Identification of germline mutation using 30-gene sequencing and clinical characteristic of Chinese with hereditary breast cancer

Abstract

Background: With the recent discovery of other breast cancer susceptibility genes (e.g. CDH1, ATM, CHEK2, PALB2, RAD50), molecular diagnosis of hereditary breast and ovarian cancers (HBOC) using multigene panels could help to identify other moderate/low penetrance genes in patients who tested negative for BRCA mutation. However, the clinical management of these cancer predisposition genes have not been clearly defined, therefore only BRCA1 and BRCA2 are routinely included in the genetic screening. In view of the differences in the mutation spectrum across ethnicity, it is important to identify other HBOC genes to estimate the associated breast cancer risk in Chinese. Methods: High-risk breast cancer patients who were negative for BRCA1, BRCA2, TP53 and PTEN were selected from the Hong Kong Hereditary Breast Cancer Family Registry between 2007-2016. In the study, 745 patients were subjected to 30-gene panel by next-generation sequencing (Color Genomics). All detected pathogenic mutations were further validated by bi-directional DNA sequencing. The sequencing data was co-analyzed by our in-house developed bioinformatics pipeline. Result: Thirty-five pathogenic variants were identified in this series (4.7%), which correspond to 11 different cancer predisposition genes. Majority of the carriers (74.29%) had early-onset of breast cancer (age <45), 42.86% had ³ 2 family members with cancer and 17.14% were triple-negative. The most common mutated genes were PALB2 (1.21%), RAD51D (0.94%) and ATM (0.67%). However, the cancer risk of RAD51D in breast cancer warrants further investigation. Moreover, over 28% of patients had a variant of unknown significance (VUS) in these genes (excluding BRCA1, BRCA2, TP53 and PTEN), which account for 183 types of VUS. Data from large-cohort studies and international consortiums will help to define the pathogenicity and clinical interpretation/management of the variants. Conclusions: Our findings suggested that detection of PALB2 should be included in the genetic test panel in Chinese with breast cancer. Multigene panel testing is an efficient tool in the diagnosis of HBOC, this could help patients to understand the cancer risk and aid the development of effective treatments