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GARCÍA-DORADO, A., C. LÓPEZ-FANJUL e A. CABALLERO. "Properties of spontaneous mutations affecting quantitative traits". Genetical Research 74, n. 3 (dicembre 1999): 341–50. http://dx.doi.org/10.1017/s0016672399004206.
Testo completoAbstract (sommario):
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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Ellis, Nathan A. "Mutation-causing mutations". Nature 381, n. 6578 (maggio 1996): 110–11. http://dx.doi.org/10.1038/381110a0.
Testo completo
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Matsutani, Taro, Yuki Ueno, Tsukasa Fukunaga e Michiaki Hamada. "Discovering novel mutation signatures by latent Dirichlet allocation with variational Bayes inference". Bioinformatics 35, n. 22 (16 aprile 2019): 4543–52. http://dx.doi.org/10.1093/bioinformatics/btz266.
Testo completoAbstract (sommario):
Abstract Motivation A cancer genome includes many mutations derived from various mutagens and mutational processes, leading to specific mutation patterns. It is known that each mutational process leads to characteristic mutations, and when a mutational process has preferences for mutations, this situation is called a ‘mutation signature.’ Identification of mutation signatures is an important task for elucidation of carcinogenic mechanisms. In previous studies, analyses with statistical approaches (e.g. non-negative matrix factorization and latent Dirichlet allocation) revealed a number of mutation signatures. Nonetheless, strictly speaking, these existing approaches employ an ad hoc method or incorrect approximation to estimate the number of mutation signatures, and the whole picture of mutation signatures is unclear. Results In this study, we present a novel method for estimating the number of mutation signatures—latent Dirichlet allocation with variational Bayes inference (VB-LDA)—where variational lower bounds are utilized for finding a plausible number of mutation patterns. In addition, we performed cluster analyses for estimated mutation signatures to extract novel mutation signatures that appear in multiple primary lesions. In a simulation with artificial data, we confirmed that our method estimated the correct number of mutation signatures. Furthermore, applying our method in combination with clustering procedures for real mutation data revealed many interesting mutation signatures that have not been previously reported. Availability and implementation All the predicted mutation signatures with clustering results are freely available at http://www.f.waseda.jp/mhamada/MS/index.html. All the C++ source code and python scripts utilized in this study can be downloaded on the Internet (https://github.com/qkirikigaku/MS_LDA). Supplementary information Supplementary data are available at Bioinformatics online.
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Lee, Joon-Hyop, Jiyoung Ahn, Won Seo Park, Eun Kyung Choe, Eunyoung Kim, Rumi Shin, Seung Chul Heo et al. "Colorectal Cancer Prognosis is Not Associated with BRAF and KRAS Mutations-A STROBE Compliant Study". Journal of Clinical Medicine 8, n. 1 (17 gennaio 2019): 111. http://dx.doi.org/10.3390/jcm8010111.
Testo completoAbstract (sommario):
Background: We investigated the associations between v-Raf murine sarcoma viral oncogene homolog B1 (BRAFV600E, henceforth BRAF) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and colorectal cancer (CRC) prognosis, using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GSE39582) datasets. Materials and Methods: The effects of BRAF and KRAS mutations on overall survival (OS) and disease-free survival (DFS) of CRC were evaluated. Results: The mutational status of BRAF and KRAS genes was not associated with overall survival (OS) or DFS of the CRC patients drawn from the TCGA database. The 3-year OS and DFS rates of the BRAF mutation (+) vs. mutation (−) groups were 92.6% vs. 90.4% and 79.7% vs. 68.4%, respectively. The 3-year OS and DFS rates of the KRAS mutation (+) vs. mutation (−) groups were 90.4% vs. 90.5% and 65.3% vs. 73.5%, respectively. In stage II patients, however, the 3-year OS rate was lower in the BRAF mutation (+) group than in the mutation (−) group (85.5% vs. 97.7%, p <0.001). The mutational status of BRAF genes of 497 CRC patients drawn from the GSE39582 database was not associated with OS or DFS. The 3-year OS and DFS rates of BRAF mutation (+) vs. mutation (−) groups were 75.7% vs. 78.9% and 73.6% vs. 71.1%, respectively. However, KRAS mutational status had an effect on 3-year OS rate (71.9% mutation (+) vs. 83% mutation (−), p = 0.05) and DFS rate (66.3% mutation (+) vs. 74.6% mutation (−), p = 0.013). Conclusions: We found no consistent association between the mutational status of BRAF nor KRAS and the OS and DFS of CRC patients from the TCGA and GSE39582 databases. Studies with longer-term records and larger patient numbers may be necessary to expound the influence of BRAF and KRAS mutations on the outcomes of CRC.
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Bustamante, A. V., A. M. Sanso, D. O. Segura, A. E. Parma e P. M. A. Lucchesi. "Dynamic of Mutational Events in Variable Number Tandem Repeats ofEscherichia coliO157:H7". BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/390354.
Testo completoAbstract (sommario):
VNTRs regions have been successfully used for bacterial subtyping; however, the hypervariability in VNTR loci is problematic when trying to predict the relationships among isolates. Since few studies have examined the mutation rate of these markers, our aim was to estimate mutation rates of VNTRs specific for verotoxigenicE. coliO157:H7. The knowledge of VNTR mutational rates and the factors affecting them would make MLVA more effective for epidemiological or microbial forensic investigations. For this purpose, we analyzed nine loci performing parallel, serial passage experiments (PSPEs) on 9 O157:H7 strains. The combined 9 PSPE population rates for the 8 mutating loci ranged from 4.4 × 10−05to 1.8 × 10−03mutations/generation, and the combined 8-loci mutation rate was of 2.5 × 10−03mutations/generation. Mutations involved complete repeat units, with only one point mutation detected. A similar proportion between single and multiple repeat changes was detected. Of the 56 repeat mutations, 59% were insertions and 41% were deletions, and 72% of the mutation events corresponded to O157-10 locus. For alleles with up to 13 UR, a constant and low mutation rate was observed; meanwhile longer alleles were associated with higher and variable mutation rates. Our results are useful to interpret data from microevolution and population epidemiology studies and particularly point out that the inclusion or not of O157-10 locus or, alternatively, a differential weighting data according to the mutation rates of loci must be evaluated in relation with the objectives of the proposed study.
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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, n. 3_suppl (20 gennaio 2014): 210. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.210.
Testo completoAbstract (sommario):
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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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, n. 10 (30 settembre 2021): 1434–42. http://dx.doi.org/10.1038/s41588-021-00930-y.
Testo completoAbstract (sommario):
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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Trindade, Sandra, Lilia Perfeito e 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, n. 1544 (27 aprile 2010): 1177–86. http://dx.doi.org/10.1098/rstb.2009.0287.
Testo completoAbstract (sommario):
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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Watters, M. K., e D. R. Stadler. "Spontaneous mutation during the sexual cycle of Neurospora crassa." Genetics 139, n. 1 (1 gennaio 1995): 137–45. http://dx.doi.org/10.1093/genetics/139.1.137.
Testo completoAbstract (sommario):
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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Lee, Seung-Shin, Jae-Sook Ahn, Taehyung Kim, Hyeoung Joon Kim, Yeo-Kyeoung Kim, Seo-Yeon Ahn, Sung-Hoon Jung et al. "RUNX1 Mutation in Cytogenetically Normal Acute Myeloid Leukemia : Clinical Implications, Co-Mutation Analysis". Blood 128, n. 22 (2 dicembre 2016): 5253. http://dx.doi.org/10.1182/blood.v128.22.5253.5253.
Testo completoAbstract (sommario):
Abstract Background and Objectives Acute Myeloid Leukemia (AML) is a cytogenetically and molecularly heterogeneous disease. In the recent decades, many genetic mutations and their clinical significances in AML have been identified with the development of new genomics technology. Based on these advances, new 2 entities were added to the WHO 2008 classification : AML with mutated NPM1 and AML with mutated CEBPA. Likewise, AML with RUNX1 mutation are now considered as a new provisional entity in the next update of WHO classification. In this work, we characterized patients with cytogenetically normal AML according to RUNX1 mutational status and analyzed several co-mutations by next generation sequencing. Patients and Methods A total of 419 patients were included in the present study who met the following eligibility criteria: 1) age ≥ 15 years; 2) a diagnosis of AML with normal karyotype confirmed by conventional cytogenetic analysis. Analysis of genetic mutations were performed using targeted resequencing by Illumina Hiseq 2000 (Sureselect custom probe set targeting 94 myeloid gene panel including RUNX1 mutation). Samples for the confirmation of first complete response were also analyzed in 163 patients. The majority of patients (97%) received '3+7' standard induction chemotherapy. Median age was 53(range 15-84). Results Overall, most common mutations for this cohort were NPM1(33.9%), DNMT3A(30.3%), NRAS(20.2%), IDH2(15.0%), FLT3(12.2%), CEBPA(11.1%). RUNX1 mutations were found in 22 of 419 (5.4%) patients. 7 of 13 available samples in complete remission still had RUNX1 mutation. The patients with RUNX1 mutations were older than those with wild-type RUNX1. (p=0.006) and RUNX1 mutation had a trend of male preponderance. The WBC count and blast percentage of peripheral blood and bone marrow were not different according to RUNX1 mutational status. The complete response rate was significantly lower in RUNX1 mutated group compared with wild-type group. (57% vs. 84%, p=0.005) In univariable survival analysis, RUNX1 mutations were significantly associated with inferior event-free survival (EFS) (p<0.001), relapse-free survival (RFS) (p=0.009) and overall survival (OS) (p=0.002). However, in multivariable analysis, RUNX1 mutation was not an independent prognostic factor for inferior EFS (hazard ratio(HR) 1.48, p=0.286), RFS (HR 2.15, p=0.057) OS (HR 1.14, p=0.716). Co-mutation analysis revealed that ASXL1 (26%,p=0.001), KRAS (26%, p=0.009), BCOR (16%, p=0.032) were correlated with RUNX1 mutation. None of the patients with RUNX1 mutation had NPM1 mutation and only one patient had CEBPA mutation. Conclusion In cytogenetically normal AML, RUNX1 mutation is observed in 5.4% and is mutually exclusive of the NPM1 and CEBPA mutation. Older age and lower complete response rate is correlated with RUNX1 mutation. In univariable survival analysis, RUNX1 mutation is associated with poor clinical outcomes. Disclosures No relevant conflicts of interest to declare.
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Wayne, Marta L., e Trudy F. C. Mackay. "Quantitative Genetics of Ovariole Number in Drosophila melanogaster. II. Mutational Variation and Genotype-Environment Interaction". Genetics 148, n. 1 (1 gennaio 1998): 201–10. http://dx.doi.org/10.1093/genetics/148.1.201.
Testo completoAbstract (sommario):
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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Pálinkás, Hajnalka Laura, Lőrinc Pongor, Máté Balajti, Ádám Nagy, Kinga Nagy, Angéla Békési, Giampaolo Bianchini, Beáta G. Vértessy e Balázs Győrffy. "Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer". International Journal of Molecular Sciences 23, n. 2 (6 gennaio 2022): 633. http://dx.doi.org/10.3390/ijms23020633.
Testo completoAbstract (sommario):
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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Tarlock, Katherine, Todd M. Cooper, Todd A. Alonzo, Robert Gerbing, Jessica Pollard, Richard Aplenc, E. Anders Kolb, Alan S. Gamis e Soheil Meshinchi. "Mutational Concordance from Diagnosis and Relapse in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group". Blood 128, n. 22 (2 dicembre 2016): 2846. http://dx.doi.org/10.1182/blood.v128.22.2846.2846.
Testo completoAbstract (sommario):
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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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, n. 12_Supplement (15 giugno 2022): 5754. http://dx.doi.org/10.1158/1538-7445.am2022-5754.
Testo completoAbstract (sommario):
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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Kapoor, Ritika R., Sarah E. Flanagan, Piers Fulton, Anupam Chakrapani, Bernadette Chadefaux, Tawfeg Ben-Omran, Indraneel Banerjee, Julian P. Shield, Sian Ellard e Khalid Hussain. "Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations". European Journal of Endocrinology 161, n. 5 (novembre 2009): 731–35. http://dx.doi.org/10.1530/eje-09-0615.
Testo completoAbstract (sommario):
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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Balamurugan, Kuppareddi, Martin L. Tracey, Uwe Heine, George C. Maha e George T. Duncan. "Mutation at the Human D1S80 Minisatellite Locus". Scientific World Journal 2012 (2012): 1–8. http://dx.doi.org/10.1100/2012/917235.
Testo completoAbstract (sommario):
Little is known about the general biology of minisatellites. The purpose of this study is to examine repeat mutations from the D1S80 minisatellite locus by sequence analysis to elucidate the mutational process at this locus. This is a highly polymorphic minisatellite locus, located in the subtelomeric region of chromosome 1. We have analyzed 90,000 human germline transmission events and found seven (7) mutations at this locus. The D1S80 alleles of the parentage trio, the child, mother, and the alleged father were sequenced and the origin of the mutation was determined. Using American Association of Blood Banks (AABB) guidelines, we found a male mutation rate of1.04×10-4and a female mutation rate of5.18×10-5with an overall mutation rate of approximately7.77×10-5. Also, in this study, we found that the identified mutations are in close proximity to the center of the repeat array rather than at the ends of the repeat array. Several studies have examined the mutational mechanisms of the minisatellites according to infinite allele model (IAM) and the one-step stepwise mutation model (SMM). In this study, we found that this locus fits into the one-step mutation model (SMM) mechanism in six out of seven instances similar to STR loci.
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Claes, Kathleen, Eva Machackova, Michel De Vos, Bruce Poppe, Anne De Paepe e 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, n. 1-3 (1999): 69–73. http://dx.doi.org/10.1155/1999/241046.
Testo completoAbstract (sommario):
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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Wood, Anthony C., Yonghong Zhang, Qianxing Mo, Ling Cen, Jacques Fontaine, Sarah E. Hoffe, Jessica Frakes et al. "Evaluation of Tumor DNA Sequencing Results in Patients with Gastric and Gastroesophageal Junction Adenocarcinoma Stratified by TP53 Mutation Status". Oncologist 27, n. 4 (26 febbraio 2022): 307–13. http://dx.doi.org/10.1093/oncolo/oyac018.
Testo completoAbstract (sommario):
Abstract Background Gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ) are molecularly diverse. TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. This qualitative study describes the distinct genomic alterations in GCs and GEJs stratified by TP53 mutation status. Patients and Methods Tumor DNA sequencing results of 324 genes from 3741 patients with GC and GEJ were obtained from Foundation Medicine. Association between gene mutation frequency and TP53 mutation status was examined using Fisher’s exact test. Functional gene groupings representing molecular pathways suggested to be differentially mutated in TP53 wild-type (TP53WT) and TP53 mutant (TP53MUT) tumors were identified. The association of the frequency of tumors containing a gene mutation in the molecular pathways of interest and TP53 mutation status was assessed using Fisher’s exact test with a P-value of <.01 deemed statistically significant for all analyses. Results TP53 mutations were noted in 61.6% of 2946 GCs and 81.4% of 795 GEJs (P < .001). Forty-nine genes had statistically different mutation frequencies in TP53WT vs. TP53MUT patients. TP53WT tumors more likely had mutations related to DNA mismatch repair, homologous recombination repair, DNA and histone methylation, Wnt/B-catenin, PI3K/Akt/mTOR, and chromatin remodeling complexes. TP53MUT tumors more likely had mutations related to fibroblast growth factor, epidermal growth factor receptor, other receptor tyrosine kinases, and cyclin and cyclin-dependent kinases. Conclusion The mutational profiles of GCs and GEJs varied according to TP53 mutation status. These mutational differences can be used when designing future studies assessing the predictive ability of TP53 mutation status when targeting differentially affected molecular pathways.
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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, n. 21 (6 dicembre 2014): 1052. http://dx.doi.org/10.1182/blood.v124.21.1052.1052.
Testo completoAbstract (sommario):
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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Kang, S., S. S. Seo, H. J. Chang, C. W. Yoo, S. Y. Park e S. M. Dong. "Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma". International Journal of Gynecologic Cancer 18, n. 6 (2008): 1339–43. http://dx.doi.org/10.1111/j.1525-1438.2007.01172.x.
Testo completoAbstract (sommario):
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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FRY, JAMES D. "Rapid mutational declines of viability in Drosophila". Genetical Research 77, n. 1 (febbraio 2001): 53–60. http://dx.doi.org/10.1017/s0016672300004882.
Testo completoAbstract (sommario):
High rates of mildly deleterious mutation could cause the extinction of small populations, reduce neutral genetic variation and provide an evolutionary advantage for sex. In the first attempts to estimate the rate of mildly deleterious mutation, Mukai and Ohnishi allowed spontaneous mutations to accumulate on D. melanogaster second chromosomes shielded from recombination and selection. Viability of the shielded chromosomes appeared to decline rapidly, implying a deleterious mutation rate on the order of one per zygote per generation. These results have been challenged, however; at issue is whether Mukai and Ohnishi may have confounded viability declines caused by mutation with declines resulting from environmental changes or other extraneous factors. Here, using a method not sensitive to non-mutational viability changes, I reanalyse the previous mutation-accumulation (MA) experiments, and report the results of a new one. I show that in each of four experiments, including Mukai's two experiments, viability declines due to mildly deleterious mutations were rapid. The results give no support for the view that Mukai overestimated the declines. Although there is substantial variation in estimates of genomic mutation rates from the experiments, this variation is probably due to some combination of sampling error, strain differences and differences in assay conditions, rather than to failure to distinguish mutational and non-mutational viability changes.
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Delaugerre, Constance, Mireille Mouroux, Anne Yvon-Groussin, Anne Simon, Francis Angleraud, Jean-Marie Huraux, Henri Agut, Christine Katlama e 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, n. 3 (1 marzo 2001): 946–48. http://dx.doi.org/10.1128/aac.45.3.946-948.2001.
Testo completoAbstract (sommario):
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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Golding, G. Brian, Patricia J. Gearhart e Barry W. Glickman. "Patterns of Somatic Mutations in Immunoglobulin Variable Genes". Genetics 115, n. 1 (1 gennaio 1987): 169–76. http://dx.doi.org/10.1093/genetics/115.1.169.
Testo completoAbstract (sommario):
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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Dunson, David B., e Kenneth R. Tindall. "Bayesian Analysis of Mutational Spectra". Genetics 156, n. 3 (1 novembre 2000): 1411–18. http://dx.doi.org/10.1093/genetics/156.3.1411.
Testo completoAbstract (sommario):
Abstract Studies that examine both the frequency of gene mutation and the pattern or spectrum of mutational changes can be used to identify chemical mutagens and to explore the molecular mechanisms of mutagenesis. In this article, we propose a Bayesian hierarchical modeling approach for the analysis of mutational spectra. We assume that the total number of independent mutations and the numbers of mutations falling into different response categories, defined by location within a gene and/or type of alteration, follow binomial and multinomial sampling distributions, respectively. We use prior distributions to summarize past information about the overall mutation frequency and the probabilities corresponding to the different mutational categories. These priors can be chosen on the basis of data from previous studies using an approach that accounts for heterogeneity among studies. Inferences about the overall mutation frequency, the proportions of mutations in each response category, and the category-specific mutation frequencies can be based on posterior distributions, which incorporate past and current data on the mutant frequency and on DNA sequence alterations. Methods are described for comparing groups and for assessing doserelated trends. We illustrate our approach using data from the literature.
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Astudillo, H., J. Sanchez-Guillen, P. Romero-Garcia, J. Bastarrachea-ortiz, G. Morgan-Villela, J. M. Salazar, V. M. Vazquez-Rivera, H. Ruiz-Calzada e P. Cortes-Esteban. "Polymorphism detection of K-Ras mutations using high-resolution melting analysis in Mexican patients with metastatic colorectal cancer (mCRC)". Journal of Clinical Oncology 27, n. 15_suppl (20 maggio 2009): e15135-e15135. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15135.
Testo completoAbstract (sommario):
e15135 Background: Metastatic carcinoma of the colorectum remains a major problem. Nowadays the mutational polymorphism detection of K-ras gene is useful for patients with diagnosis of mCRC especially when an anti-EGFR biological therapy is considered to be used. The purpose of this study was to analyze and establish a molecular method to detect the mutational polymorphism of K-Ras gene in paraffin-embedded biopsies from Mexican patients with mCRC. Methods: The presence and polymorphism of K-ras gene mutations were analyzed in paraffin-embedded biopsies from 156 patients using a real time PCR technique with target specific oligomer competitor shifting the PCR amplification towards the mutated target, thus yielding an enriched PCR product containing variations. Results: K-ras mutations were detected in 89 of 156 patients (59%). There was not evaluated a relationship between the presence of a K-ras mutations and clinicopathological features. 39 of the 89 (42.85%) biopsies with a positive K- ras mutation had a 12G mutation polymorphism, 11 of the 89 (12.08%) biopsies had a 12D mutation polymorphism and 10 of the 89 (10.98%) biopsies had a 12S mutation polymorphism. Of the 64 biopsies without K-ras mutation (wild type), none clinicopathological correlation was determine in this group. The rate of the K-ras mutation was higher than that of the K-ras mutation negative group (wild type). Conclusions: This study demonstrates that the determination of mutational polymorphism of k-ras gene is possible and could be implemented as a predictor response in patients with mCRC to benefit from antibody based anti-EGFR therapies. No significant financial relationships to disclose.
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Piombino, Claudia, Angela Toss, Alessandra Bologna, Elisa Gasparini, Vittoria Tarantino, Maria Elisabetta Filieri, Luca Cottafavi et al. "The prognostic role of somatic BRCA mutations in ovarian cancer: Preliminary results from an observational multicenter cohort study." Journal of Clinical Oncology 38, n. 15_suppl (20 maggio 2020): e13674-e13674. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13674.
Testo completoAbstract (sommario):
e13674 Background: BRCA germline (gBRCA) mutations occur in 11-15% of women with unselected ovarian cancers (OC), whereas somatic BRCA (sBRCA) mutations occur in approximately 5-7% of cases. The impact of sBRCA mutations on OC outcome is still debated. Methods: With the aim to explore the prognostic role of sBRCA mutations, the BRCA mutational status of 149 non-mucinous and non-borderline OC and their clinical-pathological features were evaluated. BRCA1 and BRCA2 mutational profiles, either for sequence variants or copy number alterations, were evaluated by amplicon next-generation sequencing (NGS) technology. Results: 29 (19.5%) patients carried a gBRCA mutation (12.7% BRCA1 and 6.7% BRCA2). 26 (17.5%) patients presented a sBRCA mutation (6.7% BRCA1, 10% BRCA2, 0.6% BRCA1+BRCA2). Patients carrying a gBRCA mutation were slightly younger (57 years) than the others (60 years). The FIGO stage at the diagnosis was III-IV in 77.2% of cases, with no significant difference among subgroups. The most frequent histotype was serous for all the subgroups (93.1% in gBRCA, 84.6% in sBRCA, 77.7% in BRCA-negative, p = 0.08). 80.7% of sBRCA mutation carriers, 62.1% of gBRCA mutation carriers and 62.7% of BRCA-negative patients underwent upfront surgery (p = 0.46). 29.1% of sBRCA mutation carriers, 17.8% of gBRCA mutation carriers and 25.6% of BRCA-negative patients presented macroscopic residual disease after surgery (p = 0.68). Although non-statistically significant, gBRCA-associated OC were more likely to be platinum-sensitive (96.6%) than the other patients (92% in sBRCA and 87.1% in BRCA-negative patients). Overall, the median platinum-free interval (PFI) resulted shorter in sBRCA mutation patients compared to gBRCA and BRCA-negative patients (p = 0.051). No patient took PARP inhibitors as maintenance after the first line therapy. Also progression free survival 2 (PFS2) resulted shorter for sBRCA mutation patients (p = 0.008). Three sBRCA and 5 gBRCA mutation carriers took a PARP inhibitor as maintenance after the second line therapy. Finally, sBRCA mutated patients showed worse overall survival (OS) compared to the other subgroups (p = 0.014). Conclusions: Overall, 19.5% of OC patients presented a gBRCA mutation, while 17.5% of patients showed sBRCA mutations. sBRCA-related OC did not show significantly differences in clinical-pathological features (stage at diagnosis, histotype, time to surgery and residual after surgery). To our knowledge this is the first study showing shorter PFI, PFS2 and OS in patients carrying sBRCA mutations.
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Kuang, Shelley, Sally C. M. Lau, Kieran Sharma, Juehea Lee, Malcolm Isaiah Ryan, Sabine Schmid, Penelope Ann Bradbury et al. "Impact of KRAS mutational variant on response to immunotherapy in metastatic NSCLC." Journal of Clinical Oncology 39, n. 15_suppl (20 maggio 2021): e21127-e21127. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21127.
Testo completoAbstract (sommario):
e21127 Background: KRAS alterations constitute the most common driver mutations in metastatic non-small cell lung cancers (mNSCLC) and occur in approximately 30% of patients. KRAS mutational subtype as well as the presence of co-mutations has been associated with altered activation of downstream signaling pathways in preclinical models. We hypothesize that different KRAS G12C mutational subsets will be associated with variable clinical outcome and response to therapy. To this end, we have performed a retrospective analysis of survival and treatment outcomes by KRAS mutation subtype (G12C vs non-G12C). Methods: A review of KRAS-mutated mNSCLC patients treated with immunotherapy between 2013 and 2020 was conducted. Patient demographics, smoking status, KRAS mutational subtype, co-mutations and PD-L1 status were collected. Overall response rate (ORR) and progression-free survival (PFS) were analyzed in each subgroup. Results: 98 KRAS mutant mNSCLC patients were treated with immune checkpoint inhibitors (ICI): 37% with a KRAS G12C mutation, 62% with a non-G12C mutation. Patients with a G12C mutation were more likely to be of Caucasian ancestry (86% vs 56%; p = 0.01) whereas all other characteristics were similar between the groups including smoking history, PD-L1 expression ≥50% (61% vs 40%) and the presence of a TP53 co-mutation (48% vs. 54%); all p > 0.05. Treatment patterns were similar between the groups, with PD-1 inhibitor monotherapy given in 86% vs 79% of KRAS G12C and non-G12C patients. Overall response rate was 51% vs 27% in G12C vs non-G12C (p = 0.03). PFS was superior in G12C mutants (19.6 months vs 4.0 months), even after adjusting for smoking history, TP53 co-mutation status and PD-L1 expression (adjusted HR 0.51; p = 0.02). In subgroup analyses, the superiority in PFS was driven by the G12C mutants with high PD-L1 expression (n = 19): 26.8 months in G12C, PD-L1 high vs 4.7 months in G12C, PD-L1 low vs. 4.7 months in KRAS transversion mutations, PD-L1 high vs 4.0 months in transversion mutations, PD-L1 low vs. 3.0 months in transition mutations; p < 0.001. Conclusions: The presence of a KRAS G12C mutation is associated with improved ORR and PFS after treatment with ICI compared to non-G12C mutations in mNSCLC. The greatest benefit in PFS was observed in the subgroup with G12C mutation and high PD-L1 expression. Differential activation of downstream signaling associated with specific KRAS codon 12 mutation variants may modulate the composition of the tumor immune microenvironment thereby contributing to the variable response to immunotherapy. Further understanding on these molecular mechanisms may direct the development of new treatment strategies in KRAS mutant lung cancers.
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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 (gennaio 2020): 175883592090753. http://dx.doi.org/10.1177/1758835920907534.
Testo completoAbstract (sommario):
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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Machado, Heather E., Nina Friesgaard Øbro, Emily Mitchell, Megan Davies, Anthony R. Green, Kourosh Saeb-Parsy, Daniel James Hodson, David Kent e Peter J. Campbell. "Life History of Normal Human Lymphocytes Revealed By Somatic Mutations". Blood 134, Supplement_1 (13 novembre 2019): 1045. http://dx.doi.org/10.1182/blood-2019-128188.
Testo completoAbstract (sommario):
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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Zeineddine, Fadl, Benjamin Garmezy, Timothy A. Yap e John Paul Y. C. Shen. "PMC: A more precise classifier of POLE mutations to identify candidates for immune therapy." Journal of Clinical Oncology 39, n. 15_suppl (20 maggio 2021): 3548. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3548.
Testo completoAbstract (sommario):
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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Stratton, Michael R. "Abstract PL02-01: The pathogenesis of cancer susceptibility due to inherited DNA repair defects". Cancer Research 82, n. 12_Supplement (15 giugno 2022): PL02–01—PL02–01. http://dx.doi.org/10.1158/1538-7445.am2022-pl02-01.
Testo completoAbstract (sommario):
Abstract The landscapes of somatic mutation in the genomes of normal human cells have, until recently, been poorly described compared with those of cancer cells. However, advances in technology are now changing this picture and are enabling exploration of the earliest stages of cancer development. In this talk, the patterns of somatic mutation found in normal colorectal epithelial cells are outlined and serve as a backdrop to understanding the pathogenesis of colorectal cancer susceptibility syndromes. Multiple mutational signatures are present in normal colorectal epithelial cells indicating that multiple mutational processes are operative in them during the course of life. Some of these mutational signatures are ubiquitous, present in every colorectal epithelial cell, with mutations generated at constant rates throughout life. Others are sporadic, found only in some cells or in some people, with mutations generated in bursts. Some are of endogenous origins whereas others are caused by exogenous exposures. Several inherited colorectal cancer predisposition syndromes are known to be mediated by DNA repair deficiencies that ultimately generate elevated somatic mutation rates. The results presented here show that in some of these syndromes all normal colorectal cells, and probably all cells in the body, have markedly elevated somatic mutation rates throughout life with mutational signatures not found in healthy individuals. Conversely, in other syndromes normal cells have normal mutation rates with standard mutational signatures but a small minority of cells acquire elevated mutation rates during the course of life. In both scenarios only a small proportion of cells with elevated mutation rates ever become adenomas or carcinomas. The results elucidate the different ways in which elevated somatic mutation rates due to DNA repair deficiencies lead to cancer and potentially offer a new modality contributing to clinical management of colorectal cancer susceptibility. They also provide a new perspective on the role of somatic mutations in ageing. Citation Format: Michael R. Stratton. The pathogenesis of cancer susceptibility due to inherited DNA repair defects [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 PL02-01.
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Jaffar, Nazish, Shahnaz Imdad Kehar, Aliya Zaman, Saadia Akram e Kiran Abbas. "Spectrum of Tp53 gene mutation in basal cell carcinoma and its morphological subtypes in people of color." Professional Medical Journal 26, n. 10 (10 ottobre 2019): 1783–88. http://dx.doi.org/10.29309/tpmj/2019.26.10.4141.
Testo completoAbstract (sommario):
Objectives: Basal cell carcinoma (BCC) is the most common cutaneous malignancy in white population. The pattern of exon specific p53 mutations in BCC and its subtypes remain undetected in our population. This study was designed to evaluate the prevalence and mutational spectrum of p53 mutations in basal cell carcinoma (BCC) and its subtypes in people of color in the population of Karachi, Pakistan. Study Design: Retrospective cross sectional study. Setting: Department of Pathology, Basic Medical Sciences Institute, Jinnah Post Graduate Medical Center Karachi, Pakistan. Period: Five-year study from January 2012 to December 2016. Material and Methods: Convenient sampling technique was used. Sample size was calculated using open EPI software. Analysis of 32 BCC cases for p53 gene mutations in exons 5-8 was detected by polymerase chain reaction technique. Sebaceous carcinoma and malignant melanoma were used as positive controls and normal skin was used as negative control. Results: Out of 32 BCC cases, 26 (81.2%) displayed p53 exon mutations. The number of cases with single exon mutation was 17 (65.3%). Exon 5 mutation was most frequently observed in 8 (30.7%) cases. This was followed by 5 (19.2%) cases with exon 6 mutation and 4 (15.3%) cases with exon 8 mutation. None of the cases revealed exon 7 mutation. A considerable number 9 (34.6%) of BCC displayed dual exon mutation. Dual mutations of exon 6 & 8 were seen in 6 (23%) cases. Exon 5 & 7 mutation was noted in 2 (7.6%) cases followed by a single (3.8%) case with exon 6&7 mutation. The highest number 12 (46.1%) of single and dual exon mutations was recorded in nodular subtype of BCC. Conclusion: The current study confirms the expression of p53 gene mutation in BCC in colored population. Majority of the single mutations were observed in exon 5. Dual exon mutation was the most notable finding of this study. The highest number of single and dual exon mutations was recorded in nodular form of BCC.
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Lee, Ye Ji, Yejin Lee, Youn Jung Kim, Zang Hee Lee e Jung-Wook Kim. "Novel PAX9 Mutations Causing Isolated Oligodontia". Journal of Personalized Medicine 14, n. 2 (8 febbraio 2024): 191. http://dx.doi.org/10.3390/jpm14020191.
Testo completoAbstract (sommario):
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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Jeffers, Michael, Christian Kappeler, Iris Kuss, Georg Beckmann, Daniel H. Mehnert, Johannes Fredebohm e 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, n. 3 (20 gennaio 2022): 598–608. http://dx.doi.org/10.1007/s10120-021-01274-6.
Testo completoAbstract (sommario):
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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Xu, Hong-Tao, Maureen Oliveira, Peter K. Quashie, Matthew McCallum, Yingshan Han, Yudong Quan, Bluma G. Brenner e Mark A. Wainberg. "Subunit-Selective Mutational Analysis and Tissue Culture Evaluations of the Interactions of the E138K and M184I Mutations in HIV-1 Reverse Transcriptase". Journal of Virology 86, n. 16 (23 maggio 2012): 8422–31. http://dx.doi.org/10.1128/jvi.00271-12.
Testo completoAbstract (sommario):
The emergence of HIV-1 drug resistance remains a major obstacle in antiviral therapy. M184I/V and E138K are signature mutations of clinical relevance in HIV-1 reverse transcriptase (RT) for the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and emtricitabine (FTC) and the second-generation (new) nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV), respectively, and the E138K mutation has also been shown to be selected by etravirine in cell culture. The E138K mutation was recently shown to compensate for the low enzyme processivity and viral fitness associated with the M184I/V mutations through enhanced deoxynucleoside triphosphate (dNTP) usage, while the M184I/V mutations compensated for defects in polymerization rates associated with the E138K mutations under conditions of high dNTP concentrations. The M184I mutation was also shown to enhance resistance to RPV and ETR when present together with the E138K mutation. These mutual compensatory effects might also enhance transmission rates of viruses containing these two mutations. Therefore, we performed tissue culture studies to investigate the evolutionary dynamics of these viruses. Through experiments in which E138K-containing viruses were selected with 3TC-FTC and in which M184I/V viruses were selected with ETR, we demonstrated that ETR was able to select for the E138K mutation in viruses containing the M184I/V mutations and that the M184I/V mutations consistently emerged when E138K viruses were selected with 3TC-FTC. We also performed biochemical subunit-selective mutational analyses to investigate the impact of the E138K mutation on RT function and interactions with the M184I mutation. We now show that the E138K mutation decreased rates of polymerization, impaired RNase H activity, and conferred ETR resistance through the p51 subunit of RT, while an enhancement of dNTP usage as a result of the simultaneous presence of both mutations E138K and M184I occurred via both subunits.
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Juriloff, D. M., S. D. Porter e M. J. Harris. "Three spontaneous mutations at the albino locus in SELH/Bc mice". Genome 37, n. 2 (1 aprile 1994): 190–97. http://dx.doi.org/10.1139/g94-026.
Testo completoAbstract (sommario):
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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Maldonado, J. Alberto, Chin-Hsien Tai e Christine Alewine. "Genomic characterization of somatic mutations by race and ethnicity in pancreatic cancer defined through AACR project GENIE." Journal of Clinical Oncology 41, n. 16_suppl (1 giugno 2023): 4138. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.4138.
Testo completoAbstract (sommario):
4138 Background: KRAS, TP53, SMAD4, and CDKN2A are widely recognized as the most common somatic mutations amongst patients with pancreatic ductal adenocarcinoma (PDAC); however, previous genomic studies have disproportionately included non-Hispanic White (NHW) patients with little to no inclusion of racial and ethnic minorities, particularly non-Hispanic Black (NHB) and Hispanic patients. Additionally, little is known about the distribution of KRAS point mutations in PDAC in specific racial and ethnic groups. Here, we describe somatic mutation differences in a larger and more racially and ethnically representative PDAC cohort than previously characterized. Methods: PDAC mutational data was downloaded from AACR Project GENIE (Genomics Evidence Neoplasia Information Exchange) v13.0, an international data registry of sequenced tumor samples from nearly 150,000 patients, on cBioPortal. PDAC cancer type was identified using OncoTree code. NHW, NHB, Hispanic (of any race), and Asian patients were then selected. Mutational frequency was calculated for all mutations. The primary objective was to compare the mutation frequencies between NHW and other races with respect to the most common mutations. To maximize power, we included any mutation with a frequency ≥5.0% where testing for mutation of that gene had been performed in at least 150 patients. Specific point mutations in KRAS were also extracted with stratification for racial and ethnic group. Fisher’s Exact Test was used to calculate the statistical significance of the differences in mutation frequency between NHW and minority groups. Results: Patients in the PDAC cohort included 5,292 individuals (NHW N = 4296, 80.7%; NHB N = 264, 5.0%; Hispanic N = 460, 8.7%; Asian N = 299, 5.7%). As compared to the NHW group, NHB patients had higher rates of TP53 (78.7% vs 69.0%, P = 0.0006) and PTPRT (5.3% vs 1.8%, P = 0.0095) mutations but fewer GNAS (0.4% vs 2.8%, P = 0.0097) mutations while Asian patients had higher frequency of ARID1A mutations (13.0% vs 8.8%, P = 0.024). KRAS G12D mutation was more prevalent in Hispanic patients (47.0% Hispanic vs 41.1% NHW, P = 0.0238), although rate of KRAS mutation overall was the same. Prevalence of KRAS G12C mutation was equivalent amongst all groups with an overall 1.6% frequency. Conclusions: Understanding the genomic landscape of PDAC is critical as we move towards increased use of targeted therapies to treat this disease. In this study, TP53, PTPRT, GNAS, and ARID1A mutations were shown to occur at different frequencies in specific racial and ethnic groups. G12D mutation of KRAS was disproportionately increased in Hispanics. These differences in molecular landscape amongst racial and ethnic groups could contribute to precision medicine strategies used to address this deadly disease.
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Wiens, G. D., K. A. Heldwein, M. P. Stenzel-Poore e M. B. Rittenberg. "Somatic mutation in VH complementarity-determining region 2 and framework region 2: differential effects on antigen binding and Ig secretion." Journal of Immunology 159, n. 3 (1 agosto 1997): 1293–302. http://dx.doi.org/10.4049/jimmunol.159.3.1293.
Testo completoAbstract (sommario):
Abstract The extent to which somatic mutation impairs the Ig complementarity-determining region (CDR) and framework region (FRW) structure/function is not clear. Previously, we found that the VH CDR2 of the murine T15 Ab is highly sensitive to mutation; 56% (26 of 46) of Abs mutated in vitro had reduced or no Ag binding capability, and 9% were secretion impaired. Here we test whether the T15 VH CDR2 structure is unique by mutating the VH CDR2 of the anti-PC-protein murine Ab, PCG1-1. PCG1-1 VH is encoded by the M141 gene and is unrelated in sequence or structure to that of T15 VH1. The majority (54%, 20 of 37) of PCG1-1 mutants carrying one to five mutations in VH CDR2 had reduced or abolished Ag binding, while 10% were secretion impaired. Taken together, mutational analysis of the VH1 and VH M141 genes demonstrates that impaired binding and secretion may be common outcomes of CDR2 somatic mutation. We also tested the tolerance of the VH FRW2 of T15 to mutation, expecting this sequence-conserved region to be highly sensitive to alterations. However, FRW2 accommodated many nonconservative changes, and only 12% (3 of 25) of secreted mutants had impaired Ag binding. Moreover, mutations in FRW2 caused secretion defects in 24% (8 of 33), a frequency twice that of VH CDR2 mutants. A total of 16 unique secretion mutants have now been identified. These findings suggest that B cell losses from somatic mutation may be extensive and due to varied causes not all related to Ag binding.
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Lin, Selena Y., Ting-Tsung Chang, Jamin D. Steffen, Sitong Chen, Surbhi Jain, Wei Song, Yih-Jyh Lin e Ying-Hsiu Su. "Detection of CTNNB1 Hotspot Mutations in Cell-Free DNA from the Urine of Hepatocellular Carcinoma Patients". Diagnostics 11, n. 8 (14 agosto 2021): 1475. http://dx.doi.org/10.3390/diagnostics11081475.
Testo completoAbstract (sommario):
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The beta-catenin gene, CTNNB1, is among the most frequently mutated in HCC tissues. However, mutational analysis of HCC tumors is hampered by the difficulty of obtaining tissue samples using traditional biopsy. Here, we explored the feasibility of detecting tumor-derived CTNNB1 mutations in cell-free DNA (cfDNA) extracted from the urine of HCC patients. Using a short amplicon qPCR assay targeting HCC mutational hotspot CTNNB1 codons 32–37 (exon 3), we detected CTNNB1 mutations in 25% (18/73) of HCC tissues and 24% (15/62) of pre-operative HCC urine samples in two independent cohorts. Among the CTNNB1-mutation-positive patients with available matched pre- and post-operative urine (n = 13), nine showed apparent elimination (n = 7) or severalfold reduction (n = 2) of the mutation in urine following tumor resection. Four of the seven patients with no detectable mutations in postoperative urine remained recurrence-free within five years after surgery. In contrast, all six patients with mutation-positive in post-operative urine recurred, including the two with reduced mutation levels. This is the first report of association between the presence of CTNNB1 mutations in pre- and post-operative urine cfDNA and HCC recurrence with implications for minimum residual disease detection.
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Patterson, Andrew, Abdurrahman Elbasir, Bin Tian e Noam Auslander. "Computational Methods Summarizing Mutational Patterns in Cancer: Promise and Limitations for Clinical Applications". Cancers 15, n. 7 (24 marzo 2023): 1958. http://dx.doi.org/10.3390/cancers15071958.
Testo completoAbstract (sommario):
Since the rise of next-generation sequencing technologies, the catalogue of mutations in cancer has been continuously expanding. To address the complexity of the cancer-genomic landscape and extract meaningful insights, numerous computational approaches have been developed over the last two decades. In this review, we survey the current leading computational methods to derive intricate mutational patterns in the context of clinical relevance. We begin with mutation signatures, explaining first how mutation signatures were developed and then examining the utility of studies using mutation signatures to correlate environmental effects on the cancer genome. Next, we examine current clinical research that employs mutation signatures and discuss the potential use cases and challenges of mutation signatures in clinical decision-making. We then examine computational studies developing tools to investigate complex patterns of mutations beyond the context of mutational signatures. We survey methods to identify cancer-driver genes, from single-driver studies to pathway and network analyses. In addition, we review methods inferring complex combinations of mutations for clinical tasks and using mutations integrated with multi-omics data to better predict cancer phenotypes. We examine the use of these tools for either discovery or prediction, including prediction of tumor origin, treatment outcomes, prognosis, and cancer typing. We further discuss the main limitations preventing widespread clinical integration of computational tools for the diagnosis and treatment of cancer. We end by proposing solutions to address these challenges using recent advances in machine learning.
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Lyons, Daniel, e Adam Lauring. "Mutation and Epistasis in Influenza Virus Evolution". Viruses 10, n. 8 (3 agosto 2018): 407. http://dx.doi.org/10.3390/v10080407.
Testo completoAbstract (sommario):
Influenza remains a persistent public health challenge, because the rapid evolution of influenza viruses has led to marginal vaccine efficacy, antiviral resistance, and the annual emergence of novel strains. This evolvability is driven, in part, by the virus’s capacity to generate diversity through mutation and reassortment. Because many new traits require multiple mutations and mutations are frequently combined by reassortment, epistatic interactions between mutations play an important role in influenza virus evolution. While mutation and epistasis are fundamental to the adaptability of influenza viruses, they also constrain the evolutionary process in important ways. Here, we review recent work on mutational effects and epistasis in influenza viruses.
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Hwang, Tae Sook, Wook Youn Kim, Hye Seung Han, So Dug Lim, Wan-Seop Kim, Young Bum Yoo, Kyoung Sik Park, Seo Young Oh, Suk Kyeong Kim e Jung Hyun Yang. "Preoperative RAS Mutational Analysis Is of Great Value in Predicting Follicular Variant of Papillary Thyroid Carcinoma". BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/697068.
Testo completoAbstract (sommario):
Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n=57), BRAF K601E (n=11), or RAS (n=64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.
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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, n. 5 (2023): 1398–406. http://dx.doi.org/10.4103/jcrt.jcrt_1986_21.
Testo completoAbstract (sommario):
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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Ito-Harashima, Sayoko, Phillip E. Hartzog, Himanshu Sinha e John H. McCusker. "The tRNA-Tyr Gene Family ofSaccharomyces cerevisiae: Agents of Phenotypic Variation and Position Effects on Mutation Frequency". Genetics 161, n. 4 (1 agosto 2002): 1395–410. http://dx.doi.org/10.1093/genetics/161.4.1395.
Testo completoAbstract (sommario):
AbstractExtensive phenotypic diversity or variation exists in clonal populations of microorganisms and is thought to play a role in adaptation to novel environments. This phenotypic variation or instability, which occurs by multiple mechanisms, may be a form of cellular differentiation and a stochastic means for modulating gene expression. This work dissects a case of phenotypic variation in a clinically derived Saccharomyces cerevisiae strain involving a cox15 ochre mutation, which acts as a reporter. The ochre mutation reverts to sense at a low frequency while tRNA-Tyr ochre suppressors (SUP-o) arise at a very high frequency to produce this phenotypic variation. The SUP-o mutations are highly pleiotropic. In addition, although all SUP-o mutations within the eight-member tRNA-Tyr gene family suppress the ochre mutation reporter, there are considerable phenotypic differences among the different SUP-o mutants. Finally, and of particular interest, there is a strong position effect on mutation frequency within the eight-member tRNA-Tyr gene family, with one locus, SUP6, mutating at a much higher than average frequency and two other loci, SUP2 and SUP8, mutating at much lower than average frequencies. Mechanisms for the position effect on mutation frequency are evaluated.
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Keightley, Peter D., e Ohmi Ohnishi. "EMS-Induced Polygenic Mutation Rates for Nine Quantitative Characters in Drosophila melanogaster". Genetics 148, n. 2 (1 febbraio 1998): 753–66. http://dx.doi.org/10.1093/genetics/148.2.753.
Testo completoAbstract (sommario):
Abstract Polygenic mutations were induced by treating Drosophila melanogaster adult males with 2.5 mm EMS. The treated second chromosomes, along with untreated controls, were then made homozygous, and five life history, two behavioral, and two morphological traits were measured. EMS mutagenesis led to reduced performance for life history traits. Changes in means and increments in genetic variance were relatively much higher for life history than for morphological traits, implying large differences in mutational target size. Maximum likelihood was used to estimate mutation rates and parameters of distributions of mutation effects, but parameters were strongly confounded with one another. Several traits showed evidence of leptokurtic distributions of effects and mean effects smaller than a few percent of trait means. Distributions of effects for all traits were strongly asymmetrical, and most mutations were deleterious. Correlations between life history mutation effects were positive. Mutation parameters for one generation of spontaneous mutation were predicted by scaling parameter estimates from the EMS experiment, extrapolated to the whole genome. Predicted mutational coefficients of variation were in good agreement with published estimates. Predicted changes in means were up to 0.14% or 0.6% for life history traits, depending on the model of scaling assumed.
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Alohali, Sama, Alexandra E. Payne, Marc Pusztaszeri, Mohannad Rajab, Véronique-Isabelle Forest, Michael P. Hier, Michael Tamilia e 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, n. 2 (8 gennaio 2023): 413. http://dx.doi.org/10.3390/cancers15020413.
Testo completoAbstract (sommario):
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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Li, Hongxia, Qianqian Duan e Yuan Tan. "Somatic and germline mutation profiles of Chinese young colorectal cancer patients." Journal of Clinical Oncology 39, n. 15_suppl (20 maggio 2021): e15522-e15522. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15522.
Testo completoAbstract (sommario):
e15522 Background: In recently years, although CRC morbidity and mortality can be mitigated through appropriate screening and surveillance, the incidence rate of colorectal cancer (CRC) younger than 50 years old increased annually. Limited studies have investigated the underpinnings driving CRC development in Chinese younger population. In our study, we aim to explore the comprehensive mutational profile of Chinese CRC patients old (＞50) and young (≤50) diagnosed with CRC. Methods: Targeted sequencing with a 539 cancer-related genes panel was performed on 235 patients diagnosed with CRC. We investigate the landscape and difference of old and young CRC somatic and germline mutations in our Chinese cohort and compare with TCGA CRC cohort (N = 592). Results: Analysis revealed an overall 20.9% (49/235) mutation detection rate of young CRC in our Chinese cohort, which is higher than TCGA cohort (13.9%, 82/592). In our cohort, all Chinese young CRC patients can detect mutation and median mutation count is 10 mutations which is similar to old CRC patients (11 mutations). Comparing high frequency somatic mutations (young group with top 20), we found that BRCA2 mutation in young CRC group is significantly higher than old group (18.4% vs 7.0%, P = 0.025). In TCGA cohort, there is no difference between two groups with top 20 mutations and frequency of BRCA2 is 13.4% (11/82) in young CRC. For germline mutation, 12.29% (29/236) patients in our Chinese cohort harbored pathogenic and likely pathogenic (P/LP) germline mutations and 24.1% (7/29) CRC with P/LP germline mutations is young patients. In these seven P/LP mutation young patients, three patients have MMR gene mutation, two patients harbor ATM mutation, one patient has APC and another has SLX4 mutation. Moreover, young CRC have higher frequency MSI-H than old CRC patients (28.6% vs 18.2%). Conclusions: Our study has identified that young CRC patients account for a higher proportion in Chinese population and BRAC2 mutation may be an important factor in the early development of colorectal tumors in younger patients. In addition, our results also support the role of MSI statues in tumor oncogenesis in Chinese patients with early-onset CRC, indicating the need to include a more comprehensive germline mutation and genetic screening in our population.
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Ha, Jung Sook, Jae Hee Lee, Sung Gyun Park, Nam Hee Ryoo, Dong Suk Jeon, Jae Ryong Kim, Young Rok Do et al. "Correlations Between TET2 Mutation and Clinicohematologic Parameters in Myeloproliferative Neoplasms". Blood 120, n. 21 (16 novembre 2012): 1455. http://dx.doi.org/10.1182/blood.v120.21.1455.1455.
Testo completoAbstract (sommario):
Abstract Abstract 1455 Background: Since the acquired somatic mutation, JAK2 V617F, was discovered as a first molecular marker of myeloproliferative neoplasms (MPN), and it has been detected variably in each MPN subtypes. However, JAK2 V617F does not found in all of MPN cases and not necessarily specific to a particular clinicpathologic entity. Recently, mutation of the putative tumor suppressor gene, Ten-Eleven-Translocation-2(TET2), has been identified in MPN patients. However, the frequency of TET2 mutation or its relationship with JAK2 V617F mutation or pathologic function in MPN has not been concluded, yet. The aim of our study was to evaluate the frequency of TET2 in MPN patients, and whether there is any correlation of TET2 mutation with JAK2V617F mutation or the clinicohematologic parameters. Materials and Methods: Total 99 adult MPN patients (18 PV, 62 ET, 11 PMF and 8 MPN unclassified) whose bone marrow cells had been stored from 2007 to 2010 at point of first diagnosis were included in this study. Hematological diagnoses and subtyping were reconfirmed according to the 2008 WHO classification and clinicohematologic datas were collected from patient records. Direct sequencing for TET2(exon3–11) and JAK2 (exons 12 and 14) were performed using an ABI 3730XL DNA analyzer. The JAK2V617F allele burdens were determined by pyrosequencing for samples available and MPL was analyzed by allele-specific PCR. Results: The overall TET2 mutational frequency was 12.1%, and disease-specific mutational frequencies were 22.2% in PV, 9.7% in ET and 18.2% in PMF. The found mutations included 11 mutations, 7 frame-shift (p.Lys95AsnfsX18, p.Gln967AsnfsX40, p.Lys1022GlufsX4, p.Asp1314MetfsX49, p.Gln1534AlafsX43, p.Tyr1618LeufsX4, p.Leu1609GlufsX45), 1 nonsense (p.Gly1735X), 1 missense (Q599R) and 2 splicing mutations (c.3409+1G>T, c.4044+2insT). Those mutations most frequently involved exon 3(four mutations) and exon 11(four mutaions), and rarely intron 3, intron 8 and exon 7. None of the mutations were associated with a karyotypically apparent 4q24 rearrangement. All patients were also screened for JAK2 V617F, and the overall JAK2 V617F positive rate was 68%(94.4% in PV, 69.4% in ET, 45.5% in PMF and 37.5% in MPN, unclassified). All TET2 mutations occurred in JAK2 V617F positive cases. JAK2 exon12 mutation was not found in all patients. MPL W515L was found in one ET patient who also carried JAK2V617F, but not TET2 mutation. Information on JAK2 V617F allele burden was available in 78 patients. Considering all 99 patients, the patient age, hematologic indexes (leukocyte count, neutrophil fraction, lymphocyte fraction, monocyte fraction, Hb, Hct and platelet count), the frequency of organomegaly, marrow fibrosis or thrombotic/hemorrhagic complications were not different according to carrying TET2 mutation. However, TET2 mutation was more frequently found in JAK2 V617F carriers than non-carriers (P=0.008), but JAK2 V617F allele burden did not correlated with the presence of mutant TET2. When analysis was performed for each PV, ET, and PMF (no TET2 mutation in MPN-unclassifiable patients), correlation between TET2 and JAK2 V617F mutational status was not found in each subtypes (P=0.078 in PV, P=0.099 in ET and P=0.182 in PMF). However, the JAK2 V617F allele burden was significantly higher in PMF harboring TET2 mutation than PMF patients did not (88.0 ± 4.3% vs 19.1 ± 28.7%, P=0.034). In statistical analysis for the correlations of clinicohematologic parameters with TET2 mutation in each PV, ET and PMF patients, only a few statistically significant results were identified. The presence of TET2 mutation was correlated with high Hct in PMF (47.4 ± 5.4 vs 25.5 ± 6.2, P=0.037), and TET2 positive ET patients showed relatively higher frequency of organomegaly compared to ET patients without TET2 mutation (50% vs 19.6%, P=0.018). Conclusions: The overall and disease-specific frequencies of TET2 mutation in our study are similar with previous studies, and frame-shift mutation is the most frequent mutation type. There is no specific relationship between JAK2 V617F and TET2 mutation occurrence, but TET2 mutant PMF has higher JAK2 V617F allele burden than non-mutant. TET2 mutation is also associated with a higher Hct in PMF and higher frequency of organomegaly in ET. Larger scale studies involving more MPN patients are needed. Disclosures: No relevant conflicts of interest to declare.
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Müller, Martin C., Jorge Cortes, Dong-Wook Kim, Brian J. Druker, Philipp Erben, Ricardo Pasquini, Timothy P. Hughes, Yousif Matloub, Lynn Ploughman e Andreas Hochhaus. "Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations". Blood 112, n. 11 (16 novembre 2008): 449. http://dx.doi.org/10.1182/blood.v112.11.449.449.
Testo completoAbstract (sommario):
Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 >3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 >200 nM; n=21) achieved a response. Among 70 patients with >1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 >3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 >3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 >3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD >3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had >1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 >3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)
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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, n. 11 (16 novembre 2007): 320. http://dx.doi.org/10.1182/blood.v110.11.320.320.
Testo completoAbstract (sommario):
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.