Abstract 606: Circulating proteins associated with ovarian cancer risk and survival are enriched for immune-related pathways

Abstract

Abstract Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and five-year survival rates in this group continue to remain very poor. Circulating proteins may illuminate EOC etiology and have the potential to serve as biomarkers for early detection and diagnosis. We performed a two-sample Mendelian randomization (MR) study with circulating protein levels as exposures and susceptibility to EOC and its histological subtypes as outcomes. We used previously identified quantitative trait loci (QTLs) robustly associated with plasma levels of 1,478 proteins as genetic instruments and corresponding summary genetic association statistics for these instruments derived from 22,406 EOC cases and 40,941 controls. Among proteins that had only a single QTL variant available as a genetic instrument, we identified 12 proteins whose circulating levels were associated with overall EOC risk at a False Discovery Rate (FDR) of < 0.1. For nine of the 12 proteins, the association was driven by variants near ABO, which is both a genome-wide significant high grade serous histotype risk locus and a hub QTL for several proteins. Three of these 12 proteins and their QTLs were, however, not linked to the ABO locus and included the products of the NOTCH signaling genes MFAP2 and DLK1. Among proteins that had multiple QTL variants available for the creation of more robust multi-variant genetic instruments, we identified 33 protein level-EOC risk associations at FDR < 0.1. Once again, we observed that the majority of associations (19/33) were driven by variants at the ABO locus. Nine of the 14 remaining associations were for overall and high grade serous EOC risk and included predominantly immune system proteins: ARTS1 (HLA class I), CPNE1 (involved in innate immunity), Macrophage mannose receptor (HLA class I), DQA2 (HLA class II), RGAP1 (innate immunity), Cathepsin H (innate immunity), and FCG2B (the low affinity receptor for the Fc region of immunoglobulin gamma). We observed one mucinous histotype-specific association (complement C4) and two clear cell histotype-specific associations (KI2S2 and PSG4). KI2S2 is a Killer cell immunoglobulin-like receptor expressed by natural killer cells and PSG4 is a member of the carcinoembryonic antigen gene family that also includes the gene encoding the tumor marker for colorectal cancer. Finally, we also performed two-sample MR analyses using survival as the outcome and identified two proteins whose plasma levels were associated with overall EOC survival at FDR < 0.1: SULT1E, a phenol sulfotransferase that conjugates sulfates to estrogens, and MA2B2. Thus, we identified circulating proteins that are candidate biomarkers for EOC risk and survival. They represent promising starting points for follow-up studies and the measurement of plasma levels of these proteins in EOC cohorts is required to validate these associations. Citation Format: Daniel P. Considine. Circulating proteins associated with ovarian cancer risk and survival are enriched for immune-related pathways [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 606.