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

Chenjie Zeng,Jirong Long,Xingyi Guo,Xiao-Ou Shu,Qiuyin Cai,Wanqing Wen,Yongbin Xiang,Jiajun Shi,Wei Zheng

doi:10.1007/s10549-020-05643-0

Abstract

PurposeLimited 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.MethodsWe 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.ResultsApproximately 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 BRCA2 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 BRCA1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants.ConclusionsThis 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.

Highlights

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Chinese women [1]
We identified 55 pathogenic variants in established breast cancer genes including ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, and TP53 and 5 pathogenic variants in candidate breast cancer genes including BARD1, BRIP1, and RAD51D (Supplementary Table S1), including 31 frameshift indels, 18 nonsense variants, 6 missense variants, 2 splicing variants, and 3 large deletions (Fig. 1)
By analyzing germline variations in breast cancer predisposition genes in population-based case–control studies using whole-exome sequencing, we found that 7.8% of cases and 0.6% of controls carried at least one pathogenic variant in 10 established and 3 candidate breast cancer predisposition genes

Summary

Introduction

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Chinese women [1]. The average age at breast cancer diagnosis in among Chinese women is 45–55 years, which is approximately 10–15 years younger than that in the United States. Our previous study and other studies in Chinese patients found a higher proportion of hormone receptornegative tumors compared with those in the United States [2, 3]. These together suggested differences in the distributions of risk factors between Chinese and their American counterparts. Multiple breast cancer predisposition genes have been identified, mainly from studies of women of

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