Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women

Abstract

Purpose Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case-control study conducted in Shanghai, China. Methods We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study. Results Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (P = 3.05 × 10 −15). Among cases, 3.7% had a BRCA 2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D. Patients with BRCA 1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants. Conclusions This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach

“…This however is not unlike other genomics testing methods including the classic techniques such as MLPA 5 and copy number microarrays as well as other NGS-based CNV detection algorithms (Park and Mori, 2010;Zhao et al, 2013). This study has identified pathogenic (ACMG 1 and ACMG 2) CNVs in 32 of 2870 (1.1%) patients, or 32 of 431 (7.4%) of all PVs identified, a proportion roughly in line with few previous reports (Mancini-DiNardo et al, 2019;Tsaousis et al, 2019;Zeng et al, 2020). A significant subset of these CNVs have been identified in some of the less well characterized cancer predisposition genes and adds to the spectrum of variants 5 www.mrcholland.com reported in these genes (Table 2).…”

BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

“…It is worth emphasizing that we have performed a screening of CNVs in our cohort of HC patients, resulting in the identification of two large deletions (exons 7 to 8 and exons 7 to 11), accounting for 10.5% of the PVs. To our knowledge, only a small fraction of published studies have also performed this analysis and only seven CNVs have been identified so far: exon 1 deletion [33], exon 2 deletion [34], exon 1 to 6 deletion [35], exon 5 to 7 deletion [36], exon 8 to 11 deletion [37] and two whole-gene deletions [37,38]. While no CNVs were identified in the gnomAD SV control population dataset, analysis of BARD1 CNVs in HC cohorts is strongly recommended considering the significant contribution in our series of this kind of variant.…”

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

“…A panel NGS analysis involving 8085 Chinese breast cancer patients revealed only 18 (0.3%) carriers of pathogenic CHEK2 mutations [ 141 ]; eight of them carried the novel founder nonsense mutation c.C417A (p.Y139*) [ 142 ]. Only two carriers (0.24%) of CHEK2 mutations were identified in a recent analysis of 831 breast cancer patients from Shanghai [ 143 ]. Studies of breast and prostate cancer patients from Japan included analyses in control populations that revealed the presence of pathogenic CHEK2 germline mutations in 0.1% of both female and male noncancer controls [ 144 , 145 ].…”