9 (May 2024): e30438. http://dx.doi.org/10.1016/j.heliyon.2024.e30438.
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Babenko, Vladimir, Olga Redina, Dmitry Smagin, Irina Kovalenko, Anna Galyamina, and Natalia Kudryavtseva. "Elucidation of the Landscape of Alternatively Spliced Genes and Features in the Dorsal Striatum of Aggressive/Aggression-Deprived Mice in the Model of Chronic Social Conflicts." Genes 14, no. 3 (February 27, 2023): 599. http://dx.doi.org/10.3390/genes14030599.
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Both aggressive and aggression-deprived (AD) individuals represent pathological cases extensively studied in psychiatry and substance abuse disciplines. We employed the animal model of chronic social conflicts curated in our laboratory for over 30 years. In the study, we pursued the task of evaluation of the key events in the dorsal striatum transcriptomes of aggression-experienced mice and AD species, as compared with the controls, using RNA-seq profiling. We evaluated the alternative splicing-mediated transcriptome dynamics based on the RNA-seq data. We confined our attention to the exon skipping (ES) events as the major AS type for animals. We report the concurrent posttranscriptional and posttranslational regulation of the ES events observed in the phosphorylation cycles (in phosphoproteins and their targets) in the neuron-specific genes of the striatum. Strikingly, we found that major neurospecific splicing factors (Nova1, Ptbp1, 2, Mbnl1, 2, and Sam68) related to the alternative splicing regulation of cAMP genes (Darpp-32, Grin1, Ptpn5, Ppp3ca, Pde10a, Prkaca, Psd95, and Adora1) are upregulated specifically in aggressive individuals as compared with the controls and specifically AD animals, assuming intense switching between isoforms in the cAMP-mediated (de)phosphorylation signaling cascade. We found that the coding alternative splicing events were mostly attributed to synaptic plasticity and neural development-related proteins, while the nonsense-mediated decay-associated splicing events are mostly attributed to the mRNA processing of genes, including the spliceosome and splicing factors. In addition, considering the gene families, the transporter (Slc) gene family manifested most of the ES events. We found out that the major molecular systems employing AS for their plasticity are the ‘spliceosome’, ‘chromatin rearrangement complex’, ‘synapse’, and ‘neural development/axonogenesis’ GO categories. Finally, we state that approximately 35% of the exon skipping variants in gene coding regions manifest the noncoding variants subject to nonsense-mediated decay, employed as a homeostasis-mediated expression regulation layer and often associated with the corresponding gene expression alteration.
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Lobón-Iglesias, María Jesús, Ingrid Laurendeau, Léa Guerrini-Rousseau, Arnault Tauziède-Espariat, Audrey Briand-Suleau, Pascale Varlet, Dominique Vidaud, et al. "NF1-like optic pathway gliomas in children: clinical and molecular characterization of this specific presentation." Neuro-Oncology Advances 2, Supplement_1 (December 20, 2019): i98—i106. http://dx.doi.org/10.1093/noajnl/vdz054.
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Abstract Background Pediatric neurofibromatosis type 1 (NF1)–associated optic pathway gliomas (OPGs) exhibit different clinico-radiological features, treatment, and outcome compared with sporadic OPGs. While NF1-associated OPGs are caused by complete loss-of-function of the NF1 gene, other genetic alterations of the RAS-MAPK pathway are frequently described in the sporadic cases. We identified a group of patients who presented OPGs with typical radiological features of NF1-associated OPGs but without the NF1 diagnostic criteria. We aim to investigate into the possible molecular mechanisms underlying this “NF1-like” pediatric OPGs presentation. Methods We analyzed clinico-radiological features of 16 children with NF1-like OPGs and without NF1 diagnostic criteria. We performed targeted sequencing of the NF1 gene in constitutional samples (n = 16). The RAS-MAPK pathway major genes were sequenced in OPG tumor samples (n = 11); BRAF FISH and IHC analyses were also performed. Results In one patient’s blood and tumor samples, we identified a NF1 nonsense mutation (exon 50: c.7285C>T, p.Arg2429*) with ~8% and ~70% VAFs, respectively, suggesting a mosaic NF1 mutation limited to the brain (segmental NF1). This patient presented signs of neurodevelopmental disorder. We identified a somatic alteration of the RAS-MAPK pathway in eight tumors: four BRAF activating p.Val600Glu mutations, three BRAF:KIAA oncogenic fusions, and one putative gain-of-function complex KRAS indel inframe mutation. Conclusions NF1-like OPGs can rarely be associated with mosaic NF1 that needs specific constitutional DNA analyses for diagnosis. Further studies are warranted to explore unknown predisposition condition leading to the NF1-like OPG presentation, particularly in patients with the association of a neurodevelopmental disorder.
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Nibourel, Olivier, Olivier Kosmider, Meyling Cheok, Nicolas Boissel, Aline Renneville, Nathalie Philippe, Hervé Dombret, et al. "Association of TET2 Alterations with NPM1 Mutations and Prognostic Value in De Novo Acute Myeloid Leukemia (AML)." Blood 114, no. 22 (November 20, 2009): 163. http://dx.doi.org/10.1182/blood.v114.22.163.163.
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Abstract Abstract 163 In acute myeloid leukemia (AML), both cytogenetic and molecular abnormalities are strongly associated with prognosis. In particular, in cytogenetically normal AML (CN-AML), FLT3-ITD (internal tandem duplication) carries adverse prognostic factor whereas NPM1 or CEBPA mutations are associated with favorable outcome. Recently, mutations of the ten eleven translocation 2 gene (TET2) have been reported myeloid neoplasms. We evaluated the frequency and prognostic value of TET2 alterations, in a cohort of 111 de novo AML patients. We studied 111 patients aged between 15 years and 69 years with previously untreated de novo AML who had reached complete remission (CR) using intensive chemotherapy. 28 of them also received an allogenic bone marrow transplantation in first CR. Analysis of TET2 sequence variation was performed by direct sequencing of PCR products from 111 genomic DNA samples obtained at diagnosis. Frameshift and nonsense variations were all scored as mutation whereas missense mutations were retained when observed at diagnostic but absent in the CR paired sample obtained. Previously identified single nucleotide polymorphisms (SNP) were not considered. TET2 anomalies were numbered according to Genebank reference FM992369. Paired diagnosis and CR genomic DNAs were analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Data were analyzed using Gene Chip Genotyping Console 3.0.2 and Partek Genomics Suite (www.partek.com/). Comparisons were made by Fisher's exact test for binary variables and the Mann-Whitney‘s test for continuous variables. Disease Free Survival (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Comparisons regarding DFS and OS were performed with the log-rank test. 24 acquired TET2 mutations were observed in 19 of the 111 (17%) de novo AML patients, suggesting the alteration of the two TET2 alleles in 5 patients. They included 21 different events: 6 frameshift, 7 non-sense and 11 missense mutations. Four of the missense mutations were located in conserved regions and 7 outside. All of them were detected in the diagnostic sample but were absent in the paired remission sample. Except for two missense mutations (S282F, T492S) both detected in two patients, no recurrent TET2 mutation was observed. Acquired mutations were spread over all exons. No case of uniparental disomy (UPD) was observed and only one patient presented a small deletion of 60Kb in the TET2 gene locus without TET2 mutation. No significant difference was observed between patients with or without TET2 alterations for gender, age, hemoglobin level, platelet count, FAB subtypes distribution and cytogenetics according to MRC classification, but there was a trend for higher WBC count in patients with TET2 alteration. No significant association was observed between TET2 mutations and FLT3 or CEBPA alterations. However, TET2 alterations were significantly associated with NPM1 mutations (p=0.032). In the entire patient cohort, no difference in DFS or OS was seen between patients with and without TET2 alteration. However, a significantly worse DFS was observed for patients presenting TET2 mutations within the subgroup of patients with NPM1 mutations (3y-DFS: 0% vs 66.4%, 95% CI [45.6–87.2], p=0.008) Considering both the favorable prognosis of NPM1 mutations without FLT3-ITD in CN-AML and the absence of clear association between FLT3-ITD and TET2 alterations in this study, prognostic value of the genotype characterized by NPM1 mutation without FLT3-ITD or TET2 alteration (NPM1+FLT3-ITD-TET2-) was compared to other patients within CN-AML group (N=54). NPM1+FLT3-ITD-TET2- patients showed a significantly better DFS and OS compared to other patients in CN-AML group (3y-DFS: 82.1%, 95% CI [59.1–100] vs 37.3%, 95% CI [20.2–54.3], p=0.01; 3y-OS: 80.8%, 95% CI [56.1–100] vs 42.3%, 95% CI [23.3–61.3], p=0.04). In conclusion, we observed point mutations of TET2 in 17% of patients, whereas TET2 deletion or UPD are very rare. In our study, TET2 mutations were clearly associated with NPM1 mutations and carried a negative prognostic impact in this subgroup. Screening for TET2 mutations may improve the characterization of CN-AML and help to identify within the low-risk subgroup with NPM1 mutation and without FLT3-ITD, patients at high risk of relapse. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
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Wang, Fei Jun, and Lynn S. Ripley. "The Spectrum of Acridine Resistant Mutants of Bacteriophage T4 Reveals Cryptic Effects of the tsL141 DNA Polymerase Allele on Spontaneous Mutagenesis." Genetics 148, no. 4 (April 1, 1998): 1655–65. http://dx.doi.org/10.1093/genetics/148.4.1655.
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Abstract Mutations in the ac gene of bacteriophage T4 confer resistance to acridine-inhibition of phage development. Previous studies had localized the ac gene region; we show that inactivation of T4 Open Reading Frame 52.2 confers the Acr phenotype. Thus, 52.2 is ac. The resistance mechanism is unknown. The ac gene provides a convenient forward mutagenesis assay. Its compact size (156 bp) simplifies mutant sequencing and diverse mutant types are found: base substitutions leading to missense or nonsense codons, inframe deletions or duplications within the coding sequence, deletion or duplication frameshifts, insertions, complex mutations, and large deletions extending into neighboring sequences. Comparisons of spontaneous mutagenesis between phages bearing the wild-type or tsL141 alleles of DNA polymerase demonstrate that the impact of the mutant polymerase is cryptic when total spontaneous mutant frequencies are compared, but the DNA sequences of the ac mutants reveal a substantial alteration of fidelity by the mutant polymerase. The patterns of base substitution mutagenesis suggest that some site-specific mutation rate effects may reflect hotspots for mutagenesis arising by different mechanisms. A new class of spontaneous duplication mutations, having sequences inconsistent with misaligned pairing models, but consistent with nick-processing errors, has been identified at a hotspot in ac.
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Danziger, Natalie, Elise C. Kohn, Julia C. F. Quintanilha, Gerald Li, Julia A. Elvin, and Douglas I. Lin. "Gynecologic-cancer analysis of ARID1A alterations detected in tissue and liquid biopsies." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 5593. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.5593.
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5593 Background: The tumor suppressor gene ARID1A is an emerging target for new cancer treatment strategies including ATR inhibition. This study aimed to describe the landscape of ARID1A alterations ( ARID1Amut) in gynecologic malignancies. Methods: Patients (pts) with a diagnosis of ovarian (OC) or uterine cancer (UC) of different histologies and comprehensive genomic profiling (CGP) by Foundation Medicine Inc. were included in this study. CGP of solid tissue biopsies (Tbx; FoundationOneCDx) included evaluation of genomic loss of heterozygosity (gLOH; gLOH-high as ≥16% as validated in OC), microsatellite instability (MSI), and tumor mutational burden (TMB; high as ≥10 mutations/Megabase). CGP of peripheral whole-blood liquid biopsies (Lbx; FoundationOneLiquidCDx) included evaluation of MSI and tumor fraction (TF), a measure of the relative quantity of circulating tumor DNA (ctDNA). TF was calculated by measures of aneuploidy and allele frequency and binned as TF < 1%, TF 1 to < 10%, or TF ≥10%. Results: Tbx Cohort: 5,778/30,212 (19.1%) cases were ARID1Amut. Pts had a median age of 63 (range 21-89) years. ARID1Amut were observed across many subtypes and most frequently in endometrial endometrioid (n = 3,052, 57.7%) and ovarian clear cell (n = 982, 57.6%) but rarely in serous (OC, n = 12,258, 2.8%; UC, n = 2,682, 8.9%). Pts frequently harbored more than one ARID1Amut (2,360/5,778, 40.8%). Of the 8,484 observed ARID1Amut, 97.6% were short variants (SV), 0.5% were deletions, and 1.9% were inactivating rearrangements. SV were primarily frameshifts (68.5%) and nonsense mutations (27.6%). The most frequent alterations observed were frameshifts at the D1860 codon. SV were predicted to be homozygous in 11.9%, heterozygous in 65.3%, or unknown zygosity in 22.8%. Overall, 16.6% of ARID1Amut cases with SV had at least one homozygous alteration. 6.6% of pts with homozygous ARID1Amut were MSI-high (MSI-H), while 39.4% of pts with only heterozygous or unknown zygosity ARID1Amut were MSI-H (p < 0.0001). Overall, 1,905 (33.0%) of ARID1Amut cases were MSI-H, and 2,183 (37.8%) were TMB high. For ARID1Amut cases with evaluable gLOH (n = 4745), the median gLOH was 2.7%, and 5.9% pts were gLOH-high. The most frequently altered co-occurring genes were PTEN (62.2%), PIK3CA (54.2%), and TP53 (27.6%). 8.7% of ARID1Amut also harbored a BRCA alteration. Lbx Cohort: 59/967 (6.1%) cases were ARID1Amut. 17 (28.8%) were MSI-H. Frequency of ARID1Amut increased as TF increased, with a detected frequency of 1.3%, 6.7%, and 14.0% among Lbx with TF < 1%, TF 1 to < 10%, or TF ≥10% respectively. Conclusions: ARID1Amut are observed across a variety of Gynecologial cancer subtypes but are enriched in clear cell and endometrioid histologies and detected in both tissue and liquid biopsies. ARID1Amut were not associated with elevated gLOH but were often MSI-H and TMB ≥10mut/Mb. Clinical trials targeting ARID1A may wish to consider the context of co-occuring biomarkers.
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Seipel, Katja, Nuria Z. Veglio, Henning Nilius, Barbara Jeker, Ulrike Bacher, and Thomas Pabst. "Rising Prevalence of Low-Frequency PPM1D Gene Mutations after Second HDCT in Multiple Myeloma." Current Issues in Molecular Biology 46, no. 8 (July 29, 2024): 8197–208. http://dx.doi.org/10.3390/cimb46080484.
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Multiple myeloma (MM) first-line treatment algorithms include immuno-chemotherapy (ICT) induction, high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) consolidation, followed by lenalidomide maintenance. After these initial therapies, most patients suffer a disease relapse and require subsequent treatment lines including ICT, additional HDCT and ASCT, or novel immunotherapies. The presence of somatic mutations in peripheral blood cells has been associated with adverse outcomes in a variety of hematological malignancies. Nonsense and frameshift mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to the gain-of-function of Wip1 phosphatase, which may impair the p53-dependent G1 checkpoint and promote cell proliferation. Here, we determined the presence of PPM1D gene mutations in peripheral blood cells of 75 subsequent myeloma patients in remission after first or second HDCT/ASCT. The prevalence of truncating PPM1D gene mutations emerged at 1.3% after first HDCT/ASCT, and 7.3% after second HDCT/ASCT, with variant allele frequencies (VAF) of 0.01 to 0.05. Clinical outcomes were inferior in the PPM1D-mutated (PPM1Dmut) subset with median progression-free survival (PFS) of 15 vs. 37 months (p = 0.0002) and median overall survival (OS) of 36 vs. 156 months (p = 0.001) for the PPM1Dmut and PPM1Dwt population, respectively. Our data suggest that the occurrence of PPM1D gene mutations in peripheral blood cells correlates with inferior outcomes after ASCT in patients with multiple myeloma.
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Zingg, Daniel Kaspar, Jinhyuk Bhin, Julia Yemelyanenko, Sjors M. Kas, Catrin Lutz, Chi-Chuan Lin, Sjoerd Klarenbeek, et al. "Abstract 3488: Truncated FGFR2 - a clinically actionable oncogene in multiple cancers." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3488. http://dx.doi.org/10.1158/1538-7445.am2023-3488.
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Abstract Human cancers frequently bear driver alterations in genes encoding receptor tyrosine kinases (RTKs), which has led to effective therapeutics targeting oncogenic signaling of RTK variants. Somatic hotspot mutations and structural amplifications and fusions affecting fibroblast growth factor receptor 2 (FGFR2) likewise occur in multiple tumor types including breast cancer. However, clinical responses to FGFR inhibitors have remained variable, emphasizing a need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. We applied transposon-based screening and tumor modelling in the mouse mammary gland to uncover truncation of the last exon (E18) of Fgfr2 as a potent driver mutation. Mouse and human FGFR2-E18 encodes the C-terminus of this RTK. Human oncogenomic datasets revealed a plethora of somatic FGFR2 alterations potentially causing transcription of E18-truncated FGFR2. These alterations were comprised of canonical in-frame fusions as well as diverse FGFR2 variants of unknown significance (VUS), which included non-canonical rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations. Functional in vitro and in vivo interrogation of a compendium of E18-truncated and full-length FGFR2 variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. In contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct cooperating driver gene landscape. Notably, gradual truncation and site-directed mutagenesis of Fgfr2-E18 identified a novel 2-amino-acid motif within the C-terminus critical for kinase domain binding and suppression of oncogenic FGFR2 signaling. Aberration of this motif conspired with the loss of the receptor internalization motif to fully phenocopy oncogenicity of E18-truncated Fgfr2. These data suggest that genomic alterations that generate stable E18-truncated FGFR2 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumor models, and in a clinical trial. Thus, we uncovered a novel paradigm in oncogenic FGFR2 signaling and propose that breast and other cancers harboring any FGFR2 variant that truncates E18 should be considered for FGFR-targeted therapies. Citation Format: Daniel Kaspar Zingg, Jinhyuk Bhin, Julia Yemelyanenko, Sjors M. Kas, Catrin Lutz, Chi-Chuan Lin, Sjoerd Klarenbeek, Jessica K. Lee, Ian M. Silverman, Stefano Annunziato, Marieke van de Ven, Siraj M. Ali, Timothy C. Burn, Shridar Ganesan, Lodewyk F. Wessels, Jos Jonkers. Truncated FGFR2 - a clinically actionable oncogene in multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3488.
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Bouayed Abdelmoula, N., and B. Abdelmoula. "Behavioral signs of CHARGE syndrome and CHD7 mutational spectrum." European Psychiatry 66, S1 (March 2023): S352. http://dx.doi.org/10.1192/j.eurpsy.2023.767.
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IntroductionCHARGE syndrome is a genetic entity caused by mutations in the chromodomain helicase DNA-binding protein 7 gene (CHD7) at 8q12.1. There are pleiotropic signs among individuals with this disorder. Diagnosis is clinical using medical criteria. CHD7 gene mutations are usually found in 90% of affected patients.ObjectivesThe aim of this study was to report behavioral signs of CHARGE syndrome and their phenotype-genotype correlations.MethodsFour Tunisian males from Sfax (Tunisia) with clinical features suggestive of CHARGE syndrome were examined at our genetic counselling at the medical University of Sfax. Assessment of facial dysmorphic and behavioral features, karyotyping using RHG banding and molecular screening of CHD7 mutations were performed. Molecular analysis was made using direct Sanger sequencing of the entire CHD7 gene.ResultsMolecular genetic analysis revealed two deletions of the CHD7 gene at exon 3 for the first patient and at exon 8 for the second. The two genetic alterations were associated to retarded growth development and genital hypoplasia. Sensory impairments included for the first visual defects and for the second auditory and olfactory defects. Besides constant delayed psychomotor development, the two patients shared receptive and expressive communication disorders, anxiety, attention deficit, cognitive impairment and intellectual disability. There were no aggressive traits nor major autistic features. Learning disabilities were also present for the two patients.ConclusionsThe CHD7 gene controls the developmental pathways as a transcriptional regulator in the nucleoplasm through chromatin organization. Mutational alterations lead according to the affected domains, and the structure of the nonfunctional CHD7 protein, to the perturbation of the regulation of the developmental pathways’ genes expression. CHD7 is demonstrated as an important component of neurogenesis through two neuronal determination factors: Sox4 and Sox11. While nonsense, frameshift and missense mutations are most common, deletions and duplications are less frequent. Moreover, while exon 3 is commonly altered, mutations of exon 8, which is related to the CHD7 protein chromodomain, are very rare. Phenotype-genotype correlations according to the type of genomic alteration of CHD7 gene are rarely published, particularly concerning behavioral and psychological features of CHARGE association. Here, physical disorders of our two patients seem to be different but behavioral features seem to be common. Multidisciplinary care is thus required for CHARGE syndrome and molecular analysis must be indicated because the type of the genomic alterations may be a key step for a more accurate management of physical and behavioral disorders.Disclosure of InterestNone Declared
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McIntyre, J. F., B. Smith-Sorensen, S. H. Friend, J. Kassell, A. L. Borresen, Y. X. Yan, C. Russo, J. Sato, N. Barbier, and J. Miser. "Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma." Journal of Clinical Oncology 12, no. 5 (May 1994): 925–30. http://dx.doi.org/10.1200/jco.1994.12.5.925.
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PURPOSE We investigated the possibility that a significant proportion of children with osteosarcoma harbor germline mutations of the p53 tumor suppressor gene and, therefore, this subgroup of pediatric cancer patients should be considered for large-scale predictive testing. PATIENTS AND METHODS Genomic DNA extracted from peripheral-blood leukocytes from 235 unselected children with osteosarcoma from 33 institutions were screened for the presence of germline p53 mutations using constant denaturant gel electrophoresis (CDGE). Exons 5 through 8 were evaluated in all patients and exon 2 and exon 9 were analyzed in 59 and 95 patients, respectively. Those samples that showed aberrant migration on CDGE were sequenced or analyzed by restriction enzyme digestion of polymerase chain reaction (PCR) products to confirm the nature of the gene alteration. RESULTS In 18 samples, CDGE showed fragments of the p53 gene with altered electrophoretic mobilities compared with wild-type p53. DNA sequencing showed that 11 samples had an identical, previously described polymorphism. The other seven contained heterozygous p53 mutations located in exon 5 (n = 3), exon 6 (n = 1), exon 7 (n = 1), and exon 8 (n = 2). Six alterations were missense mutations and one was a nonsense mutation. Three of these patients had first-degree relatives with cancer. One of these three kindreds had a family history consistent with Li-Fraumeni syndrome (LFS). CONCLUSION We identified germline p53 mutations in seven of 235 (3.0%) children with osteosarcoma. Four of these mutations were found in patients who did not have first-degree relatives with cancer. Although genetic transmission of the altered p53 gene could not be tested in this survey because of how it was designed, it is possible that predictive testing for p53 mutations could identify unaffected relatives of gene carriers who also have a high risk for the development of cancer. This study provides evidence for the importance of considering children with osteosarcoma for predictive testing for germline p53 mutations.
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Żołądek, Teresa, Anna Tobiasz, Gabriela Vaduva, Magda Boguta, Nancy C. Martin, and Anita K. Hopper. "MDP1, a Saccharomyces cerevisiae Gene Involved in Mitochondrial/Cytoplasmic Protein Distribution, Is Identical to the Ubiquitin-Protein Ligase Gene RSP5." Genetics 145, no. 3 (March 1, 1997): 595–603. http://dx.doi.org/10.1093/genetics/145.3.595.
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Alteration of the subcellular distribution of Mod5p-I, a tRNA modification enzyme, member of the sorting isozyme family, affects tRNA-mediated nonsense suppression. Altered suppression efficiency was used to identify MDP genes, which, when mutant, change the mitochondrial/cytosolic distribution of Mod5p-I,KR6. MDP2 is the previously identified VRP1, which encodes verprolin, required for proper organization of the actin cytoskeleton. MDP3 is identical to PAN1, which encodes a protein involved in initiation of translation and actin cytoskeleton organization. We report here the cloning and characterization of wild-type and mutant MDP1 alleles and the isolation and characterization of a multicopy suppressor of mdp1 mutations. MDP1 is identical to RSP5, which encodes ubiquitin-protein ligase, and mdp1 mutations are suppressed by high copy expression of ubiquitin. All four characterized mdp1 mutations cause missense changes located in the hect domain of Rsp5p that is highly conserved among ubiquitin-protein ligases. In addition to its well-known function in protein turnover, ubiquitination has been proposed to play roles in subcellular sorting of proteins via endocytosis and in delivery of proteins to peroxisomes, the endoplasmic reticulum and mitochondria. mdp1, as well as mdp2/vrp1 and mdp3/pan1 mutations, affect endocytosis. Further, mdp1 mutations show synthetic interactions with mdp2/vrp1 and mdp3/pan1. Identification of MDP1 as RSP5, along with our previous identification of MDP2/VRP1 and MDP3/PAN1, implicate interactions of the ubiquitin system, the actin cytoskeleton and protein synthesis in the subcellular distribution of proteins.
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Rücker, Frank G., Richard F. Schlenk, Lars Bullinger, Helena Kett, Annegret Becker, Carla-Maria Kugler, Thorsten Zenz, et al. "In Acute Myeloid Leukemia with Complex Karyotype TP53 Alterations Are Associated with Specific Genomic Aberrations and Predict Inferior Survival." Blood 114, no. 22 (November 20, 2009): 2632. http://dx.doi.org/10.1182/blood.v114.22.2632.2632.
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Abstract Abstract 2632 Poster Board II-608 In acute myeloid leukemia (AML) complex karyotype is defined as the presence of ≥3 chromosome abnormalities in the absence of one of the chromosomal rearrangements listed in the category “AML with recurrent genetic abnormalities” (WHO 2008). This subset of AML accounts for approximately 10 to 15 % of all AML and it is characterized by a very poor prognosis. To identify novel genomic regions of interest in this AML subgroup, we recently applied microarray-based techniques (array-comparative genomic hybridization [CGH] and single nucleotide polymorphism [SNP] analysis) allowing high-resolution genome-wide screening of genomic imbalances in 245 patients; 171 of the 245 (70%) patients were enrolled in clinical protocols using intensive chemotherapy. Applying these techniques, we identified deletions of 17p13 encompassing the TP53 locus in 94 of 245 (38%) cases. Based on these findings and the fact that TP53 is a frequently affected gene in numerous malignancies, we aimed to investigate its role in complex karyotype AML. Therefore, we screened 188 of the 245 patients forTP53 mutations either by direct sequencing of exon 5 to 9 or by denaturating high-performance liquid chromatography of exon 4 to 10 on a WAVE® system followed by direct sequencing of the positive cases. In total, we identified 137 mutations (exon 4 [e4] n=2; e5 n=41; e6 n=26; e7 n=35; e8 n=26; e10 n=1; splice sites n=6) in 106 patients (56%) with a maximum of four mutations per case. Of these 137 mutations, 108 were missense mutations, 15 frame shift mutations, 8 nonsense mutations, and 6 were located at intronic splice sites. Combining the findings from array-based and mutation analyses, TP53 gene alterations were identified in 129 of 188 (69%) patients. Of note, 29% of these cases showed biallelic TP53 gene alterations with deletion of one allele and at least one mutation in the remaining allele. When correlating TP53 alterations (mutations and/or deletions) with genomic data from array-based analyses, we found positive correlations with the presence of 5q and 7q losses (Chi-square test P < .001 and P = .001, respectively), total number of deletions (P < .001), gains (P = .002), high-level DNA amplifications (P < .001), and genomic complexity as measured by total number of aberrations per case (P < .001). Correlation of TP53 alterations with clinical characteristics revealed that patients with TP53 alterations were older (median age 60 versus 55 years, P = .01) and showed in trend a lower WBC (median, 6.6 versus 14.2 × 109/L, P = .14); there was no difference in bone marrow and blood blast counts, in platelet counts, or in type of AML (de novo vs. secondary vs. treatment-related). Clinical outcome analyses were restricted to patients enrolled in prospective clinical trials (n=171). AML exhibiting a TP53 alteration had significantly lower complete remission (CR) rates [25% (26/104) versus 56% (24/43), P < .001], inferior event-free survival (EFS, P = .009), relapse-free survival (RFS, P = .02), and overall survival (OS, P < .001) compared with TP53 wild type AML. In multivariate models for achievement of CR, RFS, and OS, TP53 alteration retained its significance as an independent risk factor (CR: OR 0.38, P < .001; RFS: HR 1.65, P = .02; OS: HR: 2.15, P = .002). In conclusion, TP53 is the most frequently known affected gene in complex karyotype AML. We found that the TP53 status is associated with specific genomic aberrations as well as the degree of genomic complexity, a finding that fits well into the TP53 pathomechanism of genomic instability. Importantly, among AML with complex karyotype TP53 alterations significantly predicted inferior outcome allowing for a further refinement of this AML subgroup. Disclosures: No relevant conflicts of interest to declare.
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Zanella, Alberto, Paola Bianchi, Luciano Baronciani, Manuela Zappa, Elena Bredi, Cristina Vercellati, Fiorella Alfinito, Giovanni Pelissero, and Girolamo Sirchia. "Molecular Characterization of PK-LR Gene in Pyruvate Kinase–Deficient Italian Patients." Blood 89, no. 10 (May 15, 1997): 3847–52. http://dx.doi.org/10.1182/blood.v89.10.3847.3847_3847_3852.
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We studied the PK-LR gene in 15 unrelated Italian patients with congenital hemolytic anemia associated with erythrocyte pyruvate kinase (PK) deficiency. Fourteen different mutations were detected among 26 mutated alleles identified: a five-nucleotide (nt) deletion (227 to 231), two splice-site (1269C and IVS3(−2)c), 10 missense (514C, 787T, 823A, 993A, 994A, 1168A, 1456T, 1529A, 1552A, and 1594T) and one nonsense mutation(s) (721T). Eight of these (deletion 227-231, 1269C, IVS3(−2)c, 514C, 787T, 823A, 1168A, and 1552A) were novel. Moreover, a new polymorphic site was detected in the 3′ untranslated region of the mRNA (C/T, nucleotide 1738). The deletion 227-231 causes a stop codon after amino acid 77, probably resulting in an unstable gene product. Mutations 1269C and IVS3(−2)c lead to an alteration of the 5′ and 3′ splice-site consensus sequence, respectively; cDNA analysis failed to reveal any abnormal transcript, suggesting that these mutations generate an unstable mRNA that is rapidly degraded. Of the five new missense mutations, 823A (Gly275-Arg) and 1168A (Asp390-Asn) involve highly conserved amino acids, 514C (Glu172-Gln) and 1552A (Arg518-Ser), although found in less conserved regions, affect the balance of the electric charges of the protein. Mutation 787T (Gly263-Trp) is likely to determine strong modifications in the local structure of the molecule. The most frequent mutation in Italy appears to be 1456T (seven of 30 alleles), followed by 1529A (three of 30) and 994A (three of 30). A correlation was found between mutations, biochemical characteristics of the enzyme, and clinical course of the disease.
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Li, Ke, Fabien Zoulim, Christian Pichoud, Karen Kwei, Stéphanie Villet, Jack Wands, Jisu Li, and Shuping Tong. "Critical Role of the 36-Nucleotide Insertion in Hepatitis B Virus Genotype G in Core Protein Expression, Genome Replication, and Virion Secretion." Journal of Virology 81, no. 17 (June 13, 2007): 9202–15. http://dx.doi.org/10.1128/jvi.00390-07.
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ABSTRACT Frequent coinfection of hepatitis B virus genotype G with genotype A suggests that genotype G may require genotype A for replication or transmission. In this regard, genotype G is unique in having a 12-amino-acid extension in the core protein due to a 36-nucleotide insertion near the core gene translation initiation codon. The insertion alters base pairing in the lower stem of the pregenome encapsidation signal, which harbors the core gene initiator, and thus has the potential to affect both core protein translation and pregenomic RNA encapsidation. Genotype G is also unusual for possessing two nonsense mutations in the precore region, which together with the core gene encode a secreted nonstructural protein called hepatitis B e antigen (HBeAg). We found that genotype G clones were indeed incapable of HBeAg expression but were competent in RNA transcription, genome replication, and virion secretion. Interestingly, the 36-nucleotide insertion markedly increased the level of core protein, which was achieved at the level of protein translation but did not involve alteration in the mRNA level. Consequently, the variant core protein was readily detectable in patient blood. The 12-amino-acid insertion also enhanced the genome maturity of secreted virus particles, possibly through less efficient envelopment of core particles. Cotransfection of genotypes G and A did not lead to mutual interference of genome replication or virion secretion. Considering that HBeAg is an immunotolerogen required for the establishment of persistent infection, its lack of expression rather than a replication defect could be the primary determinant for the rare occurrence of genotype G monoinfection.
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Fil, Daniel, Balu K. Chacko, Robbie Conley, Xiaosen Ouyang, Jianhua Zhang, Victor M. Darley-Usmar, Aamir R. Zuberi, Cathleen M. Lutz, Marek Napierala, and Jill S. Napierala. "Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia." Disease Models & Mechanisms 13, no. 7 (June 25, 2020): dmm045229. http://dx.doi.org/10.1242/dmm.045229.
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ABSTRACTFriedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of FXN, whereas a fraction of patients are compound heterozygotes, with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring an Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure-to-thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA lesions and fragmentation are accompanied by marked amplification of mitochondrial DNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life, and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.
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Vivenza, Daniela, Michela Godi, Maria Felicia Faienza, Simona Mellone, Stefania Moia, Anna Rapa, Antonella Petri, et al. "A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing." European Journal of Endocrinology 164, no. 5 (May 2011): 705–13. http://dx.doi.org/10.1530/eje-11-0047.
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ObjectiveMutations in HESX1 represent a rare cause of GH deficiency (GHD) associated with a broad spectrum of other anomalies. We searched for causative mutations in a cohort of 244 Italian patients affected by combined and isolated GHD (IGHD).MethodsThe HESX1 gene-coding region and exon–intron boundaries were screened by denaturing HPLC scanning.ResultsA novel mutation adjacent to the invariant donor splice site of intron 2 (c.357+3G>A) was identified at the heterozygous state in an IGHD patient. The in vitro and in vivo mRNA analysis of the wild-type HESX1 allele revealed the presence of the whole cDNA and two isoforms lacking exon 2 and exons 2–3 respectively. The mutant HESX1 allele yielded only two splicing products, the whole cDNA and the cDNA missing exons 2–3, whereas the mRNA lacking exon 2 was absent. An in vitro assay demonstrated that the exon 2-deleted mRNA, predicting a prematurely truncated protein, is subjected to nonsense-mediated mRNA decay (NMD).ConclusionsThe c.357+3G>A mutation prevents the generation of one of the alternative isoforms normally produced by the wild-type allele, predicting a truncated HESX1 protein. The mutation is likely to cause IGHD in the heterozygous patient by interfering with the downregulation of HESX1 expression mediated by alternative splicing and NMD.Our results open new insight into the mechanism of HESX1 regulation suggesting that the coupling of alternative splicing and NMD might play a fundamental role in directing the HESX1 expression, and that the alteration of this process might lead to severe consequences.
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Rossi, Adam, Gregory Verona, Ann Ritter, Hope Richard, India Sisler, and Zhihong Wang. "RARE-43. FAVORABLE OUTCOME OF A YOUNG GIRL WITH RECURRENT METASTATIC PINEOBLASTOMA ASSOCIATED WITH A DICER1 MUTATION." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii451—iii452. http://dx.doi.org/10.1093/neuonc/noaa222.753.
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Abstract Pineoblastomas have been thought to portend a poor prognosis, especially in younger children or those with metastases. Long term survivors after relapse, especially for those with metastatic disease are rare. We report a young girl with a DICER1 mutation who survived recurrent metastatic pineoblastoma. She was initially diagnosed at the age of 3 with a localized pineoblastoma, underwent gross total surgical resection, and received high dose chemotherapy with autologous stem cell transplant per COG ACNS0334 without radiation therapy. 16 months after completion of treatment, she relapsed at primary site with widespread spinal metastasis. She then received cranial spinal radiation of 3600Gy with proton beam, with boost to primary to 5580Gy, followed by chemotherapy with Temozolomide, Irinotecan and Avastin per COG ACNS0821. She is now 3 years and 3 months from completion of treatment, is doing well clinically with stable imaging findings. No particular alteration was identified from the tumor molecular testing of her initial pineoblastoma. Of note, she was diagnosed with pleuropulmonary blastoma soon after her initial diagnosis of pineoblastoma, and was found to have a DICER1 mutation (c.2062C>T; pR688*) thought to be a nonsense mutation. While radiation therapy following recurrence is known to improve the outcome, more recent studies suggest that tumors lacking the molecular features of high grade glioma also has a positive impact on prognosis. In addition, we speculate that DICER1 mutations might increase sensitivity of cancer cells to some chemotherapy through modulating gene expression and /or interfering with DNA repair mechanisms, therefore, affecting treatment outcome.
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Wei, JIA, Min Xiao, Zekai Mao, Yang Cao, Yi Xiao, Fankai Meng, Yicheng Zhang, Jianfeng Zhou, and Liang Huang. "Outcomes of Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (r/r B-NHL) Patients with TP53 Gene Disruption Treated with CD19/22 Cocktail CAR T-Cell Therapy Alone or Incorporated with Autologous Stem Cell Transplantation (ASCT)." Blood 138, Supplement 1 (November 5, 2021): 94. http://dx.doi.org/10.1182/blood-2021-147278.
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Abstract Disruption of TP53 gene occur in a subset of patients with refractory/relapse B-cell non-Hodgkin lymphoma (r/r B-NHL) and confer inferior prognosis. Recently, we reported the safety and efficacy of two clinical trials, administrating CAR T-cell infusion either alone (Trail A) or incorporated in ASCT (Trial B), in the treatment of r/r B-NHL. To address the prognostic impact of TP53 alterations on r/r aggressive B-cell lymphoma when treated with CAR T-cell therapy, in the present study, we systemically evaluate the therapeutic effects among the patients with TP53 alterations in these 2 trials with expanded cohort size and extended follow-up. In two trials, we enrolled 34 patients in group A (TP53wt in trial A), 32 patients in group B (TP53 alteration in trial A) and 28 patients in group C (TP53 alteration in trial B). Baseline features of patients in three groups were balanced. Heterozygous mutations and/or deletions of TP53 gene detected in 60 patients. A total of 42 (70.0%) patients carried either TP53 mutation(s) or sole del(17p), including 27 (45.0%) harboring TP53 mutation(s) and 15 (25.0%) carrying TP53 deletions. Biallelic TP53 aberration was revealed in the remaining 18 (30.0%) patients. They harbored TP53 mutation also carried del(17p) in the second allele. Among the 51 mutations that identified (Figure 1A), 37 were missense mutations, 6 were splice-site mutations, 4 were nonsense mutations, 3 were frameshift insertions or deletions (indels), and 1 was non-frameshift indel. Forty-five mutations (88.0%) located in DNA-binding domain (DBD, amino acid 101 - 294). Totally, 40 (66.7%) patients carried loss-of-function aberrations that resulted in TP53 inactivation, including either copy number loss or truncated mutations. Of the patients harboring TP53 alterations (group B), with a median follow-up of 16.7 months (range: 3.1 to 41.0 months), the median DOR and OS was not reached. The median PFS was 14.8 months (95% CI: 5.1 - NE). The estimated 24-month PFS and OS rates were 48.4% (95% CI: 30.2% - 64.4%) and 56.3% (95% CI: 36.6% - 72.0%). Notably, the DoR, PFS and OS were similar between the patients with (group B) or without (group A) TP53 alterations when treated with CAR19/22 T-cell cocktail therapy (Figure 1B). Since prognostic relevance varied according to distinct TP53 alterations, four different functional classification systems were applied to further elucidate whether CAR T-cell cocktail therapy can overcome the unfavorable prognostic impact conferred from TP53 alterations. Remarkably, in each classification system, either best ORR or survivals did not differ significantly between patients stratified in distinct risk subgroups, indicating CAR19/22 T-cell cocktail therapy could overcome the negative impact of TP53 alterations in these patients. Among the 28 patients (group C in trial B) who had TP53 alterations and were treated with ASCT incorporating CAR19/22 T-cell cocktail, 26 patients (92.9%, 95% CI: 77.4% - 98.7%) achieved best ORR, with 23 (82.1%, 95% CI: 64.4% - 92.1%) having a CR. With a median follow-up of 21.2 (range: 4.0 - 48.7) months, the median DOR, PFS and OS were not reached. The estimated 24-month PFS and OS rates were 77.5% (95% CI: 56.5% to 89.3%) and 89.3% (95% CI: 70.4% - 96.4%), respectively. At data cutoff date, 22 patients (78.6%, 95% CI: 60.5% - 89.8%) maintained their initial responses while 6 patients (21.4%, 95% CI: 10.2% - 39.5%) experienced disease progression. Strikingly, among the patients with TP53 alterations, as compared with CAR19/22 T-cell cocktail therapy (Group B), significantly extended DOR (P = .040), PFS (P = .024) and OS (P = .012) were achieved when CAR T-cell cocktail infusion was incorporated in ASCT (Figure 1C). In conclusion, our study, at first time, has proved that CAR T-cell cocktail therapy is effective for TP53-disrupted r/r aggressive B-NHL. Incorporating CAR-T cell infusion in ASCT can further improve the long-term outcome of these patients. Future clinical trials need to be performed with larger cohort to get more definitive conclusion that if CAR T-cell therapy should be moved earlier for r/r B-NHL in the coming era of immunotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Hosono, Naoko, Hideki Makishima, Bartlomiej Przychodzen, Jarnail Singh, Richard A. Padgett, Mikkael A. Sekeres, Andres Jerez, et al. "Spliceosomal Gene LUC7L2 Mutation Causes Missplicing and Alteration Of Gene Expression In Myeloid Neoplasms." Blood 122, no. 21 (November 15, 2013): 470. http://dx.doi.org/10.1182/blood.v122.21.470.470.
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While deletion of the long arm of chromosome 7 (del(7q)) along with monosomy 7 (-7) are common in myeloid neoplasms and especially MDS, their associated pathogenetic consequences and the genes responsible for the clinico-morphologic phenotypes remain unknown. To characterize the molecular defects resultant from del(7q), we applied a combined analysis of SNP-array karyotyping, whole exome NGS, targeted deep NGS and deep whole RNA NGS to facilitate identification of somatic mutations, loss of heterozygosity (LOH) and haploinsufficiency. First, using a cohort of 1595 patients, we precisely defined 3 commonly deleted regions in 7q22, 7q34, and 7q35-36. To identify genes involved in the pathogenesis of del(7q), we applied whole exome NGS to 428 patients with MDS and related conditions, including 72 cases of -7/del(7q) or UPD7. We found that both recurrent deletions with haploinsufficient expression and somatic nonsense/frameshift mutations were present in the genes CUX1 (7q22), LUC7L2 (7q34) and EZH2 (7q36), located on 7q. For this project we focused our study on the LUC7L2 gene encoding a spliceosomal protein that interacts with U1 snRNP to recognize 5’ splice sites. This function is in contrast to other spliceosomal genes mutated in MDS, such as SF3B1, U2AF1, SRSF2 and SF3A1that interact with the U2 snRNP complex and the 3’ splice site. Initially, we found 8 cases of LUC7L2 mutation including 2 cases of hemizygous and 1 case of homozygous mutations; all LUC7L2 mutations result in premature stop codons. The concomitant mutational spectrum in LUC7L2 mutant cases differed from those with EZH2 or CUX1 mutations. For example, TP53 and TET2 are mostly mutually exclusive with LUC7L2 mutations. While LUC7L2 mutant cases were low grade-MDS (RCUD or RCMD) or CMML, the survival impact of LUC7L2 mutation was similar to that seen in -7/del(7q) (LUC7L2; HR=2.36). Most of the mutations are heterozygous (diploid chr7) or homozygous (UPD7q). However, in addition to a few hemizygous mutations, wild type expression of LUC7L2 is haploinsufficient in del(7q). In total we found 117 cases (9%) with del(7q) and resultant decreased expression of LUC7L2, showing comparably poor survival as in the mutant cases (HR=1.99). Next, we hypothesized that dysfunction of LUC7L2 causes splicing defects (missplicing) in specific genes involved in leukemogenesis. Using deep RNA NGS we compared splicing patterns of 201,837 exons between the cases with deficient function of LUC7L2 (mutation/low-expression; n=11) versus wild-type (n=11), and identified concordant alternative splicing patterns in 44 genes (increased exon skipping in 27 genes; increased exon retention in 17 genes). For example, we found abnormal splicing of genes involved in functionally important pathways including the RAS pathway (NF1) and the TGF-β pathway (SMAD5). In cases of mutation/low-expression of LUC7L2, as a result of increased skipping of NF1 exon 31(NM_001042492), the type I isoform of NF1 predominates as compared to wild type (types I/II ratio; 0.76 vs. 0.45, p<.01, respectively). Missplicing also occurred in SMAD5 exon 2 (5’UTR site) resulting in a significantly lower SMAD5 expression. In agreement with RNA sequencing results, lentivirus-mediated shRNA knockdown of LUC7L2 in K562 cells resulted in the concordant effects on NF1 type 1 isoform and SMAD5 exon 2 skipping. Similar splicing patterns were observed in MDS cases with -7/del(7q), involving the LUC7L2gene. In conclusion, novel somatic mutations of LUC7L2 suggest that it could be a candidate gene associated with the poor prognosis of -7/del(7q) and UPD7. Loss of function or low expression of LUC7L2 results in distinctly altered splicing patterns involving genes associated with proliferation or leukemogenesis. Disclosures: Makishima: AA & MDS international foundation: Research Funding; Scott Hamilton CARES grant: Research Funding.
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Navrkalova, Veronika, Ludmila Sebejova, Jana Zemanova, Jana Kminkova, Blanka Kubesova, Michael Doubek, Yvona Brychtova, et al. "Defects of ATM Gene Involving Mutation Lead to Complete Elimination of ATM Function in Chronic Lymphocytic Leukemia." Blood 120, no. 21 (November 16, 2012): 3902. http://dx.doi.org/10.1182/blood.v120.21.3902.3902.
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Abstract Abstract 3902 Abnormalities of ATM gene are frequent in chronic lymphocytic leukemia (CLL) patients and represent important predictive and prognostic factor. ATM defects are commonly assessed through monitoring of 11q deletion (11q-) using I-FISH. However, 11q- does not mean ATM inactivation if the other allele remains intact, and there are patients who harbor ATM mutation(s) without accompanying 11q-. In CLL, studies addressing the presence of ATM mutations and their impact on ATM protein function are rare due to the extreme gene size and lack of well characterized (hot-spot) mutations. Our aims were to (i) identify ATM mutations in a cohort of predominantly high-risk CLL patients, and (ii) assess their functional consequences. We used the following complementary methodologies: (a) resequencing microarray (Affymetrix platform), which was designed to detect 1-nt substitutions (i.e. missense, nonsense and splicing mutations) (b) western blotting (WB) to disclose patients with null ATM protein level (c) functional test based on induction of CDKN1A (p21) gene after treatment of CLL cells with fludarabine and doxorubicin in parallel; in case of ATM mutation, the former drug leads to p21 expression induction, while the latter does not (d) direct Sanger sequencing to confirm alterations detected by microarray or mutations indicated by functional test and/or WB. The resequencing on microarray (which is neutral regarding a function of identified mutations) was performed in 107 predominantly high-risk CLL patients (83% harbored either 11q or 17p deletion). We detected 13 different polymorphisms with distinct frequency among patients and 14 ATM mutations (11 missense, 2 nonsense, 1 splicing) in 13 patients (12%). These mutated samples were subjected to the WB analysis and functional test, which showed a loss of ATM protein and/or its dysfunction in all cases. In order to disclose other potential mutations not detected by the array, 64 patients were also analyzed by WB and functional test. One or both of these tests indicated mutation in 7 patients and in 5 cases mutation(s) were identified (5 short deletions, 2 missense mutations). To obtain a more balanced cohort of CLL patients, we applied WB analysis and functional test on additional 33 samples (not analyzed by microarray) with prevalent TP53-wt/ATM-wt status. Among them, both or one of these tests indicated mutation in 4 patients and in all these patients a mutation was identified by Sanger sequencing. In total, we identified 22 patients (16%) with demonstrable ATM defect (non-functional state and/or null protein level backed up by mutation). High specificity of our functional test for identification of ATM mutations (16 out of 18 patients with indicated ATM mutation had causative DNA alteration) prompted us to perform analysis of overall cell viability in subgroups “mut-ATM” vs. sole “del-ATM.” Cells with ATM mutation showed clearly increased resistance to doxorubicin but not fludarabine in comparison with cells having sole 11q-. In conclusion, several complementary methodologies should preferably be used to effectively assess overall ATM status. All mutations identified in our study led to the loss of ATM protein or its function and they occurred predominantly in patients harboring 11q-. The work was supported by grants MUNI/A/0784/2011 and CZ.1.07/2.3.00/20.0045. Disclosures: No relevant conflicts of interest to declare.
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Zanella, Alberto, Paola Bianchi, Luciano Baronciani, Manuela Zappa, Elena Bredi, Cristina Vercellati, Fiorella Alfinito, Giovanni Pelissero, and Girolamo Sirchia. "Molecular Characterization of PK-LR Gene in Pyruvate Kinase–Deficient Italian Patients." Blood 89, no. 10 (May 15, 1997): 3847–52. http://dx.doi.org/10.1182/blood.v89.10.3847.
Full textAbstract:
Abstract We studied the PK-LR gene in 15 unrelated Italian patients with congenital hemolytic anemia associated with erythrocyte pyruvate kinase (PK) deficiency. Fourteen different mutations were detected among 26 mutated alleles identified: a five-nucleotide (nt) deletion (227 to 231), two splice-site (1269C and IVS3(−2)c), 10 missense (514C, 787T, 823A, 993A, 994A, 1168A, 1456T, 1529A, 1552A, and 1594T) and one nonsense mutation(s) (721T). Eight of these (deletion 227-231, 1269C, IVS3(−2)c, 514C, 787T, 823A, 1168A, and 1552A) were novel. Moreover, a new polymorphic site was detected in the 3′ untranslated region of the mRNA (C/T, nucleotide 1738). The deletion 227-231 causes a stop codon after amino acid 77, probably resulting in an unstable gene product. Mutations 1269C and IVS3(−2)c lead to an alteration of the 5′ and 3′ splice-site consensus sequence, respectively; cDNA analysis failed to reveal any abnormal transcript, suggesting that these mutations generate an unstable mRNA that is rapidly degraded. Of the five new missense mutations, 823A (Gly275-Arg) and 1168A (Asp390-Asn) involve highly conserved amino acids, 514C (Glu172-Gln) and 1552A (Arg518-Ser), although found in less conserved regions, affect the balance of the electric charges of the protein. Mutation 787T (Gly263-Trp) is likely to determine strong modifications in the local structure of the molecule. The most frequent mutation in Italy appears to be 1456T (seven of 30 alleles), followed by 1529A (three of 30) and 994A (three of 30). A correlation was found between mutations, biochemical characteristics of the enzyme, and clinical course of the disease.
50
Giulino, Lisa B., Susan Mathew, Wayne Tam, Amy Chadburn, Gianna Ballon, Sharon Barouk, Giuseppina Antonicelli, Lorenzo Leoncini, and Ethel Cesarman. "TNFAIP3 (A20) Genetic Alterations In EBV Associated AIDS Related Lymphomas." Blood 116, no. 21 (November 19, 2010): 802. http://dx.doi.org/10.1182/blood.v116.21.802.802.
Full textAbstract:
Abstract Abstract 802 Introduction: AIDS related lymphomas (ARL) are a heterogeneous group of lymphoproliferative disorders that are frequently associated with Epstein Barr virus (EBV) infection. EBV expresses latent viral oncoproteins that constitutively activate the transcription factor NF-κB, a potent inducer of genes involved in B cell survival and proliferation (Keller SA et al, Blood 2006). Lymphomas that are not associated with EBV can also display increased NF-κB activity and recent reports have described mutations in regulators of NF-κB in subsets of B cell lymphomas. One of the frequently mutated regulatory genes is TNFAIP3, which encodes A20, an ubiquitin modifying enzyme involved in the termination of NF-κB signaling. Mutations resulting in the inactivation of A20 have been found in a significant proportion of marginal zone lymphoma (Novak U et al, Blood 2009), classical Hodgkin lymphoma, primary mediastinal B cell lymphoma (Schmitz R et al, J Exp Med 2009), and diffuse large B cell lymphoma (Compagno M et al, Nature 2009). In ARL the incidence of alterations in A20 and the relationship with EBV infection has not been described. Materials and Methods: We evaluated archival formalin fixed paraffin embedded tissue samples of ARL for genetic alterations in A20. Tissue was collected through an international collaboration between Weill Cornell Medical College in New York, USA and Siena University in Siena, Italy. A tissue microarray with 46 cases of ARL was prepared and characterization of lymphoma subtype and EBV viral status were determined by immunohistochemistry and in situ hybridization for Epstein-Barr encoded RNA. Fluorescent in situ hybridization (FISH) was used to evaluate for genomic deletions in A20, and translocations of cMYC, BCL-2 and BCL-6. Direct sequencing of the coding region and splice sites of A20 was performed to evaluate for additional genetic alterations. Immunohistochemistry was used to evaluate for the presence of A20 protein. Results: Fluorescent in situ hybridization revealed A20 monoallelic or biallelic deletion in 6 of 25 cases (24%). A20 point mutations were found in 3 of 23 cases (13%). Nonsense mutations coding for a premature stop codon in exon 2 were seen in 2 cases. The third case was found to have a missense mutation in exon 7 resulting in an amino acid change. Two of the 3 cases with an A20 point mutation had A20 deletion in the complementary allele indicating biallelic alteration of the A20 gene. Immunohistochemistry for A20 was performed and is reported for the first time in this abstract. Absence of A20 protein was demonstrated in 4 of 33 samples (12%). Included among the cases negative for A20 on immunohistochemistry is the single case with biallelic A20 deletion demonstrated by FISH. In total 10 of 39 (26%) cases with adequate sample for evaluation were determined to have inactivation of A20 by FISH, sequencing, immunohistochemistry, or a combination. A20 inactivation was seen among all histologic subtypes of ARL including Burkitt lymphoma (n=2), diffuse large B cell lymphoma of the germinal center B cell (n=2) and non-germinal center B cell (n=2), plasmablastic lymphoma (n=3) and B cell lymphoma, unclassifiable, intermediate between BL and diffuse large B cell lymphoma (n=1). Interestingly, the incidence of EBV infection was higher in cases with A20 inactivation than in those with intact A20. EBV was present in 6/10 cases with A20 alteration (60%) vs. 8/29 cases with intact A20 (28%). The EBV latent viral protein LMP-1, which activates NF-κB, was not expressed in cases with A20 alteration. Conclusions: This is the first report to demonstrate A20 inactivation in EBV-associated lymphoma. A20 molecular analysis has been previously reported in Hodgkin Lymphoma (HL) where A20 inactivation and EBV infection were found to be almost mutually exclusive (Schmitz R et al, J Exp Med 2009). The EBV gene expression pattern differs in HL and ARL. In HL EBV expresses the viral oncoprotein LMP-1, which leads to constitutive activation of NF-κB. In ARL viral gene expression is more heterogeneous and in this cohort of ARL, LMP-1 was not expressed in any of the cases with EBV infection and A20 loss. Our data indicate that A20 may represent a tumor suppressor gene in a significant subset of ARL and that A20 inactivation may be associated with positive EBV status. In EBV related lymphoma inactivation of A20 may be an alternative mechanism of NF-κB upregulation in the absence of LMP-1. Disclosures: No relevant conflicts of interest to declare.