Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer.

Autor: 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.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2021 Nov 01; Vol. 149 (9), pp. 1713-1722. Date of Electronic Publication: 2021 Jul 31.
DOI: 10.1002/ijc.33739
Abstrakt: 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.)
Databáze: MEDLINE
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