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Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy

Madi, A; Fisher, D; Maughan, TS; Colley, JP; Meade, AM; Maynard, J; Humphreys, V; ... Cheadle, JP; + view all (2018) Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy. European Journal of Cancer , 102 pp. 31-39. 10.1016/j.ejca.2018.07.009. Green open access

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Abstract

BACKGROUND: Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). METHODS: We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had >85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies >20%. RESULTS: Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2–2.9, P = 0.004, and OR 0.7, 95% CI 0.5–0.9, P = 0.003, respectively). Common variants in DPYD (Cys29Arg and Val732Ile) were most associated with toxicity (OR 0.8, 95% CI 0.7–1.0, P = 0.008, and OR 1.6, 95% CI 1.1–2.1, P = 0.006, respectively). Two rare DPYD variants were associated with increased toxicity (Asp949Val with neutropenia, nausea and vomiting, diarrhoea and infection; IVS14+1G>A with lethargy, diarrhoea, stomatitis, hand-foot syndrome and infection; all ORs > 3). Asp317His in DCLRE1A was most associated with peripheral neuropathy (OR 1.3, 95% CI 1.1–1.6, P = 0.003). No common variant associations remained significant after Bonferroni correction. CONCLUSIONS: DNA repair genes may play a significant role in the pharmacogenetics of aCRC. Our data suggest that both common and rare DPYD variants may be associated with toxicity to fluoropyrimidine-based chemotherapy.

Type: Article
Title: Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejca.2018.07.009
Publisher version: https://doi.org/10.1016/j.ejca.2018.07.009
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Pharmacogenetics, Toxicity, Colorectal cancer, DPYD, Dihydropyrimidine dehydrogenase, Chemotherapy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10058446
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