Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype

Dallas R English,Daniel D Buchanan,Andrew M Haydon,John L Hopper,Simon G Royce,Michael D Walsh,Jeremy J Jass,Susan Parry,Graham G Giles,Melissa A Barker,Joanne P Young,Melissa C Southey,Mark A Jenkins,Julie A Simpson,Aedan Roberts

doi:10.1158/1055-9965.epi-08-0091

Abstract

Colorectal cancers arising from serrated polyps are characterized by the CpG island methylator phenotype (CIMP) and somatic mutation (V600E) in the BRAF proto-oncogene. Few epidemiologic studies have investigated risk factors for these tumors. We conducted a cohort study of 41,328 residents of Melbourne, Australia that included 9,939 participants of southern European origin and 31,389 of Anglo-Celtic origin. Colorectal adenocarcinomas were identified from population-based cancer registries. BRAF V600E mutation in tumors was determined using a PCR-based allelic discrimination method. Tumors were classified as CIMP positive when at least three of five markers (RUNX3, CACNA1G, SOCS1, NEUROG1, and IGF2) were methylated according to MethyLight analysis. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox regression with adjustment for risk factors for colorectal cancer. During follow-up, 718 participants were diagnosed with colorectal cancer. CIMP assays were done for 579 and BRAF V600E mutation testing for 582. After adjustment for other risk factors, when compared with people of Anglo-Celtic origin, those of southern European origin had lower incidence of colorectal cancer that had CIMP (HR, 0.32; 95% CI, 0.16-0.67) or BRAF mutations (HR, 0.30; 95% CI, 0.16-0.58) but similar incidence of colorectal cancer without CIMP (HR, 0.86; 95% CI, 0.70-1.05) or BRAF (HR, 0.90; 95% CI, 0.74-1.11). People of southern European origin had lower risk of colorectal cancers with CIMP and BRAF mutation than people of Anglo-Celtic origin, which may in part be due to genetic factors that are less common in people of southern European origin.

Highlights

Colorectal cancer is a heterogeneous disorder for which molecular pathologic examination has identified distinct subsets that evolve through different pathways
After adjustment for other risk factors, when compared with people of Anglo-Celtic origin, those of southern European origin had lower incidence of colorectal cancer that had CpG island methylator phenotype (CIMP) (HR, 0.32; 95% confidence intervals (95% CI), 0.16-0.67) or BRAF mutations (HR, 0.30; 95% CI, 0.16-0.58) but similar incidence of colorectal cancer without CIMP (HR, 0.86; 95% CI, 0.70-1.05) or BRAF (HR, 0.90; 95% CI, 0.74-1.11)
Smoking was associated with risk of CIMP and BRAF-related tumors in a case-control study but not with other colorectal cancers [22], there were no clear differences in dietary risk factors between the subtypes [23]

Summary

Introduction

Colorectal cancer is a heterogeneous disorder for which molecular pathologic examination has identified distinct subsets that evolve through different pathways. One subset that arises from advanced serrated polyps rather than from adenomas has been identified [1,2,3,4,5,6,7,8,9] These tumors are characterized by activating somatic mutations in the BRAF proto-oncogene [10], predominantly V600E, and widespread hypermethylation of CpG islands, especially in the promoters of genes, referred to as the CpG island methylator phenotype Smoking was associated with risk of CIMP and BRAF-related tumors in a case-control study but not with other colorectal cancers [22], there were no clear differences in dietary risk factors between the subtypes [23]

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