Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment

Abstract

The growing population of cancer survivors often faces adverse effects of treatment, which have a substantial impact on morbidity and mortality. Although certain adverse effects are thought to have a significant heritable component, much work remains to be done to understand the role of germline genetic factors in the development of treatment-related toxicities. In this article, we review current understanding of genetic susceptibility to a range of adverse outcomes among cancer survivors (e.g., fibrosis, urinary and rectal toxicities, ototoxicity, chemotherapy-induced peripheral neuropathy, subsequent malignancies). Most previous research has been narrowly focused, investigating variation in candidate genes and pathways such as drug metabolism, DNA damage and repair, and inflammation. Few of the findings from these earlier candidate gene studies have been replicated in independent populations. Advances in understanding of the genome, improvements in technology, and reduction in laboratory costs have led to recent genome-wide studies, which agnostically interrogate common and/or rare variants across the entire genome. Larger cohorts of patients with homogeneous treatment exposures and systematic ascertainment of well-defined outcomes as well as replication in independent study populations are essential aspects of the study design and are increasingly leading to the discovery of variants associated with each of the adverse outcomes considered in this review. In the long-term, validated germline genetic associations hold tremendous promise for more precisely identifying patients at highest risk for developing adverse treatment effects, with implications for frontline therapy decision-making, personalization of long-term follow-up guidelines, and potential identification of targets for prevention or treatment of the toxicity.