Shu, Xiao‐Ou

Abstract Epithelial ovarian cancer (EOC) is the most common gynecological cancer, and ranks fifth in cancer deaths among women in the United States. Previous studies have identified several circulating proteins biomarkers for EOC risk, such as CA125 antigen and insulin-like growth factor-1 (IGF-1). However, previous studies on protein biomarkers for EOC were limited with small sample sizes, and only a few proteins investigated. In this study, we integrated genomics and proteomics data to search for novel circulating protein biomarkers for EOC risk. We constructed study instruments using genetic variants for protein quantitative trait loci (pQTL) for over 1,400 circulating proteins. Beta coefficients and standard errors of the selected pQTL variants in relation to EOC risk were obtained from 25,509 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). An inverse-variance weighted method was used to evaluate the association of these genetically predicted protein levels and risk of overall and serous EOC. We identified 35 protein biomarkers, for which their genetically predicted levels were significantly associated with the risk of either overall or serous EOC (false discovery rate <0.05). There are 25 proteins showing significant associations with both overall and serous EOC; most of the associations were stronger for serous EOC than overall EOC. The association for 31 proteins could be attributed, in part, to variants at ABO 9q34.2, a known ovarian cancer susceptibility locus. Five ABO locus-related proteins are in the PI3K-Akt signaling pathway, including insulin-like growth factor 1 receptor, hepatocyte growth factor receptor, interleukin-3 receptor subunit alpha, insulin receptor, and vascular endothelial growth factor receptor 2. Four of these proteins are also in the Rap1 and Ras signaling pathway. These five proteins are all inversely associated with the risk of overall EOC, with odds ratios ranging from 0.64 to 0.93 per unit increase in genetic risk scores (p values: 7.55×10-7 to 5.66×10-2). Four EOC associated proteins which were not influenced by variants in 9q34.2 are microfibrillar-associated protein 2, protein delta homolog 1, semenogelin-2, and netrin-G1, all of which showed significant associations with overall EOC, but not the serous subtype. Our study identifies potential novel biomarkers for ovarian cancer and suggests that genetic variants at locus 9q34.2 may play a role in the relation between levels of these proteins and risk of ovarian cancer. Citation Format: Guochong Jia, Xiang Shu, Xiao-Ou Shu, Jirong Long, Qiuyin Cai, Kirsten B. Moysich, Ellen L. Goode, Thomas A. Sellers, Wei Zheng. Genetically predicted concentration of circulating proteins and epithelial ovarian cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 598.

ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.