LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer.
Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82-0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility.
Permuth-Wey, J; Kim, D; Tsai, Y-Y; Lin, H-Y; Chen, YA; Barnholtz-Sloan, J; Birrer, MJ; Bloom, G; Chanock, SJ; Chen, Z; Cramer, DW; Cunningham, JM; Dagne, G; Ebbert-Syfrett, J; Fenstermacher, D; Fridley, BL; Garcia-Closas, M; Gayther, SA; Ge, W; Gentry-Maharaj, A; Gonzalez-Bosquet, J; Goode, EL; Iversen, E; Jim, H; Kong, W; McLaughlin, J; Menon, U; Monteiro, ANA; Narod, SA; Pharoah, PDP; Phelan, CM; Qu, X; Ramus, SJ; Risch, H; Schildkraut, JM; Song, H; Stockwell, H; Sutphen, R; Terry, KL; Tyrer, J; Vierkant, RA; Wentzensen, N; Lancaster, JM; Cheng, JQ; Sellers, TA; Ovarian Cancer Association Consortium,
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