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BACKGROUND & AIMS: Western and prudent dietary patterns have been associated with higher and lower risks of colorectal cancer (CRC), respectively. However, little is known about the associations between dietary patterns and specific anatomic subsites or molecular subtypes of CRC.

METHODS: We used multivariable Cox proportional hazards models to examine the associations between Western and prudent dietary patterns and CRC risk in the Health Professionals Follow-up Study and Nurses' Health Study.

RESULTS: After up to 32 years of follow-up of 137,217 men and women, we documented 3260 cases of CRC. Among individuals from whom subsite data were available, we observed 1264 proximal colon, 866 distal colon, and 670 rectal tumors. Western diet was associated with an increased incidence of CRC (Ptrend .0001), with a relative risk (RR) of 1.31 (95% CI, 1.15-1.48, comparing the highest to lowest quartile). The association of Western diet with CRC was evident for tumors of the distal colon (RR, 1.55; 95% CI, 1.22-1.96; Ptrend = .0004) and rectum (RR, 1.35; 95% CI, 1.03-1.77; Ptrend = .01) but not proximal colon (RR, 1.11; 95% CI, 0.91-1.35; Ptrend = .51) when we comparing extreme quartiles. In contrast, for the prudent pattern, we observed a RR of 0.86 for overall CRC (95% CI, 0.77-0.95; Ptrend = .01), with similar trends at anatomic subsites. However, the trend appeared stronger among men than women. Among 1285 cases (39%) with tissue available for molecular profiling, Western diet appeared to be more strongly associated with some CRC molecular subtypes (no mutations in KRAS [KRAS wildtype] or BRAF [BRAF wildtype], no or a low CpG island methylator phenotype, and microsatellite stability), although formal tests for heterogeneity did not produce statistically significant results.

CONCLUSIONS: Western dietary patterns are associated with an increased risk of CRC, particularly distal colon and rectal tumors. Western dietary patterns also appear more strongly associated with tumors that are KRAS wildtype, BRAF wildtype, have no or a low CpG island methylator phenotype, and microsatellite stability. In contrast, prudent dietary patterns are associated with a lower risk of CRC that does not vary according to anatomic subsite or molecular subtype.