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Tarlock, Katherine, Todd M. Cooper, Todd A. Alonzo, Robert Gerbing, Jessica Pollard, Richard Aplenc, E. Anders Kolb, Alan S. Gamis, and Soheil Meshinchi. "Mutational Concordance from Diagnosis and Relapse in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group." Blood 128, no. 22 (December 2, 2016): 2846. http://dx.doi.org/10.1182/blood.v128.22.2846.2846.
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Abstract The range of genomic drivers of leukemogenesis and clonal nature of the disease illustrate the heterogeneity of the mutational spectrum in AML. Genomic interrogation of the evolution of AML has begun to highlight the scope of somatic changes that occur between diagnosis and relapse. A total of 1,214 patients were treated on the Children's Oncology Group trials AAML03P1 and AAML0531, of which 398 had relapse after initial remission. Of this cohort, 201 patients had matching diagnostic and relapse specimens for molecular profiling for the most common somatic mutations in pediatric AML (FLT3/ITD, FLT3/ALM, NPM1, CEBPA, WT1, NRAS, and KIT). Sequencing techniques included PCR with Sanger sequencing for detection of point mutations and indels and fragment length analysis for FLT3/ITD. In the cohort, FLT3/ITD was detected in 31/201 (15%) cases at diagnosis. Of the cases with diagnostic ITD, 22 (71%) relapsed with FLT3/ITD. Conversely, of the 28 cases with FLT3/ITD detected at relapse, 6 (21%) did not have detectable ITD at diagnosis. Overall, there were 37 patients (18%) with FLT3/ITD mutations detected at either time point. Of the 37 patients, 22 (59%) demonstrated stability of the mutation from diagnosis to relapse. Discordant mutation status was observed in 15 patients (41%). Among the discordant patients, 9 had FLT3/ITD detected at diagnosis only. Conversely, 6 patients were ITD-positive at relapse only, demonstrating disease evolution with continued mutational acquisition (Table 1). In every discordant case, ultra sensitive PCR analysis confirmed absence of an ITD. The median ITD allelic ratio (AR) for patients with concordant status was 0.47 (range 0.03-2.67) vs. 0.24 (range 0.04-0.47) for those with disappearance of the ITD at relapse, suggesting an association of diagnostic AR with mutation stability. NPM1 mutations were detected in 8 patients at diagnosis and 100% concordance was observed in the cohort. CEBPA mutations were detected in 6 patients at diagnosis, and in 5 cases remained at relapse. One patient had a CEBPA mutation detected at diagnosis only. FLT3/ALM mutations were detected in 7 patients at either time point. Seven patients had an ALM at diagnosis, however concordance was observed in 2 cases, whereas 4 patients had detection at diagnosis only. There were 22 patients (11%) with NRAS mutations detected at either time point. Diagnostic NRAS mutations were detected in 18 patients, while only 3 (17%) had the identical mutation detected at relapse, as one patient had a distinct mutational sequence present at relapse. NRAS mutations were detected at diagnosis only in 13 patients (59%), where as 5 patients (23%) had a mutation detected at relapse only. NRAS was the most discordant mutations analyzed, with only 3/22 patients (14%) demonstrating stability of the mutation from diagnosis to relapse (Table 1). WT1 exon 17 indels were observed in 24 patients (12%) at either time point. Nineteen patients had diagnostic mutations, with 18 patients demonstrating stability at relapse. Five patients had mutations detected at relapse only. Overall, concordance was observed in 18 patients (75%). Only 1 alteration was detected at diagnosis in all patients, however 6 patients with concordant WT1 status had multiple indels detected at relapse, demonstrating continued mutational acquisition. KIT mutations (missense and indels) in exons 8 (n=11) and 17 (n=7) were detected in 17 patients. Mutational concordance was observed in 7 patients. Eight patients had mutations detected at diagnosis only, while 2 patients had mutations detected at relapse only (Table 1). We demonstrate the complexity of the evolving somatic landscape from diagnosis to relapse in pediatric AML. The stability of NPM1 mutations, considered an early leukemogenic event, is in contrast to the discordant NRAS and KIT mutations. There was evolution of FLT3/ITD status, and we observed overall higher ARs in the concordant cohort, perhaps suggesting mutations in this cohort served as stronger leukemic drivers. Further investigation on the biologic implications and clonal prevalence is critical to determine a mutation's significance in leukemogenesis, timing of acquisition, and if appropriate for therapeutic targeting and disease monitoring. Table 1 Mutational concordance from diagnosis to relapse. Legend: Discordant D+/R-: Discordant status with diagnostic only positive Discordant D-/R+: Discordant status with relapse only positive Table 1. Mutational concordance from diagnosis to relapse. / Legend:. / Discordant D+/R-: Discordant status with diagnostic only positive. / Discordant D-/R+: Discordant status with relapse only positive Disclosures No relevant conflicts of interest to declare.
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GARCÍA-DORADO, A., C. LÓPEZ-FANJUL, and A. CABALLERO. "Properties of spontaneous mutations affecting quantitative traits." Genetical Research 74, no. 3 (December 1999): 341–50. http://dx.doi.org/10.1017/s0016672399004206.
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Recent mutation accumulation results from invertebrate species suggest that mild deleterious mutation is far less frequent than previously thought, implying smaller expressed mutational loads. Although the rate (λ) and effect (s) of very slight deleterious mutation remain unknown, most mutational fitness decline would come from moderately deleterious mutation (s ≈ 0·2, λ ≈ 0·03), and this situation would not qualitatively change in harsh environments. Estimates of the average coefficient of dominance (h¯) of non-severe deleterious mutations are controversial. The typical value of h¯ = 0·4 can be questioned, and a lower estimate (about 0·1) is suggested. Estimated mutational parameters are remarkably alike for morphological and fitness component traits (excluding lethals), indicating low mutation rates and moderate mutational effects, with a distribution generally showing strong negative asymmetry and little leptokurtosis. New mutations showed considerable genotype–environment interaction. However, the mutational variance of fitness-component traits due to non-severe detrimental mutations did not increase with environmental harshness. For morphological traits, a class of predominantly additive mutations with no detectable effect on fitness and relatively small effect on the trait was identified. This should be close to that responsible for standing variation in natural populations.
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Watters, M. K., and D. R. Stadler. "Spontaneous mutation during the sexual cycle of Neurospora crassa." Genetics 139, no. 1 (January 1, 1995): 137–45. http://dx.doi.org/10.1093/genetics/139.1.137.
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Abstract The DNA sequences of 42 spontaneous mutations of the mtr gene in Neurospora crassa have been determined. The mutants were selected among sexual spores to represent mutations arising in the sexual cycle. Three sexual-cycle-specific mutational classes are described: hotspot mutants, spontaneous repeat-induced point mutation (RIPs) and mutations occurring during a mutagenic phase of the sexual cycle. Together, these three sexual-cycle-specific mutational classes account for 50% of the mutations in the sexual-cycle mutational spectrum. One third of all mutations occurred at one of two mutational hotspots that predominantly produced tandem duplications of varying lengths with short repeats at their end-points. Neither of the two hotspots are present in the vegetative spectrum, suggesting that sexual-cycle-specific mutational pathways are responsible for their presence in the spectrum. One mutant was observed that appeared to have been RIPed precociously. The usual prerequisite for RIP, a duplication of the affected region, was not present in the parent stocks and was not detected in this mutant. Finally, there is a phase early in the premeiotic sexual cycle that is overrepresented in the generation of mutations. This "peak" appears to represent a phase during which the mutation rate rises significantly. This phase produces a disproportionally high fraction of frame shift mutations (3/6). In divisions subsequent to this, the mutation rate appears to be constant.
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Ellis, Nathan A. "Mutation-causing mutations." Nature 381, no. 6578 (May 1996): 110–11. http://dx.doi.org/10.1038/381110a0.
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Pawlik, Timothy M., Darrell R. Borger, Yuhree Kim, David Cosgrove, Sorin Alexandrescu, Ryan Thomas Groeschl, Vikram Deshpande, et al. "Genomic profiling of intrahepatic cholangiocarcinoma: Refining prognostic determinants and identifying therapeutic targets." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 210. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.210.
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210 Background: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to define the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods: 138 patients who underwent resection at 6 centers in the United States and Europe were included in the cohort. Mutational profiling was performed using nucleic acids that were extracted from resected ICC tumor specimens; mutations were identified using a multiplexed mutational profiling platform. The frequency of mutations was ascertained and the impact on outcome determined. Results: Most patients had a solitary tumor (82%) and median tumor size was 6.0cm. Most patients had R0 resection (89%); 19% patients had N1 disease, while 15% had microscopic vascular invasion. A minority received adjuvant therapy (30%). The majority (55%) of patients had no genetic mutation identified. Among the 62 (45%) patients with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5%: IDH1 (17.4%), KRAS (8.7%), BRAF (5.8%), PIK3CA (5.1%). In contrast, other genetic mutations were identified in very low frequency: IDH2 (3.6%), NRAS (3.6%), TP53 (2.2%), MAP2K1 (1.5%), CTNNB1 (0.7%), and PTEN (0.7%). Approximately 7% of IDH1-mutant tumors were associated with a concurrent PIK3CA gene mutation, and to a much lower extent, a mutation in MAP2K1 (2%). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (OR 3.46), while KRAS-mutant tumors were more likely to be associated with perineural invasion (OR 5.72)(both P<0.05). While clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions: Most patients with resected ICC had no somatic mutation identified on multiplexed mutational profiling. IDH1 and KRAS were the most common mutations noted. While certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly impact long-term prognosis.
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Kang, S., S. S. Seo, H. J. Chang, C. W. Yoo, S. Y. Park, and S. M. Dong. "Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma." International Journal of Gynecologic Cancer 18, no. 6 (2008): 1339–43. http://dx.doi.org/10.1111/j.1525-1438.2007.01172.x.
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In endometrial carcinomas (ECs), previous report suggested that PIK3CA mutations do not coexist with KRAS mutations, but the significant mutual exclusiveness has not been demonstrated. In this study, we examined the mutation frequency of PIK3CA in EC and its mutual exclusiveness with KRAS mutation. We performed mutational analysis of PIK3CA through a polymerase chain reaction single-strand conformation polymorphism assay in 44 cases of endometrial cancer and analyzed the correlation with loss of PTEN, KRAS mutation, and RASSF1A hypermethylation. Somatic mutations of PIK3CA were detected in 14 of 44 (31.8%) of endometrial cancers. In exon 9, seven PIK3CA mutations were located, while seven mutations were located in exon 20. The most common mutation was E545A (35.7%), followed by H1047R (28.6%). Concomitant loss of PTEN expression and PIK3CA mutation was found in four cases of endometrial cancer. KRAS mutations were mutually exclusive with PIK3CA mutations, and those mutations were inversely correlated with statistical significance (P= 0.039). Also, we found that mutations in ERBB2 were mutually exclusive with PIK3CA mutations. RASSF1A and hMLH1 methylation were not correlated with the presence of PIK3CA mutations. PIK3CA was frequently mutated in endometrial cancers. KRAS and PIK3CA mutations are inversely correlated, suggesting that genetic alterations of KRAS and PIK3CA may play equivalent roles in endometrial carcinogenesis.
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Chao, Mwe, Kathrin Thomay, Gudrun Goehring, Marcin Wlodarski, Victor Pastor, Brigitte Schlegelberger, Detlev Schindler, Christian Kratz, and Charlotte Niemeyer. "Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms." Klinische Pädiatrie 229, no. 06 (November 2017): 329–34. http://dx.doi.org/10.1055/s-0043-117046.
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AbstractIndividuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in RUNX1 and genes of the RAS pathway appeared more instrumental in the pathogenesis of FA myeloid malignancies. RUNX1 mutations were associated with more advanced disease. Interestingly, one patient with refractory anemia with ring sideroblasts harbored the SF3B1 p.K700E mutation highlighting the mutation’s causative role in MDS with ring sideroblasts even in the context of FA. On the whole, our findings implicate a different genetic architecture of FA MDS/AML from adult sporadic MDS. Notably, the genetic events resemble those described in pediatric MDS.
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Pálinkás, Hajnalka Laura, Lőrinc Pongor, Máté Balajti, Ádám Nagy, Kinga Nagy, Angéla Békési, Giampaolo Bianchini, Beáta G. Vértessy, and Balázs Győrffy. "Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer." International Journal of Molecular Sciences 23, no. 2 (January 6, 2022): 633. http://dx.doi.org/10.3390/ijms23020633.
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The clonal composition of a malignant tumor strongly depends on cellular dynamics influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to identify founder mutations leading to subsequent boosts in mutation load. The overall mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation status of DNA-repair genes. The number of mutations was first determined across all patients and the proportion of genes having mutation in each percentile was ranked. Early mutations in DNA repair genes preceding a mutational expansion were designated as founder mutations. Survival analysis for gene expression was performed using microarray data with available relapse-free survival. Of the 180 genes involved in DNA repair, the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18), SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors compared to normal samples, and higher expression led to longer relapse-free survival in 1211 patients (HR = 0.72, p = 4.4 × 10−3). In an experimental setting, the mutational load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon treatments, the mutational load exposed a significant two-fold increase. Our results suggest PRKDC as a new key gene driving tumor heterogeneity.
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Hughes, Timothy, Giuseppe Saglio, Giovanni Martinelli, Dong-Wook Kim, S. Soverini, Martin Mueller, A. Haque, et al. "Responses and Disease Progression in CML-CP Patients Treated with Nilotinib after Imatinib Failure Appear To Be Affected by the BCR-ABL Mutation Status and Types." Blood 110, no. 11 (November 16, 2007): 320. http://dx.doi.org/10.1182/blood.v110.11.320.320.
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Abstract Nilotinib is a rationally designed 2nd-generation bcr-abl inhibitor. It is ∼30-fold more potent than imatinib against wild-type bcr-abl and active against 32/33 imatinib-resistant bcr-abl mutants in preclinical models. In an open-label phase II study of nilotinib in imatinib-resistant or -intolerant CML-CP patients (pts), we assessed the occurrence of mutations and the efficacy stratified by BCR-ABL mutational status. Prior to therapy, 35 mutations affecting 28 amino acids in the BCR-ABL kinase domain were identified by direct sequencing in 39% (106/270) of the pts analyzed. The incidence of baseline mutation was higher in imatinib-resistant (100/183, 55%) versus imatinib-intolerant pts (6/86, 7%). After 12 months of therapy, complete hematologic response (CHR) was achieved in 85%, major cytogenetic response (MCR) in 60%, and complete cytogenetic response (CCR) in 45% of pts without baseline mutations versus 67, 49 and 29% of pts with mutations. Among patients with baseline mutations, responses were observed broadly in all genotypes identified, but rates of responses differed by the in vitro sensitivity of the mutant clone against nilotinib. Pts with sensitive mutations of ≤100 nM cellular IC50 had the best response rate and were comparable to pts without baseline mutations. Pts with less sensitive mutations (IC50 201–800nM:Y253H, E255K, E255V, F359C) had responses but the response rate were lower then those of the two other groups (IC50 101–200nM and 201–800nM). The nilotinib-resistant T315I mutation (IC50>800nM) was identified at baseline in 5 cases (one pt had a limited response followed by progression). The less sensitive mutations (IC50 201–800nM) and the T315I mutation occurred in 8% and 2% of all pts assessed for baseline mutations, respectively. With a median follow up of 12 months, progression occurred in 15% (25/164) versus 40% (42/106) of pts without and with baseline mutations. Nine of 18 with less sensitive baseline mutations and 3 of 5 with T315I progressed, but the baseline mutation most frequently associated with progression was F359V (7/9). In 67 cases of progression, mutational data at or within 3 months of progression were available in 28 cases. Among the 28 pts, 7 (25%) had no mutation; 9 (32%) had the same baseline mutation (including F359V in 3; Y253F/H in 3; E255K in 1; and T315I in 1). A further 12 (43%) pts showed new emerging mutations at progression, 4 with T315I, 4 E255K, 3 Y253H, and 1 F359C. The other 7 pts with emerging mutations had not progressed. In total 21 pts were found with emerging mutations, 19 (90%) had a different mutation at baseline. In summary, nilotinib responses were observed across a variety of BCR-ABL mutations. Preliminary data suggest that mutational status at baseline and/or the emergence of new mutations may influence disease progression. Less sensitive or resistant mutations represented 10% of the pt population and may be associated with less favorable responses. Longer follow up is required.
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Ahn, TaeJin, and Taesung Park. "Pathway-Driven Discovery of Rare Mutational Impact on Cancer." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/171892.
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Identifying driver mutation is important in understanding disease mechanism and future application of custom tailored therapeutic decision. Functional analysis of mutational impact usually focuses on the gene expression level of the mutated gene itself. However, complex regulatory network may cause differential gene expression among functional neighbors of the mutated gene. We suggest a new approach for discovering rare mutations that have real impact in the context of pathway; the philosophy of our method is iteratively combining rare mutations until no more mutations can be added under the condition that the combined mutational event can statistically discriminate pathway level mRNA expression between groups with and without mutational events. Breast cancer patients with somatic mutation and mRNA expression were analyzed by our approach. Our approach is shown to sensitively capture mutations that change pathway level mRNA expression, concurrently discovering important mutations previously reported in breast cancer such as TP53, PIK3CA, and RB1. In addition, out of 15,819 genes considered in breast cancer, our approach identified mutational events of 32 genes showing pathway level mRNA expression differences.
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Robinson, Philip S., Tim H. H. Coorens, Claire Palles, Emily Mitchell, Federico Abascal, Sigurgeir Olafsson, Bernard C. H. Lee, et al. "Increased somatic mutation burdens in normal human cells due to defective DNA polymerases." Nature Genetics 53, no. 10 (September 30, 2021): 1434–42. http://dx.doi.org/10.1038/s41588-021-00930-y.
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AbstractMutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.
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Machado, Heather E., Nina Friesgaard Øbro, Emily Mitchell, Megan Davies, Anthony R. Green, Kourosh Saeb-Parsy, Daniel James Hodson, David Kent, and Peter J. Campbell. "Life History of Normal Human Lymphocytes Revealed By Somatic Mutations." Blood 134, Supplement_1 (November 13, 2019): 1045. http://dx.doi.org/10.1182/blood-2019-128188.
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Introduction: Mature blood cells harbor a mixture of mutations inherited from ancestral hematopoietic stem cells (HSCs) and mutations accumulated after maturation. The landscape of these somatic mutations in normal blood is poorly mapped, with questions as simple as "how many mutations does a memory T cell accumulate throughout life?" remaining unanswered. This gap in our knowledge is particularly relevant for hematopoietic malignancy- while we know that lymphomas derive from lymphocytes of particular stages of differentiation, we do not know if the patterns we see are reflected in their normal counterparts. Results: In order to characterize normal somatic mutation in lymphocytes, we performed single-cell expansion and whole genome sequencing of over 600 T and B lymphocytes and 200 HSC and progenitor cells across 5 individuals (ages 0-85). All lymphocyte subsets show increased mutation burden with respect to HSCs across all classes of variants (Figure 1). Some of this increase can explained by lymphocyte-specific mutational processes, such as the activity of RAG, accounting for at least 20% of observed structural variants. We also find a striking variation in mutation burden within and between lymphocyte subsets. Microenvironment specific mutational processes dominate the observed differences. Examples of this include germinal center ("non-canonical AID") mutations in memory B cells and UV-like mutations in memory T cells (putatively skin resident cells). Naive B and T cells show a lack of variation in discrete mutational patterns relative to their memory counterparts, and have mutational profiles and mutation burdens more similar to that of HSCs. We also observe differences in the mutational patterns between B and T cells that are indicative of the increased divergence of T lymphocytes from the HSC pool. In general, the mutation burden we observe in normal lymphocytes approach those seen in lymphoma. Conclusions: Our work highlights the substantial genetic diversity in normal lymphocytes, with some cells accumulating thousands of mutations on top of those inherited from the HSC compartment. These mutations can be used to describe the life history of each individual lymphocyte including their exposure to specific microenvironments. Our findings shed light on the biology of these cells and will help differentiate between normal and disease processes. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Ahn, Jae-Sook, Hyeoung-Joon Kim, Yeo-Kyeoung Kim, Il-Kwon Lee, Nan Young Kim, Mark D. Minden, Chul Won Jung, et al. "An Adverse Prognostic Effect of Homozygous TET2 Mutational Status on the Relapse Risk of Acute Myeloid Leukemia Patients of Normal Karyotype." Blood 124, no. 21 (December 6, 2014): 1052. http://dx.doi.org/10.1182/blood.v124.21.1052.1052.
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Abstract Purpose Ten-eleven-translocation oncogene family member 2 (TET2) mutations play leukemogenic roles in patients with acute myeloid leukemia (AML). However, the prognostic significance of such mutations in normal-karyotype (NK) AML patients remains controversial, especially that of homozygous TET2 mutations. n the present study, we attempted 1) to evaluate the prevalence of TET2 mutations in NK-AML patients; 2) to clarify the prognostic role played by TET2 mutation, especially homozygous mutation, in NK-AML patients; and, 3) to analyze associations among TET2 mutations and other mutations frequently observed in NK-AML patients, including those in FLT3-ITD, NPM1, and CEBPA. Patients and Methods We included 407 patients with NK-AML in the present study. NK-AML patients were diagnosed from October 1998 to September 2012 in seven participating institutes, and the median patient age was 52 years (range, 15–84 years). Sixty-five different TET2 mutations were detected in 54 patients (13.3%), of which 13 nonsense, 30 frameshift, and 22 missense and, homozygous mutations in 14 patients (25.9%) among TET2 mutated patients. Results A TET2 mutation was associated with poor prognostic features such as older age (p<0.001) or a high WBC count (p=0.013). Upon multivariate analysis, older patients (p=0.012, OR: 0.442, 95% CI 0.233-0.839), an NPM1 mutation (p=0.004, OR: 2.256, 95% CI 1.301-3.912), and a CEBPA mutation (p=0.001, OR: 5.031, 95% CI 1.921-13.173) were confirmed to be independent risk factors for complete remission (CR), but no TET2 mutation influenced CR (p=0.441, OR: 0.744, 95% CI 0.351-1.578). Upon multivariate analysis of factors affecting relapse incidence (RI), event-free survival (EFS), and overall survival (OS); performance of allogeneic stem cell transplantation (allo-SCT), and mutations in NPM1, CEBPA, or FLT3-ITD mutations, were independent risk factors for RI, EFS, and OS, but neither a TET2 mutation alone nor older age had any prognostic impact on RI, EFS, or OS. However, patients with homozygous TET2 mutations experienced a shorter EFS (p=0.046) and a higher relapse rate (p=0.010) than those with non-homozygous TET2 mutations or who were of TET2 wild-type status. Homozygous TET2 mutational status was an independent adverse prognostic factor for relapse upon multivariate analysis (p<0.001; HR 1.519; 95% CI 1.105-2.086), suggesting that the TET2 mutation exerted a threshold effect on relapse risk. Conclusion In summary, the TET2 mutation did not impact treatment outcomes, but homozygous TET2 mutational status did affect (elevate) the relapse rate, in particular. Our data suggest that homozygous TET2 mutational status increases the relapse risk in NK-AML patients. Disclosures Off Label Use: Rituximab has been used as an off-label drug for adult ALL, and has been provided by Roche Inc. for scientific purpose. .
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Wayne, Marta L., and Trudy F. C. Mackay. "Quantitative Genetics of Ovariole Number in Drosophila melanogaster. II. Mutational Variation and Genotype-Environment Interaction." Genetics 148, no. 1 (January 1, 1998): 201–10. http://dx.doi.org/10.1093/genetics/148.1.201.
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Abstract The rare alleles model of mutation-selection balance (MSB) hypothesis for the maintenance of genetic variation was evaluated for two quantitative traits, ovariole number and body size. Mutational variances (VM) for these traits, estimated from mutation accumulation lines, were 4.75 and 1.97 × 10−4 times the environmental variance (VE), respectively. The mutation accumulation lines were studied in three environments to test for genotype × environment interaction (GEI) of new mutations; significant mutational GEI was found for both traits. Mutations for ovariole number have a quadratic relationship with competitive fitness, suggesting stabilizing selection for the trait; there is no significant correlation between mutations for body size and competitive fitness. Under MSB, the ratio of segregating genetic variance, VG, to mutational variance, VM, estimates the inverse of the selection coefficient against a heterozygote for a new mutation. Estimates of VG/VM for ovariole number and body size were both approximately 1.1 × 104. Thus, MSB can explain the level of variation, if mutations affecting these traits are under very weak selection, which is inconsistent with the empirical observation of stabilizing selection, or if the estimate of VM is biased downward by two orders of magnitude. GEI is a possible alternative explanation.
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Jeffers, Michael, Christian Kappeler, Iris Kuss, Georg Beckmann, Daniel H. Mehnert, Johannes Fredebohm, and Michael Teufel. "Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial." Gastric Cancer 25, no. 3 (January 20, 2022): 598–608. http://dx.doi.org/10.1007/s10120-021-01274-6.
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Abstract Background In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID trial, we investigated whether a more comprehensive KIT mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern. Methods Archived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (n = 102) and next-generation sequencing (FoundationONE; n = 47). Plasma samples collected at baseline were analyzed by BEAMing (n = 163) and SafeSEQ (n = 96). Results In archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had KIT mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in PDGFR, KRAS, and BRAF. Regorafenib showed PFS benefit across all primary and secondary KIT mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment. Conclusion These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.
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Golding, G. Brian, Patricia J. Gearhart, and Barry W. Glickman. "Patterns of Somatic Mutations in Immunoglobulin Variable Genes." Genetics 115, no. 1 (January 1, 1987): 169–76. http://dx.doi.org/10.1093/genetics/115.1.169.
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ABSTRACT The mechanism responsible for somatic mutation in the variable genes of antibodies is unknown and may differ from previously described mechanisms that produce mutation in DNA. We have analyzed 421 somatic mutations from the rearranged immunoglobulin variable genes of mice to determine (1) if the nucleotide substitutions differ from those generated during meiosis and (2) if the presence of nearby direct and inverted repeated sequences could template mutations around the variable gene. The results reveal a difference in the pattern of substitutions obtained from somatic mutations vs. meiotic mutations. An increased frequency of T:A to C:G transitions and a decreased frequency of mutations involving a G in the somatic mutants compared to the meiotic mutants is indicated. This suggests that the mutational processes responsible for somatic mutation in antibody genes differs from that responsible for mutation during meiosis. An analysis of the local DNA sequences revealed many direct repeats and palindromic sequences that were capable of templating some of the known mutations. Although additional factors may be involved in targeting mutations to the variable gene, mistemplating by nearby repeats may provide a mechanism for the enhancement of somatic mutation.
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Shang, Yanhong, Hao Zhang, Aiming Zang, Shaohua Yuan, Xiaofang Li, Wenpan Zhang, Ran Huo, et al. "Abstract 5754: The molecular characteristics of EGFR co-mutations in lung adenocarcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5754. http://dx.doi.org/10.1158/1538-7445.am2022-5754.
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Abstract Background: With the development of sensitive next-generation sequencing (NGS) techniques that go beyond the genotyping of specific mutations, detection rates for uncommon mutations have risen clinically. Given this rise in mutation identification, discoveries regarding isolation or coexistent mutations with the EGFR mutation (termed a “complex” mutation) are in “uncharted territory” in terms of their biological impacts on oncogenic pathways and their sensitivity or resistance, to EGFR TKIs. Methods: Targeted NGS for 450 genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: A cohort of 262 Chinese lung adenocarcinoma patients were recruited. The most common mutated gene was EGFR (63%, 165/262), and followed by TP53 gene (59.2%, 155/262). Beyond single genetic lesions, we found that enriched co-mutations in lung adenocarcinoma were significantly different for TP53 (p < 0.001) and RTK-RAS (p = 0.0012) signaling pathways between the EGFR-positive and EGFR-negative groups. In all EGFR co-mutated patients, the frequency of co-mutation for EGFR/TP53 and the classical EGFR mutation was 106 (64.2%) and 144 (87.3%), respectively. EGFR-only mutations occurred in 50 (30.3%) patients, while co-mutation of EGFR and at least one tumor suppressor gene (TSG) occurred in 84 (50.9%) patients. Patients with EGFR-only mutation had a lower tumor mutational burden (p = 0.026) as compared to patients with only a TSG mutation. Patients with co-mutations of EGFR and at least one TSG also displayed a lower tumor mutational burden, although only a slight difference (p = 0.062) was determined. Conclusions: Profiles of EGFR co-mutational TSGs should be regarded as a unique subgroup for predictive insights in treatments for patients with co-occurrence of somatic EGFR and TSG mutations. To improve predictions related to drug sensitivity in targeted therapies for oncogenes with diverse mutations, our future studies will include publications dedicated to this topic. Citation Format: Yanhong Shang, Hao Zhang, Aiming Zang, Shaohua Yuan, Xiaofang Li, Wenpan Zhang, Ran Huo, Guotao Fang, Zhengyue Dou, Weiwei Liu, Xiao Han, Qi Zhao, Chenglin Xi. The molecular characteristics of EGFR co-mutations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5754.
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Lee, Ye Ji, Yejin Lee, Youn Jung Kim, Zang Hee Lee, and Jung-Wook Kim. "Novel PAX9 Mutations Causing Isolated Oligodontia." Journal of Personalized Medicine 14, no. 2 (February 8, 2024): 191. http://dx.doi.org/10.3390/jpm14020191.
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Hypodontia, i.e., missing one or more teeth, is a relatively common human disease; however, oligodontia, i.e., missing six or more teeth, excluding the third molars, is a rare congenital disorder. Many genes have been shown to cause oligodontia in non-syndromic or syndromic conditions. In this study, we identified two novel PAX9 mutations in two non-syndromic oligodontia families. A mutational analysis identified a silent mutation (NM_006194.4: c.771G>A, p.(Gln257=)) in family 1 and a frameshift mutation caused by a single nucleotide duplication (c.637dup, p.(Asp213Glyfs*104)) in family 2. A minigene splicing assay revealed that the silent mutation resulted in aberrant pre-mRNA splicing instead of normal splicing. The altered splicing products are ones with an exon 4 deletion or using a cryptic 5’ splicing site in exon 4. Mutational effects were further investigated using protein expression, luciferase activity assay and immunolocalization. We believe this study will not only expand the mutational spectrum of PAX9 mutations in oligodontia but also strengthen the diagnostic power related to the identified silent mutation.
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Xu, Fan, Qingshan Li, Wenxin LI, Shenglin Zhang, Yaping Zhao, Didi Guo, Zhongyu Lu, et al. "Molecular characteristics of ERBB2-activating mutations in Chinese patients with NSCLC." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 8546. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.8546.
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8546 Background: Activating mutations in the ERBB2 gene were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations have emerged as therapeutic targets in non-small cell lung cancers (NSCLC). However, Activating ERBB2 mutations have not been described in detail like other driver gene mutations, such as epidermal growth factor receptor (EGFR)-activating mutations. Methods: In this study, we retrospectively analyzed activating ERBB2 mutations using next-generation sequencing(NGS). From May 2019 to January 2022, 21745 patients who were diagnosed with NSCLC were detected. Results: A total of 686 activating ERBB2 mutations were found, and 12 patients carried double ERBB2-activating mutations. In this cohort, the average age of patients was 58 years (range, 13-90 years). 59.6% of the patients were female and 88.2% were diagnosed with lung adenocarcinoma.A total of 47 ERBB2-activating mutation subtypes were defined in 674 patients. The most common activating mutations were Y772_A775dup (55.0%, 371/674), followed by G776delinsVC (8.3%, 56/674), S310F (7.7%, 52/674), G778_P780dup (5.6%, 38/674) and V659E (4.1%, 28/674). All other mutations occurred in 14 or fewer patients. ERBB2-activating mutations occurred most frequently in the tyrosine kinase domain（TKD） (80.1%), which included mutations in exon 20 (76.2%), exon 19 (3.0%), and exon 21 (1.2%),In addition, 13.2% of activating ERBB2 mutations occur in the extracellular domain, and 5.5% in the Transmembrane domain. 23.1%(156/674) patients with ERBB2 activating mutations could be evaluated for concurrent mutations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Among these patients, ERBB2-activating mutations were most frequently co-mutated with TP53(54/156) and EGFR(21/156). The frequency of EGFR mutations was much higher in non-TKD mutation patients than in TKD mutation patients (56.7% vs. 3.2%, P < 0.001), but no difference was observed for TP53. All these patients were microsatellite stable (MSS) and low TMB ( < 10 mutations/megabase). Conclusions: We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.
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Wang, Yan, Fei Ran, Jin Lin, Jing Zhang, and Dan Ma. "Genetic and Clinical Characteristics of Patients with Philadelphia-Negative Myeloproliferative Neoplasm Carrying Concurrent Mutations in JAK2V617F, CALR, and MPL." Technology in Cancer Research & Treatment 22 (January 2023): 153303382311540. http://dx.doi.org/10.1177/15330338231154092.
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Simultaneous mutations in Janus kinase 2 ( JAK2), calreticulin , and myeloproliferative leukemia (MPL) genes are generally not considered for characterizing Philadelphia-negative myeloproliferative neoplasms (MPNs), leading to misdiagnosis. Sanger sequencing and quantitative polymerase chain reaction were used to detect gene mutations in patients with MPN. We retrospectively screened the data of patients with double mutations in our center and from the PubMed database. Two patients tested positive for both JAK2V617F and CALR mutations (2/352 0.57%) in our center, while data of 35 patients from the PubMed database, including 26 patients with essential thrombocythemia (ET), 6 with primary myelofibrosis (PMF), 2 with unexplained thrombosis, and 1 with polycythemia vera were screened for double mutations. Among these mutations, co-mutation of JAKV617F-CALR constituted the majority (80.0%), when compared with JAKV617F-MPL (17.1%) and CALR-MPL (2.9%) mutations. Moreover, patients with concurrent mutational myeloproliferative neoplasm (MPN) were relatively older ( P = .010) with significantly higher platelet counts than their counterparts with single gene mutations ( P < .001). The occurrence of palpable splenomegaly ( P < .001) and leukocyte count ( P = .041) were also significantly different between patients with single and simultaneous gene mutations. These 4 risk factors also showed significant test effectiveness in the ET and PMF cohorts ( P < .05). In terms of clinical characteristics of patients with ET, those with JAK2V617F- CALR mutation had higher but normal hemoglobin levels ( P = .0151) than those carrying JAK2V617F- MPL mutation. From a clinical perspective, patients with multiple mutational MPN are different from those with single gene mutations. The poor treatment response by patients in our center and unfavorable indicators for patients with co-mutations in published literature indicate that customized treatment may be the best choice for patients with MPN carrying co-mutations.
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Kapoor, Ritika R., Sarah E. Flanagan, Piers Fulton, Anupam Chakrapani, Bernadette Chadefaux, Tawfeg Ben-Omran, Indraneel Banerjee, Julian P. Shield, Sian Ellard, and Khalid Hussain. "Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations." European Journal of Endocrinology 161, no. 5 (November 2009): 731–35. http://dx.doi.org/10.1530/eje-09-0615.
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BackgroundActivating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.ObjectivesTo study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA.Patients and methodsTwenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.ResultsHeterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 μmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.ConclusionPatients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.
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Moltara, Maja Ebert, Srdjan Novakovic, Marko Boc, Marina Bucic, Martina Rebersek, Vesna Zadnik, and Janja Ocvirk. "Prevalence of BRAF, NRAS and c-KIT mutations in Slovenian patients with advanced melanoma." Radiology and Oncology 52, no. 3 (April 26, 2018): 289–95. http://dx.doi.org/10.2478/raon-2018-0017.
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Abstract Background BRAF, NRAS and c-KIT mutations are characteristics of tumour tissues that influence on treatment decisions in metastatic melanoma patients. Mutation frequency and their correlation with histological characteristics in Slovenian population have not been investigated yet. Patients and methods In our retrospective analysis we analysed mutational status of BRAF, NRAS and c-KIT in 230 pathological samples of patients who were intended to be treated with systemic therapy due to metastatic disease at the Institute of Oncology Ljubljana between 2013 and 2016. We collected also histological characteristics of primary tumours and clinical data of patients and correlated them with mutational status of tumour samples. Results The study population consisted of 230 patients with a mean age 59 years (range 25−85). 141 (61.3%) were males and 89 (38.7%) females. BRAF mutations were identified in 129 (56.1%), NRAS in 31 (13.5%) and c-KIT in 3 (1.3%) tissue samples. Among the 129 patients with BRAF mutations, 114 (88.4%) patients had V600E mutation and 15 (11.6%) had V600K mutation. Patients with BRAF mutations tended to be younger at diagnosis (52 vs. 59 years, p < 0.05), patients with NRAS mutations older (61 vs. 55 years, p < 0.05). Number of c-KIT mutations were too low for any statistical correlation, but there was one out of 3 melanoma located in mucus membranes. Conclusions The analysis detected high rate of BRAF mutations, low NRAS mutations and low c-KIT mutations compared to previously published studies in Europe and North America. One of the main reasons for this observation is specific characteristics of study population.
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Yeo, Joshua Yi, Darius Wen-Shuo Koh, Ping Yap, Ghin-Ray Goh, and Samuel Ken-En Gan. "Spontaneous Mutations in HIV-1 Gag, Protease, RT p66 in the First Replication Cycle and How They Appear: Insights from an In Vitro Assay on Mutation Rates and Types." International Journal of Molecular Sciences 22, no. 1 (December 31, 2020): 370. http://dx.doi.org/10.3390/ijms22010370.
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While drug resistant mutations in HIV-1 are largely credited to its error prone HIV-1 RT, the time point in the infection cycle that these mutations can arise and if they appear spontaneously without selection pressures both remained enigmatic. Many HIV-1 RT mutational in vitro studies utilized reporter genes (LacZ) as a template to investigate these questions, thereby not accounting for the possible contribution of viral codon usage. To address this gap, we investigated HIV-1 RT mutation rates and biases on its own Gag, protease, and RT p66 genes in an in vitro selection pressure free system. We found rare clinical mutations with a general avoidance of crucial functional sites in the background mutations rates for Gag, protease, and RT p66 at 4.71 × 10−5, 6.03 × 10−5, and 7.09 × 10−5 mutations/bp, respectively. Gag and p66 genes showed a large number of ‘A to G’ mutations. Comparisons with silently mutated p66 sequences showed an increase in mutation rates (1.88 × 10−4 mutations/bp) and that ‘A to G’ mutations occurred in regions reminiscent of ADAR neighbor sequence preferences. Mutational free energies of the ‘A to G’ mutations revealed an avoidance of destabilizing effects, with the natural p66 gene codon usage providing barriers to disruptive amino acid changes. Our study demonstrates the importance of studying mutation emergence in HIV genes in a RT-PCR in vitro selection pressure free system to understand how fast drug resistance can emerge, providing transferable applications to how new viral diseases and drug resistances can emerge.
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Borowczyk, Martyna, Ewelina Szczepanek-Parulska, Szymon Dębicki, Bartłomiej Budny, Małgorzata Janicka-Jedyńska, Lidia Gil, Frederik A. Verburg, et al. "High incidence of FLT3 mutations in follicular thyroid cancer: potential therapeutic target in patients with advanced disease stage." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592090753. http://dx.doi.org/10.1177/1758835920907534.
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Background: Conventional treatments for follicular thyroid cancer (FTC) can be ineffective, leading to poor prognosis. The aim of this study was to identify mutations associated with FTC that would serve as novel molecular markers of the disease and its outcome and could potentially identify new therapeutic targets. Methods: FLT3 mutations were first detected in a 29-year-old White female diagnosed with metastasized, treatment-refractory FTC. Analyses of FLT3 mutational status through next-generation sequencing of formalin-fixed, paraffin-embedded FTC specimens were subsequently performed in 35 randomly selected patients diagnosed with FTC. Results: FLT3 mutations were found in 69% of patients. FLT3 mutation-positive patients were significantly older than those that were FLT3 mutation-negative [median age at diagnosis 54 (36–82) versus 45 (27–58) ( p = 0.023)]. Patients over 60 years were 23 times more likely to be FLT3 mutation-positive ( p = 0.006). However, the number of FLT3 mutations did not correlate with age ( r-Pearson: –0.244, p-value: 0.25). A total of 26 mutations were identified in the FLT3 gene with 2–16 FLT3 mutations in each FLT3 mutation-positive patient (mean: 5.6 mutations/patient). Tyrosine kinase domain (TKD) mutations in the FLT3 gene were detected in 58% of FLT3 mutation-positive patients. All FLT3 mutation-positive patients with a disease stage of pT2N1 or worse harbored at least one mutation in the TKD of FLT3. Conclusions: There is a wide spectrum and high frequency of FLT3 mutations in FTC. The precise role of FLT3 mutations in the genesis of FTC, as well as its potential role as a therapeutic target, requires further investigation.
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Thomas, Renjan, Gautam Balaram, Hrishi Varayathu, Suhas N. Ghorpade, Prarthana V. Kowsik, Baby Dharman, Beulah Elsa Thomas, et al. "Molecular epidemiology and clinical characteristics of epidermal growth factor receptor mutations in NSCLC: A single-center experience from India." Journal of Cancer Research and Therapeutics 19, no. 5 (2023): 1398–406. http://dx.doi.org/10.4103/jcrt.jcrt_1986_21.
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ABSTRACT Background: The genetic profiling of non-small cell lung cancer (NSCLC) has contributed to the discovery of actionable targetable mutations, which have significantly improved outcomes in disease with poor prognosis. Molecular epidemiological data of driver mutations in Indian populations have not been extensively elaborated compared to western and eastern Asian NSCLC populations. This study assessed the prevalence and clinical outcomes of EGFR (epidermal growth factor receptor) mutations among the Indian NSCLC cohort in South India. Patients and Methods: Retrospective analysis of 2,003 NSCLC patients who had undergone EGFR mutational analysis from 2013 to 2020 was performed. Clinical analysis was performed for 141 patients from 2013 to 2017 using Kaplan–Meier and Chi-square methods. Descriptive and survival statistics were performed using IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. Results: EGFR-sensitizing mutations were detected in 41.6% (834/2003) in the study cohort with compound mutations detected in 7.55% (63/834) of EGFR-positive cases. A significant relationship with regard to female gender and EGFR mutation status (P <.001) was observed. Exon 18 G719X (8.7%) mutations and exon 20 T790M point mutation (3.1%) were the most frequently isolated uncommon EGFR mutations. In the clinical cohort, EGFR mutations were detected at a significantly higher prevalence in females (P =0.002) and never-smokers (P < 0.001). EGFR mutation demonstrated a significant relationship with regard to brain metastasis (P = 0.011). EGFR mutated individuals had significantly longer median overall survival compared to EGFR wild type (26 months vs. 12 months, P = 0.044). Conclusion: We reports the highest number of EGFR mutation analysis performed from India and mutational analysis indicated a loco-regional variation in India with regard to EGFR mutation frequency and its subtypes.
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Keightley, Peter D., Esther K. Davies, Andrew D. Peters, and Ruth G. Shaw. "Properties of Ethylmethane Sulfonate-Induced Mutations Affecting Life-History Traits in Caenorhabditis elegans and Inferences About Bivariate Distributions of Mutation Effects." Genetics 156, no. 1 (September 1, 2000): 143–54. http://dx.doi.org/10.1093/genetics/156.1.143.
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Abstract The homozygous effects of ethylmethane sulfonate (EMS)-induced mutations in Caenorhabditis elegans are compared across life-history traits. Mutagenesis has a greater effect on early than late reproductive output, since EMS-induced mutations tend to cause delayed reproduction. Mutagenesis changes the mean and variance of longevity much less than reproductive output traits. Mutations that increase total or early productivity are not detected, but the net effect of mutations is to increase and decrease late productivity to approximately equal extents. Although most mutations decrease longevity, a mutant line with increased longevity was found. A flattening of mortality curves with age is noted, particularly in EMS lines. We infer that less than one-tenth of mutations that have fitness effects in natural conditions are detected in the laboratory, and such mutations have moderately large effects (~20% of the mean). Mutational correlations for life-history traits are strong and positive. Correlations between early or late productivity and longevity are of similar magnitude. We develop a maximum-likelihood procedure to infer bivariate distributions of mutation effects. We show that strong mutation-induced genetic correlations do not necessarily imply strong directional correlations between mutational effects, since correlation is also generated by lines carrying different numbers of mutations.
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Maxwell, Kara Noelle, Daniel De Sloover, Lyndsey Emery, Bradley Wubbenhorst, Kurt P. D'Andrea, Jessica Long, Rebecca Mueller, et al. "The mutational spectrum of breast and ovarian tumors from BRCA1 and BRCA2 mutation carriers." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1510. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1510.
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1510 Background: Individuals who carry one mutated copy of the BRCA1 or BRCA2 genes have elevated lifetime risks of breast and ovarian cancer. A number of studies have investigated the somatic mutational spectra of breast and ovarian tumors; however, BRCA1/2mutated tumors are underrepresented. Methods: Sixty-eight formalin-fixed paraffin embedded samples from BRCA1/2patients have been identified. Massively parallel sequencing using 48 gene capture is in process, whole exome sequencing of tumor and matched germline DNA is planned. Data are analyzed using a custom bioinformatics pipeline. Results: In analysis of data from the first 26 breast (4 BRCA1, 6 BRCA2) and ovarian (8 BRCA1, 8 BRCA2) tumors, the majority (23/26, 88%) had 0-2 variants in 48 cancer genes. Known deleterious TP53 mutations were the only variants identified in 2/4 BRCA1 and 2/6 BRCA2 breast tumors. Of those remaining, 2 BRCA1 and 1 BRCA2 breast tumors had no identified deleterious mutations. Two BRCA2 breast tumors with no TP53 mutations had known deleterious mutations in a single gene each - FGFR2 and PI3KCA. One BRCA2 breast tumor with no TP53 mutation had a variant of uncertain significance in FLT3. Finally, one BRCA2 breast tumor had a very high mutational rate, with one deleterious TP53 mutation and 7 other small deletion and single nucleotide variants. For the ovarian tumors, 15/16 BRCA1 and BRCA2 tumors had known deleterious TP53 mutations; the ovarian tumor with no TP53 mutation had no other variants. TP53 mutations were the sole identified mutations in 8 ovarian tumors. One ovarian tumor carried a known JAK3 activating mutation and 4 ovarian tumors carried one variant of uncertain significance in a single gene - SMO, PDGFRA, GNA11 and NRAS. Finally, two ovarian tumors were found to have high mutational rates. Conclusions: Using a targeted resequencing panel, we confirmed the high rate of TP53 mutations in BRCA1/2 breast tumors and observed a higher than expected rate in BRCA1/2 ovarian tumors. Importantly, we have identified mutations in other known driver genes using FFPE samples, allowing generalizability to other sites. These analyses may uncover novel mutations that could be exploited in the development of targeted therapeutic agents for BRCA1/2 carriers.
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Delaugerre, Constance, Mireille Mouroux, Anne Yvon-Groussin, Anne Simon, Francis Angleraud, Jean-Marie Huraux, Henri Agut, Christine Katlama, and Vincent Calvez. "Prevalence and Conditions of Selection of E44D/A and V118I Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutations in Clinical Practice." Antimicrobial Agents and Chemotherapy 45, no. 3 (March 1, 2001): 946–48. http://dx.doi.org/10.1128/aac.45.3.946-948.2001.
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ABSTRACT Recently, it has been shown that a new mutational pattern (the E44D/A and/or V118I mutation) confers moderate phenotypic lamivudine resistance in the absence of the M184V mutation. The E44D/A and/or the V118I mutation does not exist in drug-naive patients, and the prevalence increases with the number of treatment regimens and lamivudine experience. The mutations can preexist in nucleoside-experienced but lamivudine-naive patients. They are always associated with zidovudine resistance-associated mutations, even in the absence of M184V. These mutations are more stable than the M184V substitution during antiretroviral treatment interruptions.
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Gu, Jin, Jianfei Yao, Lele Song, Dandan Huang, Zhaoya Gao, Qingkun Gao, Pengfei Niu, et al. "The mutational landscape of the adjacent paracancerous tissues confirmed the safe margin of 2-5cm in colorectal cancer resection." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16060-e16060. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16060.
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e16060 Background: Margin of 2-5cm is regarded as the safe margin in surgical resection of colorectal cancer (CRC) by macroscopic pathological examinations. However, whether 2-5cm is safe has never been verified by molecular evidence. Methods: We systematically analyzed the mutational profile of 35 CRC tissues and paired adjacent paracancerous tissues 2-3cm and 5cm adjacent to the cancer margin by whole-exome sequencing. Results: The number of SNV/INDEL mutations in the adjacent 2-3cm and 5cm tissues was much less than that in cancer. The number of common SNV/INDEL mutations between cancer and the adjacent tissues ranged from 0 to 2. Although TP53, APC and KRAS SNV/INDEL mutations exhibited the highest frequency in CRC, the APC SNV/INDEL mutations were observed in only one adjacent 5cm tissue, and no TP53 or KRAS SNV/INDEL mutations were observed in any adjacent tissues. We further determined the potential driver gene mutations in adjacent tissues by searching databases including COSMIC CGC, IntOGen, OncoKB, TCGA and Vogelstein databases. A certain mutation was determined as a driver gene mutation if all five databases predict it to be a driver gene mutation. As a result, 9 SNV/INDEL driver gene mutations (1 ATM, 1 BRCA1, 1 BRCA2, 1 MET, 1 NF1, 3 PTEN and 1 STAG2 mutations) were found in the adjacent 2-3cm group, and 9 SNV/INDEL driver gene mutations (1 APC, 1 ARID1A, 1 FBXW7, 3 PTEN, 2 STAG2 and 1 BRCA2 mutations) were found in the adjacent 5cm group. No common SNV/INDEL driver gene mutations were found between cancer tissues and the paired 2-3cm or 5cm tissues, suggesting the driver gene mutations predicted in adjacent normal tissues may not be cancer-relevant. Conclusions: We established the mutational landscape of the adjacent 2-3cm and 5cm tissues to CRC, and found almost no key driver gene SNV/INDEL mutations in adjacent tissues. No common SNV/INDEL driver gene mutations were found between cancer and the adjacent tissues, supporting a safe resection with a margin at 2 to 5cm.
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Lee, Peak-Ling, Benedict Yan, Chin-Hin Ng, Kenneth Hon-Kim Ban, Wee-Joo Chng, and Evelyn Siew-Chuan Koay. "Characterization of AML Patients with CEBPA Mutations in a South-East Asian Population." Blood 126, no. 23 (December 3, 2015): 2574. http://dx.doi.org/10.1182/blood.v126.23.2574.2574.
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Abstract Introduction: CCAAT/enhancer-binding protein alpha (CEBPA) is a known transcription factor that regulates the balance of differentiation and proliferation of myeloid progenitors. The nature of CEBPA mutations and their prognostic impact in acute myeloid leukemia (AML) have been extensively studied in the Western population, but have not been as well studied in other ethnic populations. There is some evidence that the AML mutational spectrum differs among ethnic groups (Yin et al, Leukemia Research, 2015). This study aims to characterize the AML patients with CEBPA mutations in a South-East Asian population comprising mainly Chinese, Indian and Malay ethnic groups. Methods: Sanger-based sequencing was used to detect the CEBPA mutations. DNA was isolated from bone marrow aspirate or peripheral blood. PCR amplification-direct sequencing with overlapping primers targeting the CEBPA intronless gene was carried out using an in-house validated protocol. The PCR products were purified and bi-directionally sequenced, and the sequences compared to the reference sequence for the CEBPA gene. Clinical data including patients' ethnicity were extracted. Results: Between January 2011 to April 2015, CEBPA mutational analysis was performed on 210 cases at the Molecular Diagnosis Centre (MDC) laboratory, Singapore. The patients were of mixed ethnicity, with 113 (54%) Chinese, 25 (12%) Malay, 4 (2%) Indian and 68 Others (Figure 1). When referenced to the COSMIC database, a total of 32 novel mutations were found: 27 in- or out-of-frame deletions/insertions and 5 with single base mutation. Mutations were detected in 35/210 (17%) cases, with a higher frequency of double-mutation cases (26/35; 74%) compared to single-mutation cases (9/35; 26%). In our CEBPA mutation-positive cohort, 24/26 (92%) of those with double mutations had wildtype FLT-3 and NPM1; in contrast to only 4/9 (56%) of those with single mutation having wildtype FLT-3 and NPM1 (p=0.002). 3/3 (100%), 11/13 (84.6%), 12/18 (66.7%) and 0/1 (0%) of Malay, Other ethnicities, Chinese and Indian CEBPA mutation-positive AML respectively, had double mutations (p=0.16) (Figure 1). With regards to prognostic impact, our data suggest that patients with double CEBPA mutations are highly likely (11/12; 92%) to have complete remission. Conclusions: Our observed CEBPA mutation-positive frequency of 17% is consistent with those (7 to 20%) reported elsewhere in other regions. In our study cohort, the majority (92%, p=0.002) of those with CEBPA double mutations had wildtype FLT-3 and NPM1, which is also consistent with findings reported elsewhere. Our clinical data show that only one of twelve patients (8%) with double CEBPA mutations relapsed, while the remaining eleven (92%) achieved complete remission, thus suggesting that favorable prognostic impact of double CEBPA mutations in AML patients is evident. Further research is needed to understand the frequency and prognostic implications of CEBPA mutations across the different ethnic groups. Figure 1. CEBPA mutational status across ethnic groups in a South-East Asian population (n=210) Figure 1. CEBPA mutational status across ethnic groups in a South-East Asian population (n=210) Disclosures No relevant conflicts of interest to declare.
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Serapinas, Danielius, Marius Sukys, Agne Bartkeviciute, Diana Barkauskiene, and Daiva Bartkeviciene. "The spectrum of the most common BRCA1/BRCA2 mutations in Lithuanian high risk families." Genetika 49, no. 1 (2017): 43–50. http://dx.doi.org/10.2298/gensr1701043s.
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Breast cancer is the neoplasm with the highest incidence and mortality among women in Lithuania. The aim of the study was to determine the mutational incidence in BRCA1 and BRCA2 genes in high-risk breast and/or ovarian cancer families. After written informed consent, 36 participants from Lithuanian health science university hospital provided a blood sample for genetic analysis. Molecular diagnostics was done for 6 BRCA1and BRCA2 mutations. From 36 tested subjects for BRCA1/BRCA2 mutations. Positive test for BRCA1/BRCA2 mutations test was found in 12 (33%) cases. Most common BRCA1 mutation was 5328insC - 6 (50%) cases, other mutations: 185delAG - 1 (8,3%), 300t>6(c61G) - 4 (33,3%), 4153 del A - 1 (8,3%). All mutations were BRCA1, but none of the women were positive for the analyzed BRCA2 mutation. The mean age when the cancer was diagnosed in BRCA1 mutations group was 40.40?3.39 comparing with the group without mutations - 43.29 ?2.52. Rates of BRCA1 and BRCA2 mutation testing are increasing in young women with breast and ovarian cancer. Detected mutations in BRCA1 contribute to up to one-third of the families with breast and ovarian cancer in Lithuania.
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Zeineddine, Fadl, Benjamin Garmezy, Timothy A. Yap, and John Paul Y. C. Shen. "PMC: A more precise classifier of POLE mutations to identify candidates for immune therapy." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3548. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3548.
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3548 Background: Specific somatic mutations in DNA polymerase epsilon ( POLE) can cause a hypermutant phenotype with tumor mutation burden (TMB) in excess of 100 mutations per megabase. It has been reported that POLE mutant tumors are enriched in response to immune therapy and this association is being tested in multiple active clinical trials. However, most POLE mutations are passenger mutations and have no pathogenic role. Current methods to classify POLE mutations are limited in both accuracy and completeness, which could lead to inappropriate use of immune agents in tumor such as MSS CRC, where response rate is 5% or less. Here we present a new classifier, POLE Mutation Classifier or PMC, based on the unique trinucleotide mutation signature caused by selective loss of the proofreading function (LOP) of POLE. Methods: cBioPortal was queried to identify all tumors with POLE mutation. TMB was calculated for each, additionally, trinucleotide mutation signatures were obtained for all POLE mutant tumors in TCGA. Using OncoKB to identify a gold standard of 12 functional POLE mutations (n = 98 tumors) a POLE mutational signature was created. A combination of mutational signature, amino acid location, and TMB was used to classify each POLE variant. Results: Among all 48035 unique tumors the overall frequency of POLE mutations was 2.5% (n = 1184), however only 9.2% (n = 110) were determined to cause the selective LOP. The incidence of LOP POLE mutation was highest in uterine carcinoma and CRC, these tumors also had the highest ratio of LOP to passenger mutations. In a pan-cancer analysis the overall survival of LOP POLE patients was significantly better than those with passenger mutations (not-yet-reached vs. 51 mo, HR = 4.4, p < 0.0001). A similar analysis performed using the polyphen-2 classifier to identify functional POLE mutations did not show a difference in overall survival (HR = 1.0, p-value = 0.57). To further validate the improved specificity of the PMC classifier TMB was used as a surrogate marker, using the PMC classifier 98% of tumors with LOP showed hypermutation (TMB > 20mut/Mb), vs. 53% called functional by polyphen-2. A retrospective analysis of MD Anderson CRC patients identified 25 patients with LOP POLE mutation, who had improved OS relative to 267 CRC patients with passenger POLE mutation (not-yet-reached vs. 70 mo, HR:4.2, p = 0.028). Four metastatic CRC patients with LOP POLE mutation were treated with immune therapy (nivolumab, or ipilimumab/nivolumab) in 2nd or 3rd line, all four achieved objective response and remain on therapy (mean time on treatment 15 mo). Conclusions: The PMC classifier specifically identifies mutations in POLE that cause loss of the proofreading function, outperforming both manually curated databases and machine learning-based methods. Clinical trials that use POLE mutation as a selection criteria for immune therapy should be restricted to just those POLE mutations that cause LOP.
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Trindade, Sandra, Lilia Perfeito, and Isabel Gordo. "Rate and effects of spontaneous mutations that affect fitness in mutator Escherichia coli." Philosophical Transactions of the Royal Society B: Biological Sciences 365, no. 1544 (April 27, 2010): 1177–86. http://dx.doi.org/10.1098/rstb.2009.0287.
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Knowledge of the mutational parameters that affect the evolution of organisms is of key importance in understanding the evolution of several characteristics of many natural populations, including recombination and mutation rates. In this study, we estimated the rate and mean effect of spontaneous mutations that affect fitness in a mutator strain of Escherichia coli and review some of the estimation methods associated with mutation accumulation (MA) experiments. We performed an MA experiment where we followed the evolution of 50 independent mutator lines that were subjected to repeated bottlenecks of a single individual for approximately 1150 generations. From the decline in mean fitness and the increase in variance between lines, we estimated a minimum mutation rate to deleterious mutations of 0.005 (±0.001 with 95% confidence) and a maximum mean fitness effect per deleterious mutation of 0.03 (±0.01 with 95% confidence). We also show that any beneficial mutations that occur during the MA experiment have a small effect on the estimate of the rate and effect of deleterious mutations, unless their rate is extremely large. Extrapolating our results to the wild-type mutation rate, we find that our estimate of the mutational effects is slightly larger and the inferred deleterious mutation rate slightly lower than previous estimates obtained for non-mutator E. coli .
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Olafsson, S., R. E. McIntyre, T. Coorens, T. Butler, P. Robinson, H. Lee-Six, M. Sanders, et al. "DOP50 The landscape of somatic mutations in non-neoplastic IBD-affected colon." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S088—S089. http://dx.doi.org/10.1093/ecco-jcc/jjz203.089.
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Abstract Background Under normal physiological conditions, colonic crypts accrue ~40 somatic mutations for every year of life. That somatic mutations contribute to the development of cancer is well established, but their patterns, burden and functional consequences in diseases other than cancer have not been extensively studied and our understanding of the effects of chronic inflammation on the mutational profile and clonal structure of the colon is limited. Here, we investigated how the recurrent cycles of inflammation, ulceration and regeneration seen in IBD impact the mutational and clonal structure of intestinal epithelia. Methods We isolated and whole-genome sequenced ~400 individual colonic crypts from 46 IBD patients and compared these to ~400 crypts from 41 non-IBD controls. We compared the mutation burden, mutational signature exposure, clonal structure and cancer driver mutation landscape in crypts from actively and previously inflamed regions with crypts dissected from controls. Results We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon (Figure 1), and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimetre-scale clonal expansions, even in the absence of mutations in KRAS, TP53 and APC (Figure 2). We discovered that mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients (Figure 3). With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. A previously published mouse model of ZC3H12A suggests that LoF mutations in this gene may facilitate healing of affected mucosa without promoting tumorigenesis. This could make the encoded protein an attractive drug target. The observed enrichment of mutations in PIGR and IL17 and TLR pathways suggests that somatic mutations may initiate, maintain or perpetuate IBD pathogenesis through disruption of microbe-epithelial homeostasis. Conclusion Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia. We identify the mutagens driving the increase in mutation burden and mutations which are under positive selection in the context of inflammation. Our results suggest that studying somatic mutations in the colon can reveal putative drug targets and pathogenic mechanisms for IBD.
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Dong, Chao, Hushan Zhang, Weiqing Liu, Deyu Kong, Xiao Chen, Fei Mo, Jun Deng, and Ying Qian. "Postoperative prognosis in patients with NSCLC with different EGFR mutation sites." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e20528-e20528. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e20528.
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e20528 Background: Lung cancer can be divided into small cell lung cancer and non-small cell lung cancer. At the same time, non-small cell lung cancer can be divided into non-small cell lung cancer with different molecular mutations. Among them, the EGFR mutation accounts for about 50% of the patients with non-small cell lung cancer in China, which is a large group of patients. The EGFR mutation has many sites and many forms of mutational subtypes, including common mutations such as L858R, and rare mutations. Although the proportion of rare mutations is small, it is still different from common mutations in patients with TKI treatment and immunity. Methods: This study collected and analyzed the data from Formalin-Fixed Paraffin-Embedded (FFPE) tissues of 330 NSCLC patients which received surgery and underwent a targeted next-generation sequencing (NGS) assay performed by 3DMed Clinical Laboratory Inc., a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory of 3D Medicines Inc. between January, 2019 and June, 2022 in China, to obtain a comprehensive molecular profile of EGFR mutations. genomic alterations, tumor mutational burden (TMB) and PD-L1 expression were analyzed. Gene mutation and TMB level were analyzed by NGS, detected PD-L1 expression by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. Finally, the postoperative follow-up data were also collected and analyzed in this study. Results: Therefore, we retrospectively analyzed the tissue samples of patients with non-small cell lung cancer who received surgical treatment, and carried out NGS detection and analysis, as well as postoperative follow-up. Among them, patients with EGFR mutations accounted for 51.2%. We further analyzed the TMB and PD-L1 expression levels of different EGFR mutation subtypes. First, we found that different EGFR mutation sites, whether common mutations such as L859R, 19del or unusual mutations such as S768I, There is no difference in the prognosis after operation, but it is very significant that our results show that there are two or more EGFR mutations at the same time. Conclusions: NSCLC with EGFR mutation is a very large group of patients, which should be further subdivided into different subtypes according to different EGFR mutation sites, and should perform individualized management. This study found that patients with two or more EGFR mutations and patients with EGFR single site mutations are different types of NSCLC, with different postoperative prognosis, and it may be related to the differences in the expression levels of TMB and PD-L1, which is a direction worthy of further exploration in the future.
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Hu, Zishuo Ian, Anna M. Varghese, Jinru Shia, Alice Zervoudakis, Maeve Aine Lowery, Kenneth H. Yu, Sree Bhavani Chalasani, et al. "Clinical characterization of pancreatic ductal adenocarcinomas (PDAC) with mismatch repair (MMR) gene mutations." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15791-e15791. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15791.
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e15791 Background: Tumors with mismatch repair-deficiency (MMRD) have a high mutational burden and have good responses to immunotherapy (Le, NEJM, 2015). We describe the natural course, clinicopathological, and genomic status of MMRD PDAC patients (pts) at Memorial Sloan Kettering Cancer Center (MSKCC). Methods: MSKCC institutional registry and ICD billing database queried from 2006-2016 for PDAC pts with genetically confirmed mutations in mismatch repair (MMR) genes. Mutation # determined via MSK-IMPACT, a targeted tumor next generation sequencing (NGS) test (Cheng, J Mol Diagn, 2015). Results: 5/607 (0.8%) PDAC pts had Lynch syndrome (LS) (confirmed germline mutations) (Table 1). Of the 5 LS pts, all had > 10 mutations in NGS, with 4 of 5 having > 50 mutations. 4 of 5 (80%) are alive at last follow-up (survival 30-314 months). N=4 had extensive personal/family history of cancer. Of N=3 who had resected disease, all 3 had recurrence at 11, 49 and 311 months, and all are alive (survival: 69-314 months). Of N= 2 pts that had unresectable tumors, one passed away at 30 months while the other is on checkpoint inhibitor trial and is alive at 30 months. In contrast, 7/607 (1.1%) PDAC pts had somatic mutations in MMR genes with an average of 5.7 mutations in NGS, with 4/7 having <5 mutations. 4/7 (57%) are deceased at last follow-up (survival: 10-42 months). Conclusions: All cases with germline mutations in the MMR genes, with one exception, had high mutation #. All cases with somatic mutations in the MMR genes had low mutation #. Germline mutations in MMR genes and high mutational burden may predict for a prognostically favorable subgroup of PDAC pts with high susceptibility to immune oncology agents. [Table: see text]
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Kim, Youn Jung, Hong Zhang, Yejin Lee, Figen Seymen, Mine Koruyucu, Yelda Kasimoglu, James P. Simmer, Jan C. C. Hu, and Jung-Wook Kim. "Novel WDR72 Mutations Causing Hypomaturation Amelogenesis Imperfecta." Journal of Personalized Medicine 13, no. 2 (February 14, 2023): 326. http://dx.doi.org/10.3390/jpm13020326.
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Amelogenesis imperfecta (AI) is a heterogeneous collection of hereditary enamel defects. The affected enamel can be classified as hypoplastic, hypomaturation, or hypocalcified in form. A better understanding of normal amelogenesis and improvements in our ability to diagnose AI through genetic testing can be realized through more complete knowledge of the genes and disease-causing variants that cause AI. In this study, mutational analysis was performed with whole exome sequencing (WES) to identify genetic etiology underlying the hypomaturation AI condition in affected families. Mutational analyses identified biallelic WDR72 mutations in four hypomaturation AI families. Novel mutations include a homozygous deletion and insertion mutation (NM_182758.4: c.2680_2699delinsACTATAGTT, p.(Ser894Thrfs*15)), compound heterozygous mutations (paternal c.2332dupA, p.(Met778Asnfs*4)) and (maternal c.1287_1289del, p.(Ile430del)) and a homozygous 3694 bp deletion that includes exon 14 (NG_017034.2:g.96472_100165del). A homozygous recurrent mutation variant (c.1467_1468delAT, p.(Val491Aspfs*8)) was also identified. Current ideas on WDR72 structure and function are discussed. These cases expand the mutational spectrum of WDR72 mutations causing hypomaturation AI and improve the possibility of genetic testing to accurately diagnose AI caused by WDR72 defects.
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Wille, Sandra, Vera Grossmann, Tamara Alpermann, Claudia Haferlach, Wolfgang Kern, Susanne Schnittger, Torsten Haferlach, and Alexander Kohlmann. "Landscape of TET2 Mutations In Acute Myeloid Leukemia (AML): A Next-Generation Sequencing Study Investigating 76 Cases Comprehensively Characterized for Cytogenetics and Other Molecular Markers." Blood 116, no. 21 (November 19, 2010): 1035. http://dx.doi.org/10.1182/blood.v116.21.1035.1035.
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Abstract Abstract 1035 Mutations of the ten eleven translocation (TET2) gene have been reported to be frequent in hematological malignancies. However, data are preliminary and investigation is challenging and labor-intensive with standard sequencing techniques. Here, we used massively parallel Titanium amplicon next-generation sequencing (NGS) technology (454 Life Sciences, Branford, CT) and investigated 76 patients with acute myeloid leukemia (AML), including 66 de novo AML, 6 s-AML and 4 t-AML cases, respectively, diagnosed between 8/2005 and 5/2010. The median age of the cohort was 64.7 years. According to cytogenetically defined MRC criteria (Grimwade et al., Blood 2010) 63 patients of our cohort were assigned to the intermediate prognostic risk group and 13 to the poor risk group. Patients of the favorable prognostic risk group or those with “recurrent genetic abnormalities” according to WHO classification were excluded. In detail, 61 patients had a normal karyotype, 4 had other chromosomal aberrations and 11 had a complex aberrant karyotype. All coding exons of TET2, represented by 27 distinct PCR amplicons, were examined. For each amplicon a median of 643 reads was generated, thereby allowing a sensitive detection of variants, i.e. at a cut-off value of 10% 64 bidirectional reads were generated. In total, we observed 56 variances by this molecular mutation screening. After excluding 13 different polymorphisms and 1 silent mutation, 42 distinct mutations were detected in 26/76 (34%) patients. We identified 23 point mutations (14 missense and 9 nonsense; 55%) and 18 frameshift mutations (12 deletions, 5 duplications and 1 insertion; 43%). In 1/76 (2%) patients a splice site mutation was identified. The frameshift mutations ranged from 1 bp to 8 bp for deletions and 1 bp to 52 bp for duplications/insertions. The observed TET2 mutations were found to be heterogeneous and were spread over several exons. However, exons 3 and 11 could be identified as mutational hotspot regions, where 30/42 (71%) of the mutations were located. In exons 4, 5 and 9 only one mutation each was observed, respectively. No mutation was detected in exon 8. In detail, 25/42 (60%) mutations were located outside of the two conserved regions as described by Delhommeau et al. (N Engl J Med 2009), whereas 13 mutations (31%) were observed within the first conserved region spanning from codons 1134 to 1444 and 4 mutations (9%) were found within the second conserved region covering codons 1842 to 1921, respectively. 11/13 of the variances in the conserved regions were nonsense or frameshift mutations. Of the observed 42 mutations, only 8 had previously been described in the literature. The other 36 mutations represented here are novel. Generally, our results extend data known from the literature, i.e., the frequency of 34% of TET2 mutations in our AML cohort is higher than in previous publications, reporting a frequency between 12% and 20%. Concerning the mutational burden, the median range of the identified mutations was 44% of sequence reads carrying the mutation. Mutation load <20% was only observed in 2 cases (10% and 11%, respectively) and therefore would be below the detection level of Sanger sequencing. None of the detected TET2 mutations had a mutational burden of <10%. 15/26 (58%) patients carried more than one mutation and a mean of 1.6 mutations per patient was observed. In 2 patients two mutations within the same amplicon were detected and NGS was able to delineate subclones, i.e. in both cases approximately half of the reads carried either one mutation and only 1.7% and 2.3% of reads, respectively, harbored both mutations concomitantly. We further characterized this cohort according to mutations in NPM1 (n=73 cases investigated), FLT3-ITD (n=74), FLT3-TKD (n=64), CBL (n=76), and IDH1 (n=49). TET2 mutations were concomitantly observed with mutations in other molecular markers such as NPM1, FLT3-ITD, FLT3-TKD or CBL. Surprisingly, we found that TET2 mutations significantly excluded mutations in IDH1 (p=0.004). With respect to clinical data no difference in overall survival was monitored for AML patients that carried TET2 mutations (TET2-mutated 347 days vs. TET2 wild-type 294 days, n.s.). In conclusion, TET2 is a frequently mutated gene in AML. Due to the increasing complexity of observed molecular aberrations future studies will be essential to clarify the clinical relevance of TET2 mutations in AML and its prognostic and therapeutic role. Disclosures: Wille: MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment.
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Song, Hao, Yao Huang, and Xiaoqing Jiang. "Mutation spectrum associated with metastasis of advanced cholangiocarcinoma." Journal of International Medical Research 50, no. 6 (June 2022): 030006052211020. http://dx.doi.org/10.1177/03000605221102080.
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Background The mutations associated with metastasis in advanced-stage cholangiocarcinoma (CCA) have not been investigated. Objective To explore mutations in patients with advanced CCA and independent factors related to metastasis. Methods This retrospective study performed next-generation sequencing of tumor specimens from patients with advanced CCA treated between January 2017 and December 2019. Tumor mutational burden (TMB), microsatellite instability, and programmed cell death ligand (PD-L)1 positivity were determined. Factors independently associated with metastasis were explored via logistic regression. Results Ninety-one patients were included in this study. TP53 mutation frequencies were significantly higher in extrahepatic than intrahepatic CCA, while ARID1A mutations were significantly more frequent in intrahepatic CCA. Mutation frequencies in six selected genes did not differ according to patient age or sex. SMAD4 mutations were significantly less frequent in stage IV cancer; ARID1A and PBRM1 mutation frequencies were significantly higher in TMB >10 tumors. PBRM1 mutation frequencies were significantly higher in PD-L1-positive tumors, but lower in patients with metastasis. Multivariable analysis showed that a history of biliary surgery, SMAD4 mutations, and PBRM1 mutations were independently associated with CCA metastasis. Conclusions A history of biliary surgery and mutations in SMAD4 and PBRM1 are independent protective factors for metastasis in patients with advanced CCA.
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Claes, Kathleen, Eva Machackova, Michel De Vos, Bruce Poppe, Anne De Paepe, and Ludwine Messiaen. "Mutation Analysis of the BRCA1 and BRCA2 Genes in the Belgian Patient Population and Identification of a Belgian Founder Mutation BRCA1 IVS5+3A>G." Disease Markers 15, no. 1-3 (1999): 69–73. http://dx.doi.org/10.1155/1999/241046.
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Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in “sporadic” patients with early onset disease. We completed the analysis in 49 families and in 19 “sporadic” female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5+3A>G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.
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Lin, Ming-En, Hsin-An Hou, Yuan-Yeh Kuo, Wen-Chien Chou, Ming Cheng Lee, Chien-Yuan Chen, Yan-Jun Lai, et al. "DNMT3A mutations in De Novo Myelodysplastic Syndrome: Distinct Clinico-Biological Features and Prognostic Relevance." Blood 120, no. 21 (November 16, 2012): 3799. http://dx.doi.org/10.1182/blood.v120.21.3799.3799.
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Abstract Abstract 3799 Background and Purpose Mutations of the DNMT3A gene, which encodes the enzyme DNA methyltransferase 3A, were identified in patients with myeloid malignancies and are associated with poor prognosis in primary AML patients. However, the clinical and prognostic implications of these mutations in myelodysplastic syndrome (MDS) remain to be determined. Methods and Materials A total of 328 de novo MDS patients diagnosed according to French-American-British (FAB) criteria at the National Taiwan University Hospital who had cryopreserved bone marrow cells for study were recruited into mutational analyses. Mutations in DNMT3A gene at exon 2–23 were analyzed by polymerase chain reaction and direct sequencing. The results were correlated with clinical features, cytogenetics, gene mutations and treatment outcomes. Results Among the 328 patients, 115 patients (35.0%) had refractory anemia (RA), 19 (5.8%) had RA with ring sideroblasts (RARS), 122 (37.2%) had RA with excess blasts (RAEB), 35 (10.7%) had RAEB in transformation (RAEBT), and 37 (11.3 %) had chronic myelomonocytic leukemia (CMMoL). DNMT3A mutations at 20 different positions were identified in 33 patients, including thirteen missense mutations, two nonsense mutations and five frame-shift mutations. Among these 33 patients, 31 had single mutation of DNMT3A, and the other 2 patients had double mutations. The most common mutation was R882H (n = 8), followed by R882C (n = 7), Y735C (n=2), and R720H (n=2). All other mutations were detected in only one patient each. Totally, DNMT3A mutations were identified in 33 (10.1%) of 328 patients diagnosed according to the FAB classification and in 25 (9.8%) of 256 diagnosed according to 2008 WHO classification. DNMT3A-mutated patients were older (median age, 74 years vs. 66 years, P=0.048) and had higher platelet counts at diagnosis than DNMT3A-wild patients (median, 123.5×103/μL vs. 73 ×103/μL, P=0.016). According to FAB classification, patients with RARS had the highest incidence (26.3%) of DNMT3A mutations, followed by RAEBT (14.3%), RAEB (11.5%), and CMMoL (8.1%), whereas those with RA had the lowest incidence (5.2%, P=0.035). Chromosome data were available in 308 patients (93.9%) at diagnosis and clonal chromosomal abnormalities were detected in 155 patients (50.3%). There was no difference in the distribution of 2008 WHO classification, karyotype and international prognostic scoring system (IPSS) between patients with and without DNMT3A mutations. To investigate the association of gene mutations in the pathogenesis of MDS, a mutational screening of 10 other genes was also performed. Among the 33 patients with DNMT3A mutations, 16 patients (48.5%) showed additional molecular abnormalities at diagnosis, including seven with concurrent IDH1/IDH2 mutations, seven ASXL1 mutations, five AML1/RUNX1 mutations, two MLL-PTD, two RAS mutations and one JAK2 mutation. Eight of these 16 patients (50%) had two other concurrent mutations, and the others had one additional mutation. It's clear that DNMT3A mutation was closely interacted with IDH mutation in MDS (IDH mutation occurring in 21.2% of DNMT3A-mutated patients vs. 3.4% in DNMT3A-wild ones, P=0.001). With a median follow-up of 57.6 months (range, 0.1–250.7 months), there was no significant difference in overall survival (OS) between patients with and without DNMT3A mutation by either FAB or 2008 WHO classifications (median, 22.5 months vs. 30.9 months, P=0.669 and 25.2 months vs. 34.9 months, P=0.538, respectively) as well as in the rate of acute transformation. However, among the subgroup of patients with RA by FAB classification or refractory cytopenia with unilineage dysplasia by 2008 WHO classification, DNMT3A-mutated patients had significantly shorter OS than DNMT3A-wild patients (median, 28.3 months vs. 39.8 months, P<0.001 and 23.8 months vs. 40.3 months, P=0.026, respectively). Further, DNMT3A mutation is an independent poor prognostic factor in these two subgroups. Conclusion Our findings provided evidence that DNMT3A mutations could be detected in a substantial portion of de novo MDS patients. DNMT3A mutations are associated with distinct clinical and biological features and poor prognosis in selected groups of patients. Disclosures: No relevant conflicts of interest to declare.
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Juriloff, D. M., S. D. Porter, and M. J. Harris. "Three spontaneous mutations at the albino locus in SELH/Bc mice." Genome 37, no. 2 (April 1, 1994): 190–97. http://dx.doi.org/10.1139/g94-026.
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The SELH/Bc inbred mouse stock has produced an unusually high number of spontaneous mutations, including sph2Bc, nuBc, a recessive lens opacity, and three mutations at the c locus. Classical genetic and molecular genetic studies were done to investigate the origin of the albino locus mutations. Southern blots probed with the mouse tyrosinase cDNA showed that two of the mutations, cBc and c2Bc, are deletions of exons 1, 2 and 3. The third mutation, c3Bc, showed a disruption, either a rearrangement or an insertion, in the region of exon 1. The deletion of the cBc mutation is anticipated to be large as the mutation has inactivated the Mod-2 locus 2 cM away, and an essential locus for postimplantation survival outside the c–Mod-2 interval, whereas the c2Bc mutation is viable and fertile in homozygotes. Homozygotes for c3Bc are also viable and fertile. We conclude that at least some of the molecular events leading to the three albino mutations were independent. The mutations differ from each other and from the classical albino point mutation. All three new mutations originated from parents who were germline mosaics, and the mutational events were therefore all postmeiotic. All three mosaics shared one common ancestor six generations previously, raising the possibility that an instability of the albino locus might have been inherited. SELH/Bc mice may provide an animal model for the study of mechanisms underlying genetic instability.Key words: mutation, tyrosinase, mosaicism, deletion.
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Swierczek, Sabina, Christine Bellanne-Chantelot, Donghoon Yoon, Cecile Saint-Martin, Soo Jin Kim, Albert Najman, and Josef T. Prchal. "TET2 Mutations in Polycythemia Vera (PV) in Some Cases Follow Rather Than Precede JAK2 V617F Mutation, Are Not a Disease-Initiating Event, Affect Mainly Erythropoiesis, and Contribute to Increased Aggressivity of PV Clone." Blood 114, no. 22 (November 20, 2009): 3913. http://dx.doi.org/10.1182/blood.v114.22.3913.3913.
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Abstract Abstract 3913 Poster Board III-849 The Ten-Eleven Translocation (TET) 2 gene is a tumor suppressor gene. Its mutations of which are frequently found in PV and other myeloid malignancies. The published evidence suggests that a TET2 mutational burden is present in a higher proportion than JAK2V617F in PV stem cells; its mutations typically precede the JAK2V617F mutation, and are preferentially expressed in myeloid cells. We studied 40 PV patients. Two had known TET2 mutation, one with an intronic mutation (3954+2T>A) predicted to cause aberrant splicing, and the other with a deletion of a single nucleotide in exon 3 (3138delT) leading to the predicted truncation of the TET2 peptide. We quantitated the mutational burden of JAK2V617F and TET2 and the clonality of blood lineages using X-chromosome allelic usage ratios in the blood cells and BFU-E colonies. We also followed the mutational burden of the JAK2V617F and TET2 somatic mutations and expression of TET2 mRNA and monitored the proportion of polyclonal cells, in in vitro expanded erythroid progenitors. These data were compared to the PV patients without known TET2 mutations. Using an X-chromosome-based transcriptional clonality assay, the PV patients had predominantly clonal reticulocytes, granulocytes, platelets and, in those available, CD34-positive cells. Studies of individual BFU-E found that in two PV patients, the TET2 mutations followed rather than preceded the JAK2V617F mutation. We report that only a fraction of clonal CD34+ cells carry the TET2 mutation, and demonstrate that a small proportion of largely polyclonal T cells also carry the TET2 mutation. We report that the presence of both JAK2V617 and TET2 mutations favors accumulation of the mutated erythroid progenitors, while in similar conditions the PV JAK2V617-positive and TET2-negative cells are at a proliferative disadvantage compared to normal erythroid progenitors. We also examined the clonality of these in vitro-expanded erythroid progenitors to determine if the dormant minor populations of nonclonal hematopoietic cells are preferentially expanded along with those belonging to the PV clone. We found that some PV erythroid progenitors with JAK2V617F but no known TET2 mutations became polyclonal after in vitro erythroid expansion, while two PV patients with JAK2V617F and TET2 mutations remained clonal, suggesting that the TET2 mutated clonal progenitors retained their proliferative advantage. Lastly, compared to normal erythroid progenitors wherein TET2 mRNA increases with erythroid maturation, it decreases in PV erythroid progenitors regardless of the presence of a TET2 mutation. As predicted, the intronic TET2 mutation causing aberrant splicing had decreased TET2 expression compared to controls and other PV samples in all cells examined. However, the TET2 mRNA transcript in peripheral blood granulocytes and platelets in JAK2V617F positive PV, regardless of TET2 mutations, was significantly increased compared with normal controls. We conclude that loss-of-function TET2 mutations in the two studied PV subjects are not the PV initiating events. Our data suggest that these TET2 mutations in PV preferentially affect the erythroid lineage, contribute to increased erythroid proliferation, and cause relative inhibition of PV granulopoiesis and megakaryopoiesis. However, in aggregate, these in vitro data also suggest that the acquisition of the TET2 somatic mutations increases the aggressivity of the PV clone. Disclosures: No relevant conflicts of interest to declare.
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Alohali, Sama, Alexandra E. Payne, Marc Pusztaszeri, Mohannad Rajab, Véronique-Isabelle Forest, Michael P. Hier, Michael Tamilia, and Richard J. Payne. "Effect of Having Concurrent Mutations on the Degree of Aggressiveness in Patients with Thyroid Cancer Positive for TERT Promoter Mutations." Cancers 15, no. 2 (January 8, 2023): 413. http://dx.doi.org/10.3390/cancers15020413.
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This study aimed to examine whether concurrent mutations with a TERT promoter mutation are associated with a greater likelihood of more aggressive disease than a TERT promoter mutation alone. The medical records of 1477 patients who underwent thyroid surgery at two tertiary hospitals between 2017 and 2022 were reviewed. Twenty-four patients had TERT promoter mutations based on molecular profile testing. Clinicodemographic data, mutational profiles, and histopathological features were assessed. Descriptive analysis, Fisher’s exact test, and binary logistic regression were performed. Seven patients had single-gene TERT promoter mutations, and 17 had concurrent mutations, including BRAF V600E, HRAS, NRAS, PIK3CA, and EIF1AX. The overall prevalence of malignancy was 95.8%, of which 78.3% were aggressive thyroid cancers. There was a statistically significant association between concurrent mutations and disease aggressiveness. The odds of having aggressive disease were 10 times higher in patients with a TERT promoter mutation and a concurrent molecular alteration than in those with a TERT promoter mutation alone. This is an important finding for thyroid specialists to consider when counseling patients concerning risk stratification and management options.
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Abdel-Wahab, Omar, Animesh Pardanani, Jay Patel, Terra Lasho, Adriana Heguy, Ross Levine, and Ayalew Tefferi. "Concomitant Analysis of EZH2 and ASXL1 Mutations In Myelofibrosis, Chronic Myelomonocytic Leukemia and Blast-Phase Myeloproliferative Neoplasms." Blood 116, no. 21 (November 19, 2010): 3070. http://dx.doi.org/10.1182/blood.v116.21.3070.3070.
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Abstract Abstract 3070 Background: EZH2 and ASXL1 mutations were recently described in a spectrum of myeloid malignancies; mutational analysis of small patient cohorts has suggested the highest mutational frequency in myelofibrosis (MF) and chronic myelomonocytic leukemia (CMML). The current study seeks to determine i) EZH2 and ASXL1 mutational frequencies in WHO-defined subcategories of MF, CMML and blast-phase myeloproliferative neoplasm (MPN), ii) if these mutations are mutually exclusive of TET2, IDH, JAK2 and MPL mutations and iii) clinical correlates of ASXL1 and EZH2 mutations in primary MF (PMF) and CMML. Methods: The study population included 94 patients: 46 PMF, 22 post-polycythemia vera/essential thrombocythemia MF (post-PV/ET MF), 11 blast-phase MPN and 15 CMML (10 CMML-1 and 5 CMML-2). High throughput DNA resequencing was used to screen archived bone marrow for EZH2, ASXL1, TET2, IDH, JAK2 and MPL mutations. Results: ASXL1 mutations were identified in all disease categories, including PMF (13%), post-PV/ET MF (23%), blast phase MPN (18%), and CMML (20%). We identified somatic mutations in TET2 in 15%, 14%, 18%, and 13% of PMF, post-PV/ET MF, blast phase MPN, and CMML, respectively. By contrast, mutations in EZH2 and IDH1/2 were less frequent. EZH2 mutations were seen in 3 out of 46 PMF patients (7%) and were not observed in patients with post-PV/ET MF or blast phase MPN. Mutations in IDH1/2 were restricted to blast-phase MPN (36%) and PMF (7%). No mutations in EZH2 or IDH1/2 were seen in CMML. Although we identified frequent TET2 and ASXL1 mutations, we only identified one patient with concurrent mutations in both genes. Three ASXL1 mutation-positive patients also had mutations in EZH2 or IDH and one patient had concurrent ASXL1, TET2 and IDH mutations. In addition, 7 ASXL1, 7 TET2, and 1 IDH mutated patients were JAK2V617F-positive. MPL mutations were also documented in all three mutation categories. All EZH2- and ASXL1-mutated PMF patients displayed normal karyotype and none underwent leukemic transformation during follow-up. Furthermore, mutated versus unmutated patients, in both instances, were not significantly different in age and sex distribution or clinical characteristics. The 3 EZH2-mutated PMF patients died after 29, 48 and 67 months from the time of mutation analysis. In univariate analysis, the presence of mutant ASXL1 in PMF was associated with worse survival (p=0.06) but the borderline significance was lost during multivariable analysis that included risk stratification according to DIPSS (Passamonti et al. Blood 2010; 115: 1703–1708). The 3 ASXL1 mutated CMML cases were alive after 40, 34 and 12 months from time of mutation analysis and none of them had progressed to acute leukemia; karyotype was normal in two of the patients and showed isolated trisomy 8 in one. Conclusions: ASXL1 mutations are as frequent as TET2 mutations in MF and CMML. In contrast, EZH2 mutations are infrequent and cluster with PMF. ASXL1 and EZH2 mutations are not mutually exclusive events, seem to be associated with normal karyotype and do not appear to be leukemogenic or prognostically detrimental in PMF or CMML. Disclosures: No relevant conflicts of interest to declare.
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Heinrich, Michael C., Christopher L. Corless, George D. Demetri, Charles D. Blanke, Margaret von Mehren, Heikki Joensuu, Laura S. McGreevey, et al. "Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor." Journal of Clinical Oncology 21, no. 23 (December 1, 2003): 4342–49. http://dx.doi.org/10.1200/jco.2003.04.190.
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Purpose: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. Patients and Methods: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. Results: Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P = .0006) and 0.0% (P < .0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. Conclusion: Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.
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Heinrich, Michael C., Christopher L. Corless, George D. Demetri, Charles D. Blanke, Margaret von Mehren, Heikki Joensuu, Laura S. McGreevey, et al. "Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor." Journal of Clinical Oncology 41, no. 31 (November 1, 2023): 4829–36. http://dx.doi.org/10.1200/jco.22.02771.
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PURPOSE Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. PATIENTS AND METHODS GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. RESULTS Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% ( P = .0006) and 0.0% ( P < .0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. CONCLUSION Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.
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Ries, Rhonda E., Xiaotu Ma, Claudia Tregnago, Todd A. Alonzo, Jim Wang, Tiffany Hylkema, Benjamin J. Huang, et al. "DNMT3A Mutants Are Enriched in NPMc+ AML and Associated with Adverse Outcome in Childhood AML." Blood 142, Supplement 1 (November 28, 2023): 4306. http://dx.doi.org/10.1182/blood-2023-181060.
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Background: Somatic mutations in the DNA methyltransferase 3 alphagene (DNMT3A) are common in adult acute myeloid leukemia (AML), but are rare events in childhood AML (Ho, Ped Blood Cancer, 2011). Missense mutations occur most frequently in the catalytic domain at R882, resulting in loss of enzyme methylation activity and the ability of the enzyme to bind DNA. DNMT3Amutations are associated with adverse outcome in adults, while their impact is understudied in childhood AML. Our objective was to identify the prevalence of DNMT3A -mutated AML across the childhood age spectrum utilizing a large cohort of patients enrolled on pediatric trials and compare findings with adult cohorts. Methods: Pediatric patients treated on two consecutive COG trials with publicly available data were included (n=1607). Mutational profiling was performed by whole genome and transcriptome sequencing methods. Prevalence of DNMT3Amutations, co-occurring mutations, and outcomes (5-year event-free [EFS] and 5-year overall survival [OS]) were analyzed. Results: The prevalence of DNMT3Amutations amongst the entire childhood cohort was 1.2% (n=20/1607). DNMT3A mutations were absent in children <10 years with increased incidence up to 2.6% in patients >10yrs of age. All variants were missense, with the exception of one nonsense mutation and alterations at the 882 residue were the most common (70%). Most importantly, all but 4 DNMT3A mutations occurred in patients with NPM1 mutations (NPMc+; 80%). Conversely, DNMT3A mutations were seen in 9% of all NPM positive patients, demonstrating unique enrichment of this mutation within the NPM1 mutant cohort. Further, R882 mutations were seen in all but a single patient with the dual NPM/DNMT3A variant. It is notable that 11 patients harbored additional FLT3-ITD mutations (triple positive), which we have previously reported to be associated with adverse outcome in adults. In addition to mutations in NPM1 and FLT3, co-occurring variants with DNMT3A were also found in PTPN11 (35%), and WT1, IDH1/2 and MYC each at 10% frequency (Fig.A). Given the recent report of association of NPM1 mutation genotype and association of Type D mutation with adverse outcome (Pigazzi, ASH 2023), we evaluated NPM1 mutation genotype in those with cooperating DNMT3A mutation which demonstrated lack of association of DNMT3A mutations and Type D NPM1 mutations. Current risk classification in COG pediatric AML trials treat NPMc+ patients as favorable risk. Given the prevalence of DNMT3A mutations in NPMc+ patients we inquired whether DNMT3A mutations might modify outcome in this population. The 5 yr EFS estimates for NPMc+; patients with and without DNMT3A was 26.8% vs. 74.8% (p<0.0001; Fig.B) with a corresponding OS estimate at 5yrs of 60.3% vs. 82.2% (p=0.0169). We further concluded that presence or absence of FLT3-ITD does not impact the adverse outcome with similar 5 yr EFS for those with dual NPM1/DNMT3A or triple NPM1/DNMT3A/FLT3-ITD positive AML(20.0% vs. 30.3%respectively). These data are consistent with the adult DNMT3A data previously presented last year (Torabi; ASH 2022; abstract #306) regarding clinical implications of DNMT3A mutation in the setting of cooperating NPM1 mutation. Conclusion: Mutational profiling of children with AML identified DNMT3A mutations in adolescents and young adults and is enriched in those with NPMc+ mutations. As NPMc+ patients are considered to be favorable risk, knowledge of DNMT3A mutations would provide additional information for more precise risk stratification in childhood AML. Children with de novo AML and dual DNMT3A/NPM1 mutations remain at high risk of relapse and adverse outcome regardless of FLT3-ITD status.
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Dufour, Annika, Stefan K. Bohlander, Evelyn Zellmeier, Gudrun Mellert, Karsten Spiekermann, Stephanie Schneider, Purvi Kakadia, et al. "Disruption of TP53 function by Point Mutations and Deletions Is Associated with An Increased Risk of Disease Progression within Previously Treated, Relapsed Chronic Lymphocytic Leukemia Patients." Blood 118, no. 21 (November 18, 2011): 2445. http://dx.doi.org/10.1182/blood.v118.21.2445.2445.
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Abstract Abstract 2445 Chronic lymphocytic leukemia (CLL) patients with a deletion of the TP53 tumor supressor gene located at 17p13 have a poor prognosis in first line chemotherapy regimens. Recent studies indicated somatic TP53 mutations as a prognostic factor in CLL independent of 17p13 deletion status. We aimed to further characterize the prognostic value and the impact of TP53 mutations on progression-free survival (PFS) in the presence and absence of a 17p13 deletion in previously treated and relapsed CLL patients within an international phase III clinical study comparing Fludarabine and Cyclophosphamide with or without Rituximab (FC versus R-FC: REACH trial). We analyzed 457 patients at diagnosis for mutations in the TP53 gene using a combination of a microarray-based resequencing assay (AmpliChip p53 Test, Roche Molecular Systems, USA.) and Sanger sequencing of TP53 exons 2–10. The data were correlated with clinical and biologic markers as well as with interphase fluorescence in situ hybridization (FISH) and with PFS. Association of the clinical data with PFS was assessed by Cox proportional hazard models. To estimate the functional significance of the individual TP53 mutations we used the IARC TP53 database. TP53 mutations (n=60) were detected in 52 of 457 patients (11.4%) and included 42 missense, 4 nonsense, 8 frameshift mutations, 2 in-frame deletions and 4 mutations in splice sites. Among other clinical variables, only 17p13 deletion was associated with TP53 mutations: 27 of 52 TP53 mutated patients had a 17p13 deletion (concordance rate: 52%, Fisher's test p<0.001). Median PFS for patients with TP53 mutations (n=52, 13 months, HR=1.9 (1.4–2.7), p<0.001) was significantly shorter as compared to patients without TP53 mutations (n=480, 27 months). In a sub-group analysis, chemoimmunotherapy including Rituximab did not significantly improve the PFS of patients with TP53 mutations. Multivariate analysis including treatment arm, Binet stage, age, IGVH mutational status, 17p13 deletion and TP53 mutation status confirmed TP53 mutation status (HR-TP53=1.7 (1.1–2.6), p=0.009) as a prognostic factor for PFS independent of 17p13 deletion status (HR-17p=1.7 (1.1–2.7), p=0.024) and with a similar effect size. The other independent prognostic factors were treatment (HR=0.61 (0.48–0.76), p<0.001), Binet stage (HR=1.64 (1.3–2.1), p<0.001) and IGVH mutational status (HR=2.4 (1.85–3.1), p<0.001). To further dissect the contribution of TP53 mutation and 17p13 deletion on PFS, we considered a multivariate analysis comparing patients with both TP53 mutation and 17p13 deletion (n=28), with only 17p13 deletion (n=9), with a dominant negative TP53 mutation or multiple TP53 mutations (n=8) or with a single TP53 mutation (n=16) against patients without TP53 abnormalities (n=271), adjusted for treatment, Binet stage, age and IGVH mutational status. Patients with a predicted biallelic disruption of TP53 either by a TP53 mutation in combination with a 17p13 deletion (HR: 2.8 (1.8,4.2), p=<0.001) or patients with a dominant negative TP53 mutation as predicted by the IARC TP53 database or multiple TP53 mutations (HR=3.26 (1.5,7.1), p=0.003) had a risk similar in size and which was quite high for disease progression (the reference to calculate the risk, here and in the following, is always the group of patients without TP53 abnormalities). The risk slightly decreased for patients with only a deletion 17p13 (HR=2.2, (1.1–4.3), p=0.021). Very interestingly, single TP53 mutations showed a much lower risk for disease progression (in this case not even significant) (HR=1.61 (0.9–2.8), p=0.084) especially compared to the risk conferred by a biallelic disruption. In this large cohort of previously treated CLL patients, complete disruption of TP53 function (by a combination of a 17p13 deletion and a TP53 mutation, through dominant negative TP53 mutations or through multiple TP53 mutations) was associated with a higher risk for disease progression. Prognosis of patients with a single TP53 mutation was not significantly different from patients without TP53 aberrations. It remains to be shown whether CLL patients with a single TP53 mutation are at a higher risk of acquiring additional mutations of TP53 during disease progression. Prognostic stratification of previously treated CLL patients should include a routine molecular TP53 mutational analysis in addition to deletion analysis of the TP53 locus by FISH. Disclosures: Dufour: Roche: Research Funding. Bohlander:Roche: Research Funding. Spiekermann:Roche: Research Funding. Schneider:Roche: Research Funding. Hiddemann:Roche: Research Funding. Truong:Roche: Employment. Patten:Roche: Employment. Wu:Roche: Employment. Dmoszynska:Mundipharma:; Roche: Honoraria. Robak:Centocor Ortho Biotech Research & Development: Research Funding. Geisler:Roche: Speakers Bureau. Dornan:Genentech: Employment. Lin:Genentech: Employment. Yeh:Genentech: Employment. Weisser:Roche: Employment. Duchateau-Nguyen:Roche: Employment. Palermo:Roche: Employment.
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Nicholson, Michael D., David Cheek, and Tibor Antal. "Sequential mutations in exponentially growing populations." PLOS Computational Biology 19, no. 7 (July 10, 2023): e1011289. http://dx.doi.org/10.1371/journal.pcbi.1011289.
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Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions are: how many cells are there with n alterations, and how long will it take for these cells to appear. For exponentially growing populations, these questions have been tackled only in special cases so far. Here, within a multitype branching process framework, we consider a general mutational path where mutations may be advantageous, neutral or deleterious. In the biologically relevant limiting regimes of large times and small mutation rates, we derive probability distributions for the number, and arrival time, of cells with n mutations. Surprisingly, the two quantities respectively follow Mittag-Leffler and logistic distributions regardless of n or the mutations’ selective effects. Our results provide a rapid method to assess how altering the fundamental division, death, and mutation rates impacts the arrival time, and number, of mutant cells. We highlight consequences for mutation rate inference in fluctuation assays.