Abstract PS16-08: Germline mutation landscape in Chinese breast cancer patients
Authors: Wang Nan , Zhang Jiayang , Tan Lu , Liao Hao , Liu Yaxin , Gui Xinyu , Niu Jiaxin , Xie Feng , Zhang Yue , Huang Yong , Yu Jianjun , Li Huiping 
Published: February 2021

Abstract
Background: Genetic testing for patients with breast cancer (BCa) patients may change the routine patient care and shift the paradigm towards more personalized managing and treatment strategies. In particular, testing germline mutations in BRCA1/2 has become a part of the standard clinical practice for patients with BCa. However, our understanding of genetic epidemiology of BCa is mainly driven by data from Caucasian populations and it has been evident that gene alterations may be ethnic specific in breast cancer.
Methods: Aiming to delineate the landscape of germline mutations in Chinese patients with BCa to breast cancer, we collected blood samples from in 356 BCa patients at stage I-IV in Beijing Cancer Hospital between Jan. 2013 to Dec. 2019. Peripheral blood mononuclear cells were isolated from blood samples and genomic DNA were extracted for capture-based NGS sequencing. A large comprehensive 600 gene panel (PredicineATLAS, Huidu Medical Science Techonology, Inc.) was used to detect germline mutations in the covered genes with average 300x sequencing depth.
Results: A total of 356 BCa patients were included in our study, with the median age at first diagnosis of 49 years (Range: 21-87). Among all cases, 21.9% (78/356, 95% confidence interval [CI]: 17.7-26.6%) carried pathogenic or likely pathogenic mutations in 48 cancer related genes. Twenty-seven patients (7.6%, 95% CI: 5.1-10.8%) harbored BRCA1/2 mutations, followed by 5 patients carrying ATM mutations and RAD50 mutations respectively. Other commonly mutated genes include BARD1 (1.1%), FANCD2 (1.1%), CHEK2 (0.6%), FANCC (0.6%), FANCM (0.6%), PMS2 (0.6%), and TP53 (0.6%), most of which are related to DNA damage repair pathway. Moreover, BRCA1/2 carriers were more likely to appear among those with breast or ovarian cancer family history than those without (OR=3.41, 95% CI: 1.14-9.12, P=0.01). Compared with patients that aged older than 50 years at first diagnosis, those aged 30 years or younger were 6 times more likely to detect germline mutations in BRCA1/2 (95% CI: 1.18-26.1, P=0.02). In addition, mutations in BRCA1/2 were differentially associated with breast cancer subtypes. BRCA1 mutations were strongly enriched in triple-negative breast cancer (TNBC) (OR=6.7, 95% CI: 1.54-33.13, P=0.005). There is no strong significant survival difference observed between BRCA1/2 carriers and non-carriers, however, patients carrying ATM or RAD50 mutations tend to have lower disease-free survival.
Conclusions: This is a comprehensive analysis of germline mutation spectrum in a large Chinese patient cohort with breast cancer. Collectively, a substantial proportion of patients with breast cancer had hereditary risk factors. Distinct distribution of pathogenic mutations in breast cancer subtypes and differential associations between mutation status and clinical features were further observed. All these findings will advance our understanding regarding the pathologies and heterogeneity of breast cancer.
Citation Format: Nan Wang, Jiayang Zhang, Lu Tan, Hao Liao, Yaxin Liu, Xinyu Gui, Jiaxin Niu, Feng Xie, Yue Zhang, Yong Huang, Jianjun Yu, Huiping Li. Germline mutation landscape in Chinese breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-08.