%0 Journal Article %A Mei Yang %A Yanhui Fan %A Zhi-Yong Wu %A Zhendong Feng %A Qiangzu Zhang %A Shunhua Han %A Xiaoling Li %A Teng Zhu %A Minyi Cheng %A Juntao Xu %A Ciqiu Yang %A Hongfei Gao %A Chunming Zhang %A Guangming Tan %A Michael Q. Zhang %A You-Qiang Song %A Gang Niu %A Kun Wang %T Rare non-synonymous germline mutations systematically define the risk of triple negative breast cancer %D 2019 %R 10.1101/302398 %J bioRxiv %P 302398 %X Early identification of the risk for triple-negative breast cancer (TNBC) at the asymptomatic phase could lead to better prognosis. Here we developed a machine learning method to quantify systematic impact of all rare germline mutations on each pathway. We collected 106 TNBC patients and 287 elder healthy women controls. The spectra of activity profiles in multiple pathways were mapped and most pathway activities exhibited globally suppressed by the portfolio of individual germline mutations in TNBC patients. Accordingly, all individuals were delineated into two types: A and B. Type A patients could be differentiated from controls (AUC = 0.89) and sensitive to BRCA1/2 damages; Type B patients can be also differentiated from controls (AUC = 0.69) but probably being protected from BRCA1/2 damages. Further we found that Individuals with the lowest activity of selected pathways had extreme high relative risk (up to 21.67 in type A) and increased lymph node metastasis in these patients. Our study showed that genomic DNA contains information of unimaginable pathogenic factors. And this information is in a distributed form that could be applied to risk assessment for more cancer types.Significance We identified individuals who are more susceptible to triple negative breast cancer. Our method performs much better than previous assessments based on BRCA1/2 damages, even polygenic risk scores. We disclosed previously unimaginable pathogens in a distributed form on genome and extended risk prediction to scenarios for other cancers. %U https://www.biorxiv.org/content/biorxiv/early/2019/02/26/302398.full.pdf