Novel approaches for the discovery of pharmacogenetic biomarkers of chemotoxicity in patients with colorectal cancer.

Abstract

Background and purpose: Chemotherapeutic treatment for colorectal cancer (colorectal cancer) allows for increased patient overall survival. However, current therapeutic regimens are often associated with the development of adverse drug reactions, which represent a morbidity, mortality and economic issue. We propose to identify novel germline markers that allow us to predict adverse drug reactions development after colorectal cancer chemotherapy.

Experimental approach: For that purpose, we selected 163 colorectal cancer patients with severe adverse drug reactions (CTCAE grades 3-4) and 52 controls and applied whole-exome sequencing (WES) to discover novel germline toxicity variants.

Key results: We found 13 cases carrying actionable dihydropyrimidine dehydrogenase gene (DPYD) variants and a novel, potentially pathogenic DPYD variant - c.2071G > T, p.(V691L), rs202212118. Moreover, we found 30 novel rare, high-impact variants in 14 reported genes. We also identified seven patients carrying more than one variant in the same gene or pathway, with one patient hinting at a potential digenic inheritance. Using an exome-wide approach, we discovered and independently validated three novel candidate toxicity genes (ALDH9A1, FAM83A and EPX). Gene-based analyses also provided 14 genes significantly associated with neuropathy, skin toxicity and cardiotoxicity.

Conclusions and implications: Overall, the present work has utilised state-of-the-art approaches to uncover several novel candidate toxicity variants/genes.