Founder BRCA1/BRCA2/PALB2 pathogenic variants in French-Canadian breast cancer cases and controls

Abstract

Inherited germline pathogenic variants are responsible for ~5% of breast cancer globally. Through rapid expansion and isolation since immigration in the early 17 th century, french canadians are a relatively genetically homogenous founder population and therefore represent a unique demographic for genetic contributions to disease. to date, twenty variants in BRCA1, BRCA2, and PALB2 that predispose families to breast and ovarian cancer have been identified as recurring in the French-Canadian founder population. Our objective was to evaluate the clinical efficacy and validity of targeted genetic testing for these variants in Montreal French Canadians. A total of 555 breast cancer cases unselected for family history or age of diagnosis were genotyped, along with 1940 controls without a personal or family history of cancer. A Sequenom genotyping assay identified a pathogenic variant in 0.2% (5 of 1940) of cancer-free controls, and 3.8% (21/555) of breast cancer cases. Almost 10% (12/113) of early onset cases were heterozygous for founder BRCA1 or BRCA2 pathogenic variant. of twenty variants tested, only seven were identified in this study. The option of providing this test as population-based screening is discussed.Breast cancer is the most prevalent cancer worldwide (excluding non-melanoma skin cancer) and the second leading cause of death by cancer in women 1 . A strong family history of breast and/or ovarian cancer, as well as a personal history of early-onset or bilateral breast cancer, are suggestive of a heterozygous germline variant in a high-risk breast cancer susceptibility gene. BRCA1 and BRCA2 are the canonical genes in this family 2 , and the risks for breast cancer to age 80 among female BRCA1 or BRCA2 heterozygotes is 72% and 69%, respectively 3 . Partner and localizer of BRCA2 (PALB2) is essential to homologous recombination repair in response to double-stranded breaks in DNA 4 and is a more recently identified breast cancer predisposing gene. Average cumulative risk of developing breast cancer with a pathogenic germline PALB2 mutation is approximately 35% by age 70, and risk is higher in women with a family history of breast cancer (58%) 5 .

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

“…Further analysis of other members of our cancer family showed only one of five other carriers was affected by BC (unpublished data). This case is from the French Canadian population and carries a pathogenic variant in BRCA2 c.8537_8538delAG; p.Glu2846GlyfsTer22 known to be a founder pathogenic variant as reported by our group and others [84][85][86][87][88][89][90][91][92][93].…”

Clinical value and potential mechanisms of COL8A1 upregulation in breast cancer: a comprehensive analysis

“…GO, Gene Ontology; DEGs, differentially expressed genes; CEGs, co-expressed genes; KEGG, Kyoto Encyclopedia of Genes and Genomes BAK1, BRCA2, CDK4, GRB2, HRAS, PIK3R3, and POLK) were associated with the breast cancer pathway (ID: hsa05224), even though this pathway is not in the top 30 KEGG signaling pathways. Eight of these genes (except WNT2, GADD45B, FZD2, WNT7B, POLK, and PIK3R3) have been extensively studied in breast cancer [44][45][46][47][48][49]. Our DO analysis indicated that these genes are closely associated with myeloma, bone marrow cancer, renal cell carcinoma, ovarian cancer, and other cancer types.…”

The genetic analysis of a founder Northern American population of European descent identifiesFANCIas a candidate familial ovarian cancer risk gene

“…The average age of diagnosis was 44.6 years (range 22-65) and 43.7 years (range 18-65) for HBC and HBOC families, respectively. Sporadic BC cases were diagnosed with invasive BC before the age of 70 (average = 52.7, range 25-69) 131 . We cannot exclude the possibility that some cases occurred in more than one study group: based on RRCancer biobanking sample number, OC cases from at least 13 families were also found in pedigrees from BC cases that were genotyped from the familial HBOC study group.…”

“…Where normal DNA was no longer available from the study case, genomic DNA extracted from the tumor (if available) was provided by the RRCancer biobank for genotyping. PBL DNA from sporadic BC cases were genotyped using Sequenom® iPLEX® Gold Technology at the MGC 131 . Samples that were removed from the analysis were due to poor DNA quality (n=30), duplication (n=1), or were from cases exceeding age limit criteria (70 years or older when diagnosed with first invasive BC; n=2).…”