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Role for nucleotide-excision repair gene variants in oxaliplatin-induced peripheral neuropathy

West, Hannah, Coffey, Michelle, Wagner, Michael J., McLeod, Howard L., Colley, James P., Adams, Richard A., Fleck, Oliver, Maughan, Timothy S., Fisher, David, Kaplan, Richard S., Harris, Rebecca and Cheadle, Jeremy 2018. Role for nucleotide-excision repair gene variants in oxaliplatin-induced peripheral neuropathy. JCO Precision Oncology 2 10.1200/PO.18.00090

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Abstract

PURPOSE: Oxaliplatin forms part of routine treatment for advanced colorectal cancer (aCRC); however, it often causes severe peripheral neuropathy resulting in treatment discontinuation. We sought to determine the molecular and cellular mechanism underlying this toxicity. PATIENTS AND METHODS: We exome resequenced blood DNA samples from nine aCRC patients who had severe peripheral neuropathy associated with oxaliplatin (PNAO) within 12 weeks of treatment. We Sanger sequenced the ERCC4 and ERCC6 open reading frames in 63 patients with PNAO and carried out targeted genotyping in 1,763 patients without PNAO. We tested the functionality of ERCC4 variants using viability and DNA repair assays in Schizosaccharomyces pombe and human cell lines after exposure to oxaliplatin and UV light. RESULTS: Exome resequencing identified one patient carrying a novel germline truncating mutation in the nucleotide excision repair (NER) gene ERCC4. This mutation was functionally-associated with sensitivity to oxaliplatin (P=3.5x10-2). We subsequently found that multiple rare ERCC4 nonsynonymous variants were overrepresented in affected individuals (P=7.7x10-3) and three of these were defective in the repair of UV light-induced DNA damage (P<1x10-3). We validated a role for NER genes in PNAO by finding that multiple rare ERCC6 nonsynonymous variants were similarly overrepresented in affected individuals (P=2.4x10-8). Excluding private variants, 22.2% (14/63) of patients with PNAO carried Pro379Ser or Glu875Gly in ERCC4, or, Asp425Ala, Gly446Asp or Ser797Cys in ERCC6, as compared to 8.7% (152/1,750) of unaffected patients (OR=3.0, 95% CI 1.6-5.6, P=2.5x10-4). CONCLUSIONS: Our study provides evidence for a role of NER genes in oxaliplatin-induced peripheral neuropathy, together with mechanistic insights.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Publisher: American Society of Clinical Oncology
ISSN: 2473-4284
Funders: Tenovus, Kidani Trust, CRUK, Cancer Research Wales, Wales Gene Park, Knowledge Economy Skills Scholarship, North West Cancer Research, Wales Assembly Government National Institute of Social Care and Health Research
Date of First Compliant Deposit: 23 July 2018
Date of Acceptance: 10 July 2018
Last Modified: 30 Jun 2019 02:27
URI: http://orca-mwe.cf.ac.uk/id/eprint/113376

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