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Etiological risk factors for proximal (right-sided) colon cancers may be different to those of distal colon and rectal (left-sided) cancers if these tumors develop along distinct pathways. The CpG Island Methylator Phenotype (CIMP1) occurs in approximately 15% of colorectal cancers (CRC) and predominantly in the proximal colon. CIMP1 tumors have frequent methylation of gene promoter regions and increased tissue folate levels. The aim here was to determine whether polymorphisms in 2 genes involved in cellular methyl group metabolism were associated with different risks for right-and left-sided CRC. This population-based case-control study involved 859 incident cases of CRC and 973 sex and agematched controls. Information on dietary folate and alcohol intake was obtained from food frequency questionnaires and information on the anatomical site of tumors from pathology reports. DNA was collected using FTA cards and genotyping performed for the MTHFR C677T and DDNMT3B C-149T polymorphisms. The MTHFR 677 T allele was associated with increased risk for proximal colon cancer (adjusted odds ratio, AOR 5 1.29) but decreased risk for distal cancers (AOR 5 0.87). The increased risk for proximal cancers was especially pronounced in older individuals (AOR 5 1.49) and those with a low folate diet (AOR 5 1.67) or high alcohol consumption (AOR 5 1.90). The DDNMT3B-149 TT genotype was protective against proximal colon cancers (AOR 5 0.65), but showed no association with the risk of distal colon and rectal cancers (AOR 5 1.02). Epidemiological studies on dietary and genetic risk factors for CRC should take into account these may confer different risks for right-and left-sided tumors. ' UICCKey words: MTHFR; DNMT3B; folate; methylation; CIMP There is increasing evidence that etiological factors contributing to the risk of proximal colon cancers are different to those of distal colon and rectal cancers. [1][2][3] This is likely to be due to the existence of at least 2 distinct pathways for colorectal tumorigenesis. The most common pathway accounts for approximately 80% of all colorectal cancers (CRC) and is characterized by high frequencies of chromosomal instability (CIN) and APC, p53 and KRAS gene mutations. 4 These tumors progress via the adenomacarcinoma sequence and arise typically in the left-sided colon (distal colon and rectum) of younger males. The CpG island methylator phenotype (CIMP) represents a second pathway of CRC development, which is characterized by frequent hypermethylation of gene promoter regions and activating mutations in the BRAF oncogene. 5-9 CIMP1 CRCs occur predominantly in the rightsided (proximal) colon of older women and are thought to arise from serrated adenomas. 4 Depending on the markers used to define this phenotype, it has been estimated that approximately 15-25% of CRC are CIMP1 and that 70-90% of CIMP1 tumors arise in the proximal colon. [5][6][7][8][9][10] The microsatellite instability (MSI1) phenotype occurs in approximately 10-15% of CRC and was initially thought to represent an addition...

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