Abstract
Germline genetic variants such as BRCA1/2 play an important role in tumorigenesis and clinical outcomes of cancer patients. However, only a small fraction (i.e., 5-10%) of inherited variants has been associated with clinical outcomes (e.g., BRCA1/2, APC, TP53, PTEN and so on). The challenge remains in using these inherited germline variants to predict clinical outcomes of cancer patient population. In an attempt to solve this issue, we applied our recently developed algorithm, eTumorMetastasis, which constructs predictive models, on exome sequencing data to ER+ breast (n=755) cancer patients. Gene signatures derived from the genes containing functionally germline genetic variants significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n=200 and 295, P=1.4×10−3). Furthermore, we found that recurred patients possessed a higher rate of germline genetic variants. In addition, the inherited germline variants from these gene signatures were predominately enriched in T cell function, antigen presentation and cytokine interactions, likely impairing the adaptive and innate immune response thus favoring a pro-tumorigenic environment. Hence, germline genomic information could be used for developing non-invasive genomic tests for predicting patients’ outcomes (or drug response) in breast cancer, other cancer types and even other complex diseases.
