학술논문
Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer.
Document Type
Academic Journal
Author
Watts K; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.; Wills C; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.; Madi A; The Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, UK.; Palles C; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.; Maughan TS; CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.; Kaplan R; MRC Clinical Trials Unit, University College of London, London, UK.; Al-Tassan NA; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.; Kerr R; Department of Oncology, University of Oxford, Oxford, UK.; Kerr D; Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.; Gray V; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.; West H; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.; Houlston RS; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Escott-Price V; Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.; Cheadle JP; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
Source
Publisher: Wiley-Liss Country of Publication: United States NLM ID: 0042124 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-0215 (Electronic) Linking ISSN: 00207136 NLM ISO Abbreviation: Int J Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10 -7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10 -7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0-8.3, P = 9.8 × 10 -10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10 -6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.
(© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
(© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)