Mutations In Hereditary Cancer Genes Research Articles

Impact of the 2018 ACR Supplemental Screening Recommendations on MRI Eligibility in Breast Cancer Survivors.

The 2018 American College of Radiology (ACR) recommendations for breast cancer screening in women at higher-than-average risk include new recommendations for supplemental breast MRI for patients with a personal history of breast cancer (PHBC) who either carry a hereditary cancer gene mutation, have dense breast tissue, or were diagnosed before age 50. In comparison, prior guidelines only recommended supplemental MRI for women with PHBC who carried a hereditary cancer gene mutation. In this study, we sought to quantify the increase in number of breast cancer patients for whom supplemental breast MRI would now be recommended. Data were extracted from the electronic health record of patients presenting for screening or diagnostic mammograms at an urban academic medical center between July 20, 2020 and July 19, 2021. Data extracted including patient reported PHBC, age at time of breast cancer diagnosis, and hereditary cancer gene mutation carrier status. We report descriptive statistics evaluating the rate of eligibility for supplemental Breast MRI in a retrospective population given the new ACR guidelines. Of the 2950 patients with a self-reported PHBC who presented for breast cancer screening in a year between July 2020 and 2021, 1805 (61%) of patients met criteria for supplemental breast MRI according to the 2018 guidelines compared to only 3.6% using pre-2018 guidelines. Measuring the impact of the 2018 ACR supplemental MRI recommendations using real-world data at a single urban academic medical center demonstrated a 15-fold increase in potential eligibility for supplemental breast MRI in patients with a PHBC.

HEREDITARY CANCER MUTATIONS PREVALENCE AMONG BREAST CANCER PATIENTS ACCORDING TO NGS PANEL TESTING RESULTS, ITS IMPORTANCE IN CHOOSING THE EXTENT OF SURGICAL TREATMENT

Summary. Genetic testing for hereditary cancer gene mutations is important for breast cancer patients in many aspects (including the degree of risk determining the extent of surgical treatment) and helps the patient to choose the best option, both from the point of view of risk reducing, and from the point of view of the best aesthetic result and minimizing the consequences of treatment. Aim: to determine the spectrum of gene mutations in breast cancer patients who had at least one of the risk factors for heredity of the disease. Object and methods: the study included 160 breast cancer patients who had at least one of the risk factors for heredity of the disease according to the criteria defined in the NCCN version 2.2019 guideline. All patients underwent next-generation DNA sequencing (NGS) genetic testing for a panel of 30 hereditary cancer genes. Statistical analysis of the obtained results was carried out in the EXCEL. Results: among 160 patients, 90 mutations were detected in 72 patients (45.0%). Among them, 59 patients (81.9%) had one mutation, 13 patients (18.1%) had more than one mutation. 51 pathogenic or likely pathogenic mutations were detected in 45 patients. 39 VUS (variant of uncertain significance) mutations were detected in 31 patients. The rate of hereditary breast cancer among the studied patients was 27.5%. The most frequent gene mutations were: BRCA1 (47.1%), CHEK2 (17.6%), BRCA2 (17.6%), ATM (5.9%), PALB2 (3.9%), BRIP1 (2, 0%), others (5.9%). Among them, the most frequent mutation was 5382ins C of the BRCA1 gene. For 64.3% of patients, the results of genetic testing had the highest importance when choosing the extent of surgical intervention, and for only 5.1% of patients they were completely unimportant. Conclusion: genetic testing is important for patients in many aspects, from the choice of the scope of surgical treatment to the features of followup, preventive measures to reduce the risk of new events (multiple primary neoplasms), the feasibility of testing children, etc. It is relevant to continue studying the role of genetic testing for breast cancer patients in various aspects, in particular, in choosing the scope of surgical treatment.

Hereditary Cancer Gene Variants in Hispanic Men With a Personal or Family History of Prostate Cancer.

Mutations in several common hereditary cancer genes are associated with prostate cancer, but there is limited information on the prevalence of these mutations in Hispanic men. We selected men at high risk for genetic mutations from 1515 Hispanic men enrolled in the San Antonio Biomarkers of Risk for prostate cancer (SABOR) cohort. Inclusion criteria included men with a diagnosis of prostate cancer or a first-degree family history of prostate cancer. We performed germline genetic testing using the Color Genomics platform, sequencing 30 genes associated with hereditary cancer risk. Additionally, we assessed ancestral informative markers to determine the admixture of the ethnically unique cohort. Of the 275 subjects who met selection criteria, 263 patients had sufficient samples for sequencing. We identified 3.8% of patients (10 of 263) with a pathogenic or likely pathogenic mutation in the 30 genes tested, of whom 70% would not have met established criteria for genetic testing. Six of these mutations were in BRCA1/2 or ATM. There was a significant inverse association between the percentage of Native American ancestry and the risk of prostate cancer, OR 0.11 (95% CI 0.02-0.76, P=.025). Hispanic men with either a personal or family history of prostate cancer carry mutations in hereditary cancer genes at a significant rate, on par with non-Hispanic counterparts with similar risk factors.

Germline alterations in patients with testicular cancer.

397 Background: There are limited data for the association of testis cancer (TC) with hereditary cancer genes. We report the prevalence of germline mutations among men with TC completing germline genetic testing through a large, commercial laboratory. Methods: We reviewed a de-identified dataset of men from across the USA with history of TC who underwent testing of 1 to 130 genes via massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. P/LP variants including single nucleotide variants/indels/copy number variants are reported. Fisher’s Exact test was used to analyze categorical variables. Results: The cohort of 250 men was 84% White/Caucasian. The median number of genes tested was 48. P/LP variants were found in 18% (n = 45) of subjects. P/LP variants occurred in several moderate to high penetrance genes, including CHEK2 (n = 10 [4.0%]), BRCA1/2 (n = 6 [2.4%]), ATM (n = 6 [2.4%]) and Lynch syndrome genes (n = 4 [1.6%]). Heterozygous MUTYH (n = 6) and NTHL1 (n = 1) mutations were also found. DNA damage repair (DDR) mutations were found in 14.8% (n = 37) of subjects. Of the 45 carriers, 18 (40%) had no other personal cancer history while 27 (60%) had an additional primary cancer, but there was no significant association between having another primary and risk of carrying a mutation (p = 0.253). CHEK2 was the single most frequently mutated gene, with 2 of the low penetrance I157T mutations identified, but 8 other higher penetrance variants, including 2 1100delC mutations. Conclusions: A high percentage of hereditary cancer gene mutations were found in testicular cancer patients, many which were not associated with a history of another malignancy. Several mutations were in high penetrance DDR genes such as BRCA1/2 and Lynch genes, which may also serve as actionable targets. CHEK2 mutations were common, supporting prior data suggesting an association with testicular cancer. Further multigene panel testing in unselected patients and the study of association with histologic subtype, race, stage and family history is warranted.

Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients.

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.

Women with breast and uterine cancer are more likely to harbor germline mutations than women with breast or uterine cancer alone: A case for expanded gene testing

ObjectiveWe explored the germline mutation spectrum and prevalence among 1650 women with breast and uterine cancer (BUC) who underwent multi-gene hereditary cancer panel testing at a single commercial laboratory. MethodsThe combined frequency of mutations in 23 BC and/or UC genes was compared between BUC cases and control groups with (1) no personal cancer history; (2) BC only; and (3) UC only using logistic regression. ResultsFourteen percent (n = 231) of BUC cases tested positive for mutations in BC and/or UC genes and were significantly more likely to test positive than individuals with BC only (P < 0.001), UC only (P < 0.01), or unaffected controls (P < 0.001). Analysis of gene-specific mutation frequencies revealed that MSH6, CHEK2, BRCA1, BRCA2, ATM, PMS2, PALB2 and MSH2 were most frequently mutated among BUC cases. Compared to BC only, BRCA1, MLH1, MSH2, MSH6, PMS2 and PTEN mutations were more frequent among BUC; however, only ATM mutations were more frequent among BUC compared to UC only. All of the more commonly mutated genes have published management guidelines to guide clinical care. Of patients with a single mutation in a gene with established testing criteria (n = 152), only 81.6% met their respective criteria, and 65.8% met criteria for multiple syndromes. ConclusionsWomen with BUC are more likely to carry hereditary cancer gene mutations than women with breast or uterine cancer alone, potentially warranting expanded genetic testing for these women. Most mutations found via multi-gene panel testing in women with BUC have accompanying published management guidelines and significant implications for clinical care.

Abstract OI-1: OI-1 Decoding breast cancer predisposition genes

Abstract Women with one or more first-degree female relatives with a history of breast cancer have a two-fold increased risk of developing breast cancer. This risk increases with the number of affected family members, particularly for those diagnosed at a young age or with bilateral disease. Segregation analyses of breast cancer families led to the identification of inactivating mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes. Pathogenic variants resulting in truncation of these proteins, along with a small number of pathogenic missense variants, have been associated with 55% to 65% lifetime risk of breast cancer in the general population and up to 85% lifetime risks among women with a strong family history of the disease. In contrast, the influence on cancer risk of many rare variants of uncertain significance (VUS) is not known. Mutations in several genes in addition to BRCA1 and BRCA2 have been implicated in predisposition to breast cancer through family segregation studies. These include moderate risk mutations (relative risk between 2.0 and 5.0) in CHEK2 and ATM, high-risk mutations (relative risk greater than 5.0) in PALB2, and high-risk mutations in CDH1, PTEN, STK11, and TP53 that are associated with hereditary diffuse gastric cancer, Cowden, Peutz-Jeghers, and Li-Fraumeni syndromes. However, risks of breast and other cancers associated with mutations in these and other genes that have been suggested to predispose to cancer have not been established or have very broad confidence intervals. Despite the absence of accurate risk estimates clinical testing with gene panels for hereditary cancer gene mutations has become an integral component of medical management for high-risk families and individuals with triple negative breast cancer. To estimate breast cancer risks several large studies of breast cancer patients from the general population and from high-risk families are underway. These studies are expected to identify the subset of panel genes that are associated with increased risk of breast cancer or breast cancer subtypes and to establish more accurate risks of breast and other cancers. In addition, classification of the clinical relevance of VUS in BRCA1, BRCA2, and other predisposition genes remains a significant problem, with patients unable to benefit from enhanced risk assessment, prevention, and clinical management. Thousands of VUS in BRCA1 and BRCA2 have already been identified through clinical testing and many more in BRCA1, BRCA2, and other predisposition genes are being identified through panel-based genetic testing and tumor sequencing studies. Efforts to classify VUS as neutral or pathogenic have focused on large case-control studies and quantitative multifactorial models based on family history of cancer and pathology. However, more recent studies have established the utility of validated functional assays for VUS assessment. Hundreds of BRCA1 and BRCA2 VUS have been reclassified by commercial testing laboratories or by the ENIGMA consortium that serves as the expert review panel for variants in these genes for the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and BRCA Exchange (http://brcaexchange.org) publically accessible websites. Common genetic variants associated with breast cancer risk have also been identified through genome-wide association studies (GWAS). The magnitude of these associations have ranged from 1.03 to 1.29 in women of European ancestry. While the majority of the 179 known breast cancer variants are associated with estrogen receptor (ER) positive breast cancer, 21 of these show specific associations with ER negative or triple negative (ER negative, PR negative, HER2 negative) breast cancer. The variants in risk loci account for approximately 19% of the familial relative risk of breast cancer. Several studies have recently established that polygenic risk scores derived from these risk variants improve personalized risk assessment by identifying women at increased or reduced risk of breast cancer in the general population and by modifying risks of breast cancer among BRCA1 and BRCA2 mutation carriers. In summary, germline genetic studies have substantially changed the landscape of breast cancer, identifying mutations associated with moderate and high risks of breast cancer in up to 5% of population-based breast cancer cases and 35% of high-risk families and providing personalization of underlying breast cancer risk for all women. Citation Format: Couch FJ. OI-1 Decoding breast cancer predisposition genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OI-1.

Gender bias: Underdiagnosing hereditary cancer in men with prostate cancer.

1545Background: Men and women are equally likely to carry mutations in hereditary cancer genes and both have elevated cancer risks. Despite this, over 96% of patients undergoing hereditary cancer m...

Abstract P2-09-11: Consistency of pathogenicity determinations for hereditary cancer gene mutations

Abstract Background: As the number of laboratories offering genetic tests grows, the potential for inconsistent variant classifications increases. New resources can help address this: (a) ClinVar, a rapidly growing public database of clinical variants to which many (but not all) laboratories contribute; (b) the public release of thousands of BRCA1/2 reports from Myriad Genetics through the Sharing Clinical Reports Project (SCRP), the Free the Data (FTD) initiative, and recent publications; and (c) ExAC, a greatly improved database of population allele frequencies. These complement longstanding efforts, e.g. the ENIGMA consortium. In addition, the American College of Medical Genetics (ACMG) recently updated guidelines for the interpretation of sequence variants. Using these resources, we sought to investigate the consistency of variant classifications to help inform ongoing practice. Methods: Pathogenicity assessments for variants in hereditary cancer genes were collected from multiple sources. Among these were 15,364 BRCA1/2 submissions to ClinVar, including 5416 submissions from SCRP and 1062 from our prior work [1]. When 3 or more submissions for a variant were available, we determined a consensus interpretation requiring 2 of 3 submitters to agree (or 3 of 4, etc.) to identify outliers. For our own classifications, we established a point-based system based on the 2015 ACMG guidelines, and independently applied it to publicly available evidence of pathogenicity without regard to other labs' classifications. Results: Initially, discordance among ClinVar submissions appears high (20-30%). However, upon investigation much of this discordance is a result of (i) research submissions to ClinVar, (ii) differences in confidence (e.g. benign vs. likely benign), (iii) older data in ClinVar, (iv) single lab outliers, and (v) nuances in the detailed structure of the ClinVar database. A careful comparison using the consensus methodology of objectively filtered ClinVar data shows high concordance between our interpretations and consensus: 95% were identical and 99% were similar (e.g. benign and likely benign were considered similar). Where consensus was not achieved (8% of variants with 3 or more independent sources) or not possible (any variant with only 2 sources), pairwise comparisons showed that few of these remaining differences (5%) were clinically significant. Also, many variants with significant discordances appeared to be particularly rare in the human population, and thus would be present in few patients. The rate of discordances with SCRP/FTD data was similar with that of other ClinVar submitters. Conclusions: Evaluations of inter-laboratory concordance need to be done carefully to avoid over-counting differences. Laboratories generally agree on the clinical significance of the vast majority of variants. Furthermore, the inter-laboratory consensus classification is often reached using a careful implementation of the ACMG guidelines and publicly available data. Thoroughly understanding the remaining differences is challenging when the evidence used by any laboratory is not available for peer review. Detailed data and methods from this study are available for review and alternate analyses. [1] Lincoln et al. SABCS 2014; JMD 2015. Citation Format: Lincoln S, Nykamp K, Kobayashi Y, Yang S, Powers M, Anderson M, Monzon F, Topper S. Consistency of pathogenicity determinations for hereditary cancer gene mutations. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-11.

Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment

The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown. To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort. Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations. We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals. We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history. Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients. In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.

Update on ovarian cancer pathogenesis: history, controversies, emerging issues and future impact

Among American women, the most common cause of death from gynecologic malignancy is ovarian cancer. With the discovery and publicizing of hereditary cancer gene mutations, patients are actively seeking their physician’s advice on how to manage risk. As a cancer prevention measure, risk-reducing surgery has become a popular procedure. Based on studies of salpingo-oophorectomies from BRCA-positive women, the fallopian tube has been put forth as the cause of high-grade ovarian cancer. More recently, ovarian surface hilar stem cells have been suggested as the putative cells of origin. In this exciting time of new thinking about its origins, we stand on the threshold of new and promising strategies for more precise management of ovarian cancer patients.