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Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer.

ABSTRACT: Hereditary breast and ovarian cancer (HBOC) can be identified by genetic testing of cancer-causing genes. In this study, we identified a spectrum of genetic variations among 76 individuals of Armenian descent either with a family history of cancer or breast cancer before the age of 40. We screened 76 suspected HBOC patients and family members as well as four healthy controls using a targeted and hereditary comprehensive cancer panel (127 genes). We found 26 pathogenic (path) and 6 likely pathogenic (LPath)variants in 6 genes in 44 patients (58%); these variants were found in BRCA1 (17), BRCA2 (19), CHEK2 (4), PALB2 (2), and NBN (1). A few different variants were found in unrelated individuals; most notably, variant p.Trp1815Ter in the BRCA1 gene occurred in four unrelated patients. We did not find any known significant variants in five patients. Comprehensive cancer panel testing revealed pathogenic variants in cancer genes other than BRCA1 and BRCA2, suggesting that testing only BRCA1 and BRCA2 would have missed 8 out of 44 suspected HBOC patients (18%). These data also confirm that a comprehensive cancer panel testing approach could be an appropriate way to identify most of the variants associated with hereditary breast cancer.

SUBMITTER: Moradian MM

PROVIDER: S-EPMC7870655 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer.

Moradian Mike M MM Babikyan Davit T DT Markarian Sione S Petrosyan Jonny G JG Avanesian Nare N Arutunyan Tereza T Sarkisian Tamara F TF

Human genome variation 20210209 1

Hereditary breast and ovarian cancer (HBOC) can be identified by genetic testing of cancer-causing genes. In this study, we identified a spectrum of genetic variations among 76 individuals of Armenian descent either with a family history of cancer or breast cancer before the age of 40. We screened 76 suspected HBOC patients and family members as well as four healthy controls using a targeted and hereditary comprehensive cancer panel (127 genes). We found 26 pathogenic (path) and 6 likely pathoge ...[more]

PMID: 33558524

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Project description:BackgroundSpecific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.MethodsTP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.ResultsFive new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.ConclusionsIn all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.

Project description:BackgroundBRCA1 and BRCA2 mutations explain approximately one-fifth of the inherited susceptibility in high-risk Finnish hereditary breast and ovarian cancer (HBOC) families. EMSY is located in the breast cancer-associated chromosomal region 11q13. The EMSY gene encodes a BRCA2-interacting protein that has been implicated in DNA damage repair and genomic instability. We analysed the role of germline EMSY variation in breast/ovarian cancer predisposition. The present study describes the first EMSY screening in patients with high familial risk for this disease.MethodsIndex individuals from 71 high-risk, BRCA1/2-negative HBOC families were screened for germline EMSY sequence alterations in protein coding regions and exon-intron boundaries using Sanger sequencing and TaqMan assays. The identified variants were further screened in 36 Finnish HBOC patients and 904 controls. Moreover, one novel intronic deletion was screened in a cohort of 404 breast cancer patients unselected for family history. Haplotype block structure and the association of haplotypes with breast/ovarian cancer were analysed using Haploview. The functionality of the identified variants was predicted using Haploreg, RegulomeDB, Human Splicing Finder, and Pathogenic-or-Not-Pipeline 2.ResultsAltogether, 12 germline EMSY variants were observed. Two alterations were located in the coding region, five alterations were intronic, and five alterations were located in the 3'untranslated region (UTR). Variant frequencies did not significantly differ between cases and controls. The novel variant, c.2709 + 122delT, was detected in 1 out of 107 (0.9%) breast cancer patients, and the carrier showed a bilateral form of the disease. The deletion was absent in 897 controls (OR = 25.28; P = 0.1) and in 404 breast cancer patients unselected for family history. No haplotype was identified to increase the risk of breast/ovarian cancer. Functional analyses suggested that variants, particularly in the 3'UTR, were located within regulatory elements. The novel deletion was predicted to affect splicing regulatory elements.ConclusionsThese results suggest that the identified EMSY variants are likely neutral at the population level. However, these variants may contribute to breast/ovarian cancer risk in single families. Additional analyses are warranted for rare novel intronic deletions and the 3'UTR variants predicted to have functional roles.

Project description:BackgroundGenetic testing for breast cancer (BC) patients may shift the paradigm towards more personalized management and treatment strategies. While gene alterations may be ethnic-specific in breast cancer, our understanding of genetic epidemiology of BC remains mainly driven by data from Caucasian populations and further limited to selected handful of genes.MethodsWe collected whole blood samples from 356 BC patients at metastatic first line BC and primary stage IV disease at Beijing Cancer Hospital between Jan. 2013 to Dec. 2019. A comprehensive 600-gene cancer panel was used to detect germline variants in the covered genes with a median 300x sequencing depth. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. Pathogenic and likely pathogenic variants were considered as deleterious mutations.ResultsThe median age of 356 BC patients was 49 years (range, 21-87 years) at the first diagnosis of BC. Deleterious germline mutations across 48 cancer-related genes were identified in 21.6% (77/356) of the patients. The most prevalent mutations were BRCA1/2 mutations (7.0%), followed by ATM and RAD50 mutations (1.4% each). In addition, patients with family history were more likely to carry BRCA1 mutations (P=0.04). Moreover, patients with triple-negative breast cancer (TNBC) were more likely to harbor BRCA1 mutations than those with HR+ or HER2+ breast cancer (P=0.006). While there was no significant survival difference observed in BRCA1/2 carriers relative to non-carriers, patients with DNA damage repair (DDR) gene mutations (mostly frequently BRCA, ATM, RAD50) had worse disease-free survival (P=0.02).ConclusionsThe most prevalent germline mutations in a large cohort of Chinese patients with advanced BC were BRCA1/2 mutations, followed by ATM and RAD50 mutations. In total, approximately 16.0% (57/356) of patients carry deleterious mutations in DDR pathway. Patients with breast or ovarian cancer family history were more likely to carry BRCA1/2 mutations, and ones with DDR mutations had worse survival. These findings suggest that DDR mutations are prevalent in Chinese BC patients who may potentially benefit from treatment with Poly (ADP-ribose) polymerase inhibitors.

Dataset Information

Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer.

Publications

Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer.

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