Dietary vitamin D intake and risk of colorectal cancer according to vitamin D receptor expression in tumors and their surrounding stroma.

Background: Colorectal Cancer (CRC) has been molecularly classified into several subtypes according to tumor, stromal, and immune components. Here, we investigated whether the preventive effect of vitamin D on CRC varies with subtypes defined by Vitamin D receptor (VDR) expression in tumors and their surrounding stroma, along with the association of somatic mutations in CRC.

Methods: In a population-based prospective study of 22,743 Japanese participants, VDR expression levels in tumors and their surrounding stroma were defined in 507 cases of newly diagnosed CRC using immunohistochemistry. Hazard ratios of CRC and its subtypes according to dietary vitamin D intake were estimated using multivariable Cox proportional hazards models.

Results: Dietary vitamin D intake was not associated with CRC or its subtypes defined by VDR expression in tumors. However, an inverse association was observed for CRC with high VDR expression in the stroma (the highest tertile vs the lowest tertile: 0.46 [0.23-0.94], P_trend = 0.03), but not for CRC with low VDR expression in the stroma (P_{heterogeneity} = 0.02). Furthermore, CRC with high VDR expression in the stroma had more somatic TP53 and BRAF mutations and fewer APC mutations than those with low VDR expression in the stroma.

Conclusions: This study provides the first evidence that the preventive effect of vitamin D on CRC depends on VDR expression in the stroma rather than in the tumors. CRC with high VDR expression in the stroma is likely to develop through a part of the serrated polyp pathway, which tends to occur with BRAF but not with APC mutations.