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Genetic studies to discover common variants associated with epithelial ovarian cancer risk and variation in age of natural menopause Earp, Madalene A


Background. Epithelial ovarian cancer (EOC) and age of natural menopause (ANM) are two complex traits impacting women’s health. ANM is also an important EOC risk factor. Insight into genetic factors influencing EOC and ANM could provide novel entry points for understanding EOC pathogenesis, and the normal process of ovarian aging. Methods. A two-stage genome-wide association study (GWAS) design using DNA pooling in Stage 1 was used to discover single nucleotide polymorphisms (SNPs) associated with histology-specific EOC risk, and population-specific variation in ANM. SNP-trait associations discovered in Stage 1 of these GWAS were replicated in two different consortia; EOC association in the Ovarian Cancer Association Consortium (OCAC), and ANM associations in the ReproGen Consortium. Results. Eight subtype-specific SNP-EOC associations discovery in Stage 1 of the EOC GWAS were replicated (unadjusted P <0.05) in the datasets of the OCAC: 4 in the mucinous subtype, 2 in the endometrioid and clear cell (ENCC) subtypes combined, and 2 in the low-malignancy potential (LMP) serous subtype. These associations did not achieve genome-wide significance (P < 5x10⁻⁸). However, several of the loci implicated by these SNPs harbour attractive candidate genes for ovarian cancer biology, including the mucinous locus harbouring RAD51B, the ENCC locus harbouring GRB10, and the LMP serous locus harbouring BPIL2/C22orf26. The GWAS of ANM performed in Iranian women revealed one SNP-trait association exclusive to this population (rs10140275; unadjusted P=4.0x10⁻⁴) and one shared with the European population (rs10840211). In the replication of European GWAS findings in Iranian women one SNP at the 20p12.3 locus was replicated (rs16991615, unadjusted P=0.02). SNPs tagging the 19q13.42 locus narrowly missed replication in our dataset (rs1172822, unadjusted P= 0.08). Conclusion. Eight SNP-EOC associations warrant further replication and/or fine-mapping in samples with reliable tumour information. These SNPs tag loci harbouring candidate genes involved in DNA repair, the PI3K/AKT pathway, and immune function, suggesting these pathways and processes may be important to the etiology of the rarer EOC subtypes. The generality of the European ANM GWAS findings in established in another human population (20p12.3). Further, one genetic variant influencing ANM in the Iranian population but not the European population is reported.

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