Germline genomes of breast and lung cancer patients significantly predict clinical outcomes

Abstract Germline genetic variants such as BRCA1/2 could play an important role in tumorigenesis and even clinical outcomes of cancer patients. These germline mutations have been used for genetic counselling and testing to establish as a standard-of-care procedure in the management of cancer patients. However, only a small fraction (i.e., 5-10%) of cancer patients whose clinical outcomes have been associated with inherited mutations (e.g., BRCA1/2, APC, TP53, PTEN and so on). It is challenging to use all the inherited mutations to predict the clinical outcomes for the majority of cancer patients. To deal with this issue, we applied our recently developed algorithm which enables to construct predictive models using genome sequencing data to ER+ breast (n=755) and lung (n=436) cancer patients. Gene signatures derived from functionally mutated genes in germline genomes significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n=200 and 295, P=1.0x10-7) and the lung cancer cohort (n=176, P=1.8x10-2), and outperformed predictions using clinical factors. The signature genes are predominately impairing patients’ immune functions such as T cell function, antigen presentation and cytokine interactions (i.e., recurred patients have more such mutations). These results suggest that inherited mutations weakening patients’ immune system could impact tumorigenesis and evolution in not only genetically-(i.e., breast) but also environmentally-driven (i.e., lung) cancers. Most importantly, germline genomic information could be used for developing non-invasive genomic tests for predicting patients’ outcomes (or drug response) in breast and lung cancers, and even other cancer types and complex diseases.