Abstract PS8-29: Rare variants in the germline genome holistically determine receptor-independent Her2 signaling pathway activation and immune suppression, shaping pathological type and risk of HER2-negative breast cancer

Background: Pathogenic factors embedded in the germline genome are widely recognized as being crucial to breast cancer development. However, current knowledge is either concentrated on the pathogenic variants of a few individual genes or SNPs distributed sparsely across the genome in non-coding regions. Methods: We developed a multi-layered framework, DAGG, which converts somatic mutations or germline rare coding variants (gRCVs) into a functional spectrum of dozens of cellular functions and signaling pathways to identify potential pathogenic factors.Findings: We analyzed whole-exome sequencing (WES) data of 726 germline DNA samples and 169 breast tumor DNA samples from breast cancer patients with various pathological types and cancer-free female subjects, we found that germline pathogens of breast cancers were (1) mainly distributed in HER2-negative subtypes, and (2) involved Her2 signaling pathway activation and immune suppression. These computational discoveries were experimentally validated and can provide digital features to explain the germline differences between diseased and healthy genome (AUC = 0.76). Furthermore, an individual’s risk for breast cancer can be estimated by calculating the combined effects of these identified germline pathogens. Carriers of BRCA1/2 pathogenic variants were found to have a significantly higher average risk (p = 0.02). Interpretation: The results demonstrated that the identified pathogenic mechanisms by DAGG were compatible with our current understanding of the causes of breast cancer. Moreover, DAGG provides improved performance over currently used polygenic risk score method of measuring complex disease risks. Our framework promises possible future applications for the prevention, diagnosis, and treatment of breast cancer. Citation Format: Mei Yang, Yanhui Fan, Zhi-Yong Wu, Zhendong Feng, Qiangzu Zhang, Shunhua Han, Zhonghai Zhang, Xu Li, Yiqing Xue, Xiaoling Li, Meixia Hu, Jieqing Li, Weiping Li, Hongfei Gao, Ciqiu Yang, Chunming Zhang, Liulu Zhang, Teng Zhu, Minyi Cheng, Fei Ji, Juntao Xu, Hening Cui, Guangming Tan, Michael Q Zhang, Changhong Liang, Zaiyi Liu, You-Qiang Song, Gang Niu, Kun Wang. Rare variants in the germline genome holistically determine receptor-independent Her2 signaling pathway activation and immune suppression, shaping pathological type and risk of HER2-negative breast cancer [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 PS8-29.