Germline Variation Affects Tumor Progression and Informs Clinical Therapy Decisions Across Cancers
Chatrath, Ajay, Biochemistry and Molecular Genetics - School of Medicine, University of Virginia
Dutta, Anindya, MD-BIOC Biochem/Mole Genetics, University of Virginia
While germline variation has had a rich history of being studied in the context of cancer risk, emerging evidence now suggests that germline variation shapes the landscape of somatic aberrations in cancer and may affect the sensitivity and toxicity of chemotherapy drugs. Given these findings, we hypothesized that germline variation should not only predict the risk of acquiring cancers but also affect the rate at which the tumor progresses. We began our search for germline variants affecting tumor progression by analyzing the genomic sequencing data of approximately 500 patients diagnosed with lower grade gliomas. We identified two germline variants associated with poor outcome in these patients, one in the oncogene GRB2 and the other in the tumor suppressor gene of ANKDD1a. Our results suggested that germline variation is associated with patient outcome and that there is an interaction between common polymorphisms and the somatic landscape in lower grade gliomas.
We then searched for germline variants associated with patient outcome across 33 different types of cancers using sequencing data from over 10,000 cancer patients. In total, we identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers. The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness. Our results suggested that the idea that germline variation contributes to tumor progression is a general principle of cancer genomics as we found this to be true across essentially all cancers for which we were sufficiently powered.
Having found that germline variants impact tumor progression, we suspected that the interaction between germline variants and the landscape of somatic events could be exploited therapeutically. To assess this possibility, we developed a pan-cancer approach to identify pathogenic germline variants associated with elevated tumor mutational burden, as high tumor mutational burden is a validated biomarker of immune checkpoint inhibitor efficacy. We identified an association with overall tumor mutational burden in nine genes using a pan-cancer approach, fourteen pathways in individual cancers, and twelve pathways using a pan-cancer approach. Patients with the pathogenic germline variants described in this study may be more likely to respond to treatment with immune checkpoint inhibitors.
Together, our work suggests that germline variation affects tumor progression and is involved with shaping the landscape of somatic events in cancers in a predictable way that can likely be targeted therapeutically. These findings pave the way for future efforts to better individualize patient care.
PHD (Doctor of Philosophy)
Germline Variants, Tumor Progression, Personalized Medicine, Germline Somatic Interaction, Immune Checkpoint Inhibitors, Single Nucleotide Polymorphism, Genome Wide Association Study
University of Virginia