Figure 1.

CONSORT diagram of the analysis strategy. COIN patients were randomised 1:1:1 to receive continuous oxaliplatin and fluoropyrimidine chemotherapy (Arm A, n = 815), continuous chemotherapy with cetuximab (Arm B, n = 815), or intermittent chemotherapy (Arm C, n = 815). COIN-B patients were randomised 1:1 to receive intermittent chemotherapy and cetuximab (Arm D, n = 112) or intermittent chemotherapy and continuous cetuximab (Arm E, n = 114). Of these, 2244 were genotyped on Axiom arrays, 1950 passed genotyping quality control (QC) and 1800 were segregated into groups according to chemotherapy regimen and cetuximab status (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). We conducted genome-wide association studies for any toxicity and 10 individual toxicities together with gene and gene set analyses. Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were independently validated in the COIN and COIN-B group with the same chemotherapy regimen but alternative cetuximab status, and the COIN and COIN-B group with the alternative chemotherapy regimen but with the same cetuximab status