Role for Nucleotide Excision Repair Gene Variants in Oxaliplatin-Induced Peripheral Neuropathy.

Abstract

Oxaliplatin forms part of routine treatment of advanced colorectal cancer; however, it often causes severe peripheral neuropathy, resulting in treatment discontinuation. We sought to determine the molecular and cellular mechanism underlying this toxicity. We exome resequenced blood DNA samples from nine patients with advanced colorectal cancer who had severe peripheral neuropathy associated with oxaliplatin (PNAO) within 12 weeks of treatment. We Sanger sequenced the <i>ERCC4</i> and <i>ERCC6</i> open reading frames in 63 patients with PNAO and carried out targeted genotyping in 1,763 patients without PNAO. We tested the functionality of <i>ERCC4</i> variants using viability and DNA repair assays in <i>Schizosaccharomyces pombe</i> and human cell lines after exposure to oxaliplatin and ultraviolet light. Exome resequencing identified one patient carrying a novel germline truncating mutation in the nucleotide excision repair (NER) gene <i>ERCC4</i>. This mutation was functionally associated with sensitivity to oxaliplatin (<i>P</i> = 3.5 × 10^-2). We subsequently found that multiple rare <i>ERCC4</i> nonsynonymous variants were over-represented in affected individuals (<i>P</i> = 7.7 × 10^-3) and three of these were defective in the repair of ultraviolet light-induced DNA damage (<i>P</i> < 1 × 10^-3). We validated a role for NER genes in PNAO by finding that multiple rare <i>ERCC6</i> nonsynonymous variants were similarly over-represented in affected individuals (<i>P</i> = 2.4 × 10^-8). Excluding private variants, 22.2% of patients (14 of 63 patients) with PNAO carried Pro379Ser or Glu875Gly in <i>ERCC4</i> or Asp425Ala, Gly446Asp, or Ser797Cys in <i>ERCC6</i>, compared with 8.7% of unaffected patients (152 of 1,750 patients; odds ratio, 3.0; 95% CI, 1.6 to 5.6; <i>P =</i> 2.5 × 10^-4). Our study provides evidence for a role of NER genes in PNAO, together with mechanistic insights.