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.
Highlights
For neutropenic sepsis in patients treated with XELOX and XELOX + cetuximab, neutropenia in patients treated with XELOX + cetuximab and rash in patients treated with FOLFOX, we had insufficient power to perform the genome-wide association studies (GWASs); in total, we conducted 40 genome-wide association study (GWAS)
single nucleotide polymorphism (SNP) at 21 loci had suggestive associations with diarrhoea (Supplementary Figure 3); only rs6030266 at 20q13.12 in patients treated with XELOX + cetuximab (OR = 0.4, 95% confidence intervals (CI) = 0.280.58, P = 5.7 Â 10À7) was validated in patients receiving FOLFOX + cetuximab (OR = 0.7, 95% CI = 0.5-0.9, P = 3.6 Â 10À2); pooled
The association of MROH5 with neutropenia appeared to be due to independent sets of SNPs in patients treated with XELOX as compared to those receiving XELOX + cetuximab
Summary
Many patients diagnosed with colorectal cancer (CRC) receive chemotherapy either as part of their treatment for curative disease or to extend survival.[1]. Rare variants in the gene encoding dihydropyrimidine dehydrogenase (DPYD) are well established to be associated with severe toxicities to 5-fluorouracil (5-FU).[11,12] While the role of common genetic variation is less clear, we and others have shown that common variants in DPYD appear to affect the toxicity.[13,14,15] To date, most studies have sought to identify inherited predictive biomarkers using candidate gene and variant-based analyses, based on preconceptions as to probable biology and using small cohorts of patients with no independent validation To address such limitations, we have analysed genome-wide association study (GWAS) data on 1800 patients with advanced CRC treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab with replication in independent patient groups. Credible sets of causal SNPs were assembled for 95% coverage
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
