Hormonal and reproductive factors modulate bioavailable estrogen to influence endometrial cancer risk. Estrogen affects the microsatellite status of tumors, but the relation between these estrogen-related factors and microsatellite instability (MSI) status of endometrial tumors is not known. We evaluated associations between hormonal and reproductive factors and risks of microsatellite stable (MSS) and MSI endometrial cancer among postmenopausal women (MSS cases = 258, MSI cases = 103, and controls = 742) in a population-based case-control study in Alberta, Canada (2002-2006). Polytomous logistic regression was used to estimate ORs and 95% confidence intervals (95% CI). We observed a significant trend in risk reduction for MSI (P trend = 0.005) but not MSS (Ptrend = 0.23) cancer with oral contraceptive use; with 5-year use or more, the risk reduction was stronger for MSI (OR = 0.42; 95% CI, 0.23-0.77) than for MSS cancer (OR = 0.80; 95% CI, 0.54-1.17; Pheterogeneity = 0.05). For more recent use (<30 years), the risk reduction was stronger for MSI (OR = 0.36; 95% CI, 0.19-0.69) than for MSS cancer (OR = 0.77; 95% CI, 0.51-1.15; Pheterogeneity = 0.032). No differential risk associations were observed for menopausal hormone use, parity and age at menarche, menopause or first pregnancy. We found limited evidence for statistical heterogeneity of associations of endometrial cancer risk with hormonal and reproductive factors by MSI status, except with oral contraceptive use. This finding suggests a potential role for the MMR system in the reduction of endometrial cancer risk associated with oral contraceptive use, although the exact mechanism is unclear. This study shows for the first time that oral contraceptive use is associated with a reduced risk for MSI but not for MSS endometrial cancer.
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