Vitamin D status and colorectal neoplasm risk in Lynch syndrome

Abstract Background: Higher circulating vitamin D concentrations have been associated with a decreased colorectal neoplasm (CRN) risk in the general population. However, this association has not yet been investigated in individuals with Lynch syndrome (LS), an inherited predisposition to colorectal cancer. Methods: The study population included 2,351 LS carriers from the GEOLynch and the Colon Cancer Family Registry cohorts. Total plasma 25-hydroxyvitamin D (25(OH)D2 and 25(OH)D3) concentrations were measured using isotope-dilution Liquid Chromatography–tandem Mass Spectrometry. CRNs included adenoma, serrated lesions, and colorectal cancer. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between 25-hydroxyvitamin D concentrations and CRN risk, overall and by pathogenic variant type, age, sex, CRN history and geographic region. Results: During a median follow-up of 7.2 years [IQR: 3.3-12.6], 647 (27.5%) LS carriers developed a CRN. No association was observed for deficient (<50 nmol/L or <20 ng/mL; HR: 1.12; 95% CI: 0.91, 1.39) or optimal (≥75 nmol/L or ≥30 ng/mL; HR: 0.94; 95% CI: 0.77, 1.15) compared with sufficient (50–<75 nmol/L or 20-<30 ng/mL) vitamin D concentrations. No association was observed for each 10 nmol/L or 4 ng/mL increment in vitamin D concentration. Among PMS2 carriers, a 10 nmol/L increment was associated with a 27% lower CRN risk (HR: 0.73; 95% CI: 0.58-0.91). Conclusions: Vitamin D concentrations were not associated with CRN risk among LS carriers, whereas the association observed among PMS2 carriers warrants further investigation. Impact: If confirmed, these findings could inform personalized risk reduction strategies for PMS2 carriers.