Abstract B19: Genome-wide association study of cancer antigen 125
Authors: Sasamoto Naoko , Jiang Lai , Vitonis Allison F. , Fichorova Raina N. , Pharaoh Paul , Cramer Daniel W. , Kraft Peter , Terry Kathryn L. 
Published: August 2018

Abstract
CA125 has proven to be the most promising biomarker for ovarian cancer screening. However, results from two large randomized trials comparing screening using CA125 and transvaginal ultrasound (TVU) to usual care have shown no clinically important difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity, which could be due in part to its expression on variety of tissues, including the lung, pancreas, stomach, liver, endometrium, and breast. In addition, CA125 levels vary between individuals based on demographic, reproductive, and lifestyle characteristics. We hypothesize that, independent of ovarian cancer, genetic variation may influence CA125 levels and identification of genetic predictors of CA125 may be used to develop individualized cut-off points, in combination with personal characteristics, to improve the predictive value of CA125 as an ovarian cancer screening biomarker. Furthermore, studies showing that CA125 binds to natural killer cells and monocytes, dampening immune response, suggest that CA125 may contribute to ovarian cancer progression through immune dysregulation. Thus, identifying genetic variants associated with CA125 levels could add another layer of understanding of the biologic role of elevated CA125 in ovarian cancer progression.
To test our hypothesis, we evaluated the association between common germline genetic variants across the genome in relation to serum levels of CA125 among 347 women without ovarian cancer recruited as population-based controls in the New England Case Control Study, a population-based study of ovarian cancer that enrolled participants between 1992 and 2008 in eastern Massachusetts and New Hampshire. We used linear regression to identify SNPs associated with CA125 using the Rare variant (RV) test. To account for multiple testing, a p-value threshold of 5x10-8 was used. We adjusted for age and three principal components to account for potential population stratification.
While there were no GWAS-significant SNPs, rs12602627 on chromosome 17 was associated with a 75% increase in CA125 per additional variant allele of rs12602627 (p=6.47x10-8). Furthermore, there were two SNPs (rs12602169 and rs73990427) in close proximity that were nearly GWAS significant (p=7.12x10-8 and 8.97x10-8, respectively). rs12602627 explained 8% of the variability of CA125.
Monocyte to macrophage differentiation associated (MMD) is the closest gene to rs12602627. MMD encodes a protein expressed in differentiated mature macrophages and is involved in macrophage activation, suggesting it may play an important role in immune response. This is the first GWAS study to assess SNPs directly associated with circulating levels of CA125 in women without ovarian cancer. Validation studies are currently under way. Results from these analyses may provide important insights into genetic determinants of CA125 levels, improved ovarian cancer screening, and better understanding of how CA125 contributes to ovarian cancer pathogenesis and progression.
*Coauthors.
Citation Format: Naoko Sasamoto, Lai Jiang, Allison F. Vitonis, Raina N. Fichorova, Paul Pharaoh, Daniel W. Cramer, Peter Kraft, Kathryn L. Terry. Genome-wide association study of cancer antigen 125. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B19.