RGD Reference Report - Role for Nucleotide Excision Repair Gene Variants in Oxaliplatin-Induced Peripheral Neuropathy. - Rat Genome Database

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

Authors: 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  Cheadle, Jeremy P 
Citation: West H, etal., JCO Precis Oncol. 2018 Nov;2:1-18. doi: 10.1200/PO.18.00090.
RGD ID: 155260345
Pubmed: PMID:35135151   (View Abstract at PubMed)
DOI: DOI:10.1200/PO.18.00090   (Journal Full-text)


PURPOSE: 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.
PATIENTS AND METHODS: 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 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 ultraviolet 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 = 3.5 × 10-2). We subsequently found that multiple rare ERCC4 nonsynonymous variants were over-represented in affected individuals (P = 7.7 × 10-3) and three of these were defective in the repair of ultraviolet light-induced DNA damage (P < 1 × 10-3). We validated a role for NER genes in PNAO by finding that multiple rare ERCC6 nonsynonymous variants were similarly over-represented in affected individuals (P = 2.4 × 10-8). Excluding private variants, 22.2% of patients (14 of 63 patients) with PNAO carried Pro379Ser or Glu875Gly in ERCC4 or Asp425Ala, Gly446Asp, or Ser797Cys in ERCC6, compared with 8.7% of unaffected patients (152 of 1,750 patients; odds ratio, 3.0; 95% CI, 1.6 to 5.6; P = 2.5 × 10-4).
CONCLUSION: Our study provides evidence for a role of NER genes in PNAO, together with mechanistic insights.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
polyneuropathy due to drug treatmentIAGP 155260345associated with colorectal cancer more ...RGD 
polyneuropathy due to drug treatmentIAGP 155260345associated with colorectal cancer more ...RGD 
polyneuropathy due to drug treatmentISOERCC4 (Homo sapiens)155260345; 155260345associated with colorectal cancer more ...RGD 
polyneuropathy due to drug treatmentISOERCC6 (Homo sapiens)155260345; 155260345associated with colorectal cancer more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ercc4  (ERCC excision repair 4, endonuclease catalytic subunit)
Ercc6  (ERCC excision repair 6, chromatin remodeling factor)

Genes (Mus musculus)
Ercc4  (excision repair cross-complementing rodent repair deficiency, complementation group 4)
Ercc6  (excision repair cross-complementing rodent repair deficiency, complementation group 6)

Genes (Homo sapiens)
ERCC4  (ERCC excision repair 4, endonuclease catalytic subunit)
ERCC6  (ERCC excision repair 6, chromatin remodeling factor)


Additional Information