Germline TP53 and MSH6 mutations implicated in sporadic triple-negative breast cancer (TNBC): a preliminary study

• Published in: Human genomics Vol. 13; no. 1; p. 4
• Main Authors: Yi, Dandan, Xu, Lei, Luo, Jiaqi, You, Xiaobin, Huang, Tao, Zi, Yi, Li, Xiaoting, Wang, Ru, Zhong, Zaixuan, Tang, Xiaoqiao, Li, Ang, Shi, Yujian, Rao, Jianmei, Zhang, Yifen, Sang, Jianfeng
• Format: Journal Article
• Language: English
• Published: England BioMed Central 10-01-2019; BMC
• Subjects: Adult; Aged; Aged, 80 and over; Asian Continental Ancestry Group - genetics; Ataxia Telangiectasia Mutated Proteins - genetics; BRCA1 protein; Breast cancer; Deoxyribonucleic acid; DNA; DNA Polymerase II - genetics; DNA sequencing; DNA-Binding Proteins - genetics; Female; Gene frequency; Genomics; Germ-Line Mutation; Humans; Immunotherapy; Middle Aged; Minority & ethnic groups; MSH6; MSH6 protein; Multi-gene testing; Mutation; Neurofibromin 1 - genetics; Next-generation sequencing; NF1; p53 Protein; Patients; POLE; Poly-ADP-Ribose Binding Proteins - genetics; Primary Research; Studies; TNBC; TP53; Triple Negative Breast Neoplasms - genetics; Tumor Suppressor Protein p53 - genetics; MSH6; NF1; Multi-gene testing; TNBC; POLE; TP53
• ISSN: 1479-7364; 1473-9542; 1479-7364
• DOI: 10.1186/s40246-018-0186-y

Germline BRCA1/2 prevalence is relatively low in sporadic triple-negative breast cancer (TNBC). We hypothesized that non-BRCA genes may also have significant germline contribution to Chinese sporadic TNBC, and the somatic mutational landscape of TNBC may vary between ethnic groups. We therefore conducted this study to investigate germline and somatic mutations in 43 cancer susceptibility genes in Chinese sporadic TNBC.
Sixty-six Chinese sporadic TNBC patients were enrolled in this study. Germline and tumor DNA of each patient were subjected to capture-based next-generation sequencing using a 43-gene panel. Standard bioinformatic analysis and variant classification were performed to identify deleterious/likely deleterious germline mutations and somatic mutations. Mutational analysis was conducted to identify significantly mutated genes.
Deleterious/likely deleterious germline mutations were identified in 27 (27/66, 40.9%) patients. Among the 27 patients, 9 (9/66, 13.6%) were TP53 carriers, 5 (5/66, 7.6%) were MSH6 carriers, and 5 (5/66, 7.6%) were BRCA1 carriers. Somatic mutations were identified in 64 (64/66, 97.0%) patients. TP53 somatic mutations occurred in most of the patients (45/66, 68.2%) and with highest mean allele frequency (28.1%), while NF1 and POLE were detected to have the highest mutation counts.
Our results supported our hypotheses and suggested great potentials of TP53 and MSH6 as novel candidates for TNBC predisposition genes. The high frequency of somatic NF1 and POLE mutations in this study showed possibilities for clinical benefits from androgen-blockade therapies and immunotherapies in Chinese TNBC patients. Our study indicated necessity of multi-gene testing for TNBC prevention and treatment.