Prevalence Of Deleterious Mutations Research Articles

Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System

BackgroundGermline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil.MethodsA cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes.ResultsThe prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time.ConclusionOne in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.

Inferring the distributions of fitness effects and proportions of strongly deleterious mutations.

The distribution of fitness effects is a key property in evolutionary genetics as it has implications for several evolutionary phenomena including the evolution of sex and mating systems, the rate of adaptive evolution, and the prevalence of deleterious mutations. Despite the distribution of fitness effects being extensively studied, the effects of strongly deleterious mutations are difficult to infer since such mutations are unlikely to be present in a sample of haplotypes, so genetic data may contain very little information about them. Recent work has attempted to correct for this issue by expanding the classic gamma-distributed model to explicitly account for strongly deleterious mutations. Here, we use simulations to investigate one such method, adding a parameter (plth) to capture the proportion of strongly deleterious mutations. We show that plth can improve the model fit when applied to individual species but underestimates the true proportion of strongly deleterious mutations. The parameter can also artificially maximize the likelihood when used to jointly infer a distribution of fitness effects from multiple species. As plth and related parameters are used in current inference algorithms, our results are relevant with respect to avoiding model artifacts and improving future tools for inferring the distribution of fitness effects.

Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta-analysis.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. We performed a systematic review and meta-analysis to evaluate the prevalence of genomic alterations in NEPC and better understand its molecular features to potentially inform precision medicine. EMBASE, PubMed, and Cochrane Central Register of Controlled Trials databases were searched for eligible studies until March 2022. Study qualities were assessed using the Q-genie tool. The prevalence of gene mutations and copy number alterations (CNAs) were extracted, and meta-analysis was performed using R Studio with meta package. A total of 14 studies with 449 NEPC patients were included in this meta-analysis. The most frequently mutated gene in NEPC was TP53 (49.8%), and the prevalence of deleterious mutations in ATM/BRCA was 16.8%. Common CNAs in NEPC included RB1 loss (58.3%), TP53 loss (42.8%), PTEN loss (37.0%), AURKA amplification (28.2%), and MYCN amplification (22.9%). RB1/TP53 alterations and concurrent RB1 and TP53 alterations were remarkably common in NEPC, with a prevalence of 83.8% and 43.9%, respectively. Comparative analyses indicated that the prevalence of (concurrent) RB1/TP53 alterations was significantly higher in de novo NEPC than in treatment-emergent NEPC (t-NEPC). This study presents the comprehensive prevalence of common genomic alterations and potentially actionable targets in NEPC and reveals the genomic differences between de novo NEPC and t-NEPC. Our findings highlight the importance of genomic testing in patients for precision medicine and provide insights into future studies exploring different NEPC subtypes.

The prevalence of deleterious mutations during the domestication and improvement of soybean

Soybean (Glycine max L.) is a protein and oil crop grown worldwide. Its fitness may be reduced by deleterious mutations, whose identification and purging is desirable for crop breeding. In the published whole-genome re-sequenced data of 2214 soybean accessions, including 221 wild soybean, 1132 landrace cultivars and 861 improved soybean lines, we identified 115,275 deleterious single-nucleotide polymorphisms (SNPs). Numbers of deleterious alleles increased from wild soybeans to landraces and decreased from landraces to modern improved lines. Genes in selective-sweep regions showed fewer deleterious mutations than the remaining genes. Deleterious mutations explained 4.3%–48% more phenotypic variation than randomly selected SNPs for resistance to soybean cyst nematode race 2 (SCN2), soybean cyst nematode race 3 (SCN3) and soybean mosaic virus race 3 (SMV3). These findings illustrate how mutation load has shifted during soybean domestication, expansion and improvement and provide candidate sites for breeding out deleterious mutations in soybean by genome editing and/or conventional breeding focused on the selection of progeny with fewer deleterious alleles.

Genomic and environmental influences on resilience in a cold-water fish near the edge of its range.

Small, isolated populations present a challenge for conservation. The dueling effects of selection and drift in a limited pool of genetic diversity make the responses of small populations to environmental perturbations erratic and difficult to predict. This is particularly true at the edge of a species range, where populations often persist at the limits of their environmental tolerances. Populations of cisco, Coregonus artedi, in inland lakes have experienced numerous extirpations along the southern edge of their range in recent decades, which are thought to result from environmental degradation and loss of cold, well‐oxygenated habitat as lakes warm. Yet, cisco extirpations do not show a clear latitudinal pattern, suggesting that local environmental factors and potentially local adaptation may influence resilience. Here, we used genomic tools to investigate the nature of this pattern of resilience. We used restriction site‐associated DNA capture (Rapture) sequencing to survey genomic diversity and differentiation in southern inland lake cisco populations and compared the frequency of deleterious mutations that potentially influence fitness across lakes. We also examined haplotype diversity in a region of the major histocompatibility complex involved in stress and immune system response. We correlated these metrics to spatial and environmental factors including latitude, lake size, and measures of oxythermal habitat and found significant relationships between genetic metrics and broad and local factors. High levels of genetic differentiation among populations were punctuated by a phylogeographic break and residual patterns of isolation‐by‐distance. Although the prevalence of deleterious mutations and inbreeding coefficients was significantly correlated with latitude, neutral and non‐neutral genetic diversity were most strongly correlated with lake surface area. Notably, differences among lakes in the availability of estimated oxythermal habitat left no clear population genomic signature. Our results shed light on the complex dynamics influencing these isolated populations and provide valuable information for their conservation.

1010P - Frequency of mutations in 21 hereditary breast and ovarian cancer susceptibility genes among 882 high-risk individuals

BackgroundMultiple high- and moderate- penetrance gene (including BRCA1 and BRCA2) have been discovered as susceptibility gene for hereditary breast and ovarian cancer. Recent advances in Next-generation sequencing (NGS) have provided an efficient method to evaluate these susceptibility gene simultaneously. The prevalence and clinical prediction factors associated with the pathogenic variants (PVs) have not been well studied in Chinese population. MethodsSubjects were selected from individuals referred for genetic testing using a 21-gene panel (Oseq-BRCA) between January 2015 and March 2018. The distribution and prevalence of deleterious mutations were analyzed for the full cohort as well as subtypes. ResultsOverall, 176 deleterious mutations were observed in 19.50% (n=172) individuals. Of these, 26 mutations are not reported in public databases and literatures. In the ovarian cancer only subgroup, 115 deleterious mutations were identified in 429 patients (48.6%). Patients with ovarian cancer with mutations were enriched for a family history of breast or ovarian cancers (p<0.05). In the breast cancer only subgroup, 31 deleterious mutations were identified in 261 patients. Most mutations occurred in BRCA1 (8; 25.8%) and BRCA2 (11; 35.5%). An additional 12 deleterious mutations (38.7%) were found in 7 other susceptibility genes. An increased frequency of mutation rate (57.9%) was observed in the subgroup of subjects with histories of both breast and ovarian cancer. Taken together, 19.50% of individuals carried a deleterious mutation in HBOC susceptibility genes in our cohort. Subgroup of subjects with histories of both breast and ovarian cancer had the highest prevalence of mutations. ConclusionsOur results highlighted the genetic heterogeneity of HBOC and the efficiency of multigene panel in performing risk assessment. Clinical trial identificationOur results highlighted the genetic heterogeneity of HBOC and the efficiency of multigene panel in performing risk assessment. Legal entity responsible for the studyBGI Genomics. FundingBGI Genomics. DisclosureD. Shao: Full / Part-time employment: BGI genomics. S. Cheng: Full / Part-time employment: BGI genomics. F. Guo: Full / Part-time employment: BGI genomics. Y. Yuan: Full / Part-time employment: BGI genomics. K. Hu: Full / Part-time employment: BGI genomics. Z. Wang: Full / Part-time employment: BGI genomics. X. Meng: Full / Part-time employment: BGI genomics. X. Jin: Full / Part-time employment: BGI genomics. X. Yun: Full / Part-time employment: BGI genomics. X. Chai: Full / Part-time employment: BGI genomics. H. Li: Full / Part-time employment: BGI genomics. Y. Zhang: Full / Part-time employment: BGI genomics. H. Zhang: Full / Part-time employment: BGI genomics. M. Ye: Full / Part-time employment: BGI genomics. All other authors have declared no conflicts of interest.

Population and breast cancer patients\u2019 analysis reveals the diversity of genomic variation of the BRCA genes in the Mexican population

Interpretation of variants of unknown significance (VUS) in genetic tests is complicated in ethnically diverse populations, given the lack of information regarding the common spectrum of genetic variation in clinically relevant genes. Public availability of data obtained from high-throughput genotyping and/or exome massive parallel sequencing (MPS)-based projects from several thousands of outbred samples might become useful tools to evaluate the pathogenicity of a VUS, based on its frequency in different populations. In the case of the Mexican and other Latino populations, several thousands of samples have been genotyped or sequenced during the last few years as part of different efforts to identify common variants associated to common diseases. In this report, we analyzed Mexican population data from a sample of 3985 outbred individuals, and additional 66 hereditary breast cancer patients were analyzed in order to better define the spectrum of common genomic variation of the BRCA1 and BRCA2 genes. Our analyses identified the most common genetic variants in these clinically relevant genes as well as the presence and frequency of specific pathogenic mutations present in the Mexican population. Analysis of the 3985 population samples by MPS identified three pathogenic mutations in BRCA1, only one population sample showed a BRCA1 exon 16–17 deletion by MLPA. This resulted in a basal prevalence of deleterious mutations of 0.10% (1:996) for BRCA1 and 11 pathogenic mutations in BRCA2, resulting in a basal prevalence of deleterious mutations of 0.276% (1:362) for BRCA2, combined of 0.376% (1:265). Separate analysis of the breast cancer patients identified the presence of pathogenic mutations in 18% (12 pathogenic mutations in 66 patients) of the samples by MPS and 13 additional alterations by MLPA. These results will support a better interpretation of clinical studies focused on the detection of BRCA mutations in Mexican and Latino populations and will help to define the general prevalence of deleterious mutations within these populations.

Abstract P4-10-11: An active approach to genetic counseling in Trinidadian women with breast cancer

Abstract Introduction Breast cancer (BC) is the leading cause of cancer death in Caribbean women. The prevalence of deleterious mutations in BRCA1/2, PALB2 and RAD51C among unselected BC patients in the Caribbean is 5-25%. We previously reported data on low usage of genetic counseling services by Bahamian women. In order to improve the dissemination of genetic testing results to Caribbean probands and their families we developed a structured approach to genetic test result dissemination and family counseling. Methods After approval by the University of Miami IRB and the Ethics Committee of the Ministry of Health of Trinidad &amp; Tobago, we prospectively evaluated the active approach to genetic counseling in 32 BC mutation carriers in Trinidad &amp; Tobago in 2015. The intervention consisted of: 1) initial appointment with referring oncologist for results discussion; 2) review of family tree with proband to identify all relatives at 25% or 50% risk (ARR) who should attend the genetic counseling session; 3) preschedule a counseling appointment for ARR within 2 weeks; 4) written invitation to genetic counseling session; 5) handouts of genetic information given to proband to distribute to family members; 6) offer assistance with contacting family members; 7) free genetic testing to ARR who attended the family counseling session. Results Twenty-five carriers (78%) consented to enroll in the study. At initial counseling, probands identified 158 ARR, however full family pedigree review at post-result counseling/consultation identified 225 ARR. 101 ARR (64%) attended the information sessions and 76 participants (75.2%) consented to be tested for BC gene mutations. Genetic sequencing revealed 35 ARR (46%) were carriers of at least one mutation. The most frequent reasons for ARR not attending the meetings were: living abroad (18%), unable to be contacted (17%), refusing to participate (17%), not showing up (17%), probands being estranged from ARR (12%) or being afraid to know the results (7%). Conclusions In Trinidad &amp; Tobago, a structured approach to the dissemination of genetic test results leads to a significant improvement in the rate of family participation compared to previous efforts (64% in Trinidad &amp; Tobago vs. 9% in the Bahamas). Citation Format: George SH, Bravo GL, Sandoval AC, Palacio S, Ali J, Donenberg TR, Akbari MR, Narod S, Hurley J. An active approach to genetic counseling in Trinidadian women with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-11.

Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population.

AimMultigene panel testing for Hereditary Breast and Ovarian Cancer (HBOC) using next generation sequencing is becoming more common in medical care.We report our experience regarding deleterious mutations of high and moderate-risk breast cancer genes (BRCA1/2, TP53, STK11, CDH1, PTEN, PALB2, CHEK2, ATM), as well as more recently identified cancer genes, many of which have increased risk but less well-defined penetrance.MethodsGenetic testing was performed in 130 consecutive cases with breast cancer referred to our clinic for surgical evaluation and who met the 2016 National Comprehensive Cancer Network (NCCN) criteria for genetic testing.Results82 patients had pathogenic/likely pathogenic mutations and VUS mutations, and 48 were negative; 36 of the pathogenic mutations were in the high-risk genes and 16 were in the moderate risk genes and only 5 cases in the intermediary risk group.From the VUS mutation group 21 cases were in the intermediary risk group, 9 cases were in the moderate risk group and only 7 cases in high risk group.The most frequent BRCA1 variant was c.3607C>T (7 cases) followed by c.5266dupC and c.4035delA (each in 4 cases). Regarding BRCA-2 mutations we identified c.9371A>T and c.8755-1G>A in 6 cases and we diagnosed VUS mutations in 3 cases.ConclusionOur study identified 2 mutations in the BRCA1 gene that are less common in the Romanian population, c.3607C>T and c.4035delA. Both variants had particular molecular phenotypes, c.3607C>T variant respecting the triple negative pattern of BRCA1 breast cancer while c.4035delA were Luminal B HER positive.

Abstract PD08-06: Significant Clinical impact of recurrent BRCA1 and BRCA2 (BRCA) mutations in Mexico

Abstract Background: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cancer cause of death in Hispanic women. Although the incidence of breast cancer in Hispanics is less than that for non-Hispanic white women, our studies on the prevalence of deleterious mutations in the BRCA genes among high-risk Hispanics in the US suggest that BRCA mutations may account for a higher proportion of BC in this population. However, a lack of research on BRCA mutations in Hispanics has limited the implementation of prevention efforts and the scope of comparative studies of genetic factors that influence BC and ovarian cancer (OC) risk within Hispanic populations – this is especially true of Mexico where there has been little access to clinical BRCA gene analyses. Objective/Methods: We used an economic panel assay (HISPANEL) on a mass spectroscopy platform (Sequenom) to analyze DNA from 189 cancer cases (92 unselected OC; 97 BC) from the National Cancer Institute in Mexico City for recurrent BRCA mutations, including a large rearrangement (BRCA1 ex9-12del) that we hypothesize is a Mexican founder mutation. Results: Overall, 14% (27/189) harbored a germline BRCA mutation (25 BRCA1, 2 BRCA2) detected by the HISPANEL (17% in OC; 11% in BC). BRCA1 ex9-12del was detected in 9.8% (9/92) of unselected OC cases, representing 56% of the 16 BRCA mutations. It also represented 36% (4/11) of the BRCA mutations detected in the BC cases. Mean age at onset of BC for BRCA-associated cases (n = 11) was 46 years old (range 31–63); 8/11 were triple negative BC (TNBC) – a BRCA mutation was detected in 24% (8/34) of all TNBC cases. Conclusions: The remarkable frequency of the BRCA1 ex9-12del mutation, accounting for 56% of BRCA mutations in the OC cases and 36% of BC cases, supports our hypothesis of regional origin of this Mexican founder mutation approximately 1,474 years ago. Similar to our experience in the Mexican American population, the HISPANEL, which includes recurrent BRCA mutations found in women of Hispanic ancestry, appears to have high sensitivity and thus is likely to have clinical utility while reducing overall genotyping cost among underserved women in Mexico. Both in the US Hispanic populations and in Mexico, the prevalence of the Mexican founder mutation make it a significant public health issue, and presents an opportunity for cost effective in BC and OC prevention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD08-06.

Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165-7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25-6.64).

Characterization of a novel founder rearrangement mutation of BRCA1 in high-risk Hispanic families

10015 Background: Large rearrangements are estimated to account for 5–10% of all mutations in BRCA1 and BRCA2. Prevalent founder rearrangement mutations have been described in European populations. We sought to identify rearrangements in the BRCA genes in a cohort of Hispanic patients. Methods: We identified 34 deleterious BRCA mutations via full sequence analysis among 110 unrelated high-risk Hispanic families enrolled in an IRB approved registry who underwent cancer risk assessment (CEBP 2005;14:1–6). DNA from 67 of 76 patients without an identifiable mutation was subjected to multiplexed quantitative differential PCR (MQDP, per B. Erickson and T. Scholl, Myriad Genetics Laboratory) for detection of large rearrangements. An apparent deletion of BRCA1 exons 9–12, indicated by a 50% loss of signal was identified by MQDP in 3 unrelated families (ASHG, 2005). Long range PCR resulted in the generation of a 2.7kb product in these samples, consistent with a deletion event of 15.1kb. This putative mutation was further characterized by cloning and sequencing the breakpoint in all 3 families. RNA splicing was evaluated by sequencing RT-PCR products from lymphoblastoid cell line RNA for each family. Results: Sequence analysis identified the breakpoint within Alu elements in introns 8 and 12, and all 3 unrelated families shared the same breakpoint. Analysis of cDNA demonstrated direct splicing of exons 8–13 predicting a frameshift mutation and premature truncation of the BRCA1 protein, thus confirming the deleterious nature of this mutation. Conclusion: We identified the same novel large deletion in three unrelated families of Mexican ancestry, suggesting potential founder effect. The frequency was 2.7% of the 110 high-risk Hispanic families screened for BRCA mutations, bringing the overall prevalence of deleterious mutations to 33.6%(37/110) in this cohort. This BRCA1 rearrangement may account for a substantial proportion of high-risk Hispanic families, and should be included in all subsequent studies of this ethnic group. No significant financial relationships to disclose.