Abstract 4611: Quantification and functional characterization of the shared heritability across multiple cancer sites: results from the GAME-ON Consortium

Abstract

Abstract It is estimated that more than 1.6 million cancer diagnoses will occur in the US during 2014 and five common cancers_breast, colorectal, lung, ovarian and prostate cancer_together constitute more than 50% of new cancer diagnoses. Many cancers cluster within families and in some cases multiple tumor types affect one family. Quantifying the extent to which distinct cancer types share genetic predisposition will inform design for future genetic association studies and give insights to shared biological mechanisms underlying disease. The GAME-ON consortium set out to conduct post-GWAS research for breast, colorectal, lung, ovarian and prostate cancer. Across the five cancer sites, a total of 51,725 cases and 62,155 controls were included as part of cancer-specific GWAS and summary statistics were shared between the cancer sites to conduct cross-cancer analysis. Using the recently developed LD score regression method, we leveraged these data to quantify the genetic correlation between these five cancers. In addition, we also estimated the genetic correlation between these cancers and 59 non-cancer traits using publically available GWAS summary statistics. Finally, we also functionally characterized the heritability across the five GAME-ON cancers. We found a nominally significant positive genetic correlation between breast and lung cancer (rg = 0.26, p = 0.045), however this correlation did not remain significantly different from zero after adjusting for multiple testing. We found positive genetic correlations (all p<0.003) between lung cancer and traits related to smoking (rg = 0.53-0.64) and adiposity (rg = 0.31-0.42). We also identified a positive genetic correlation between schizophrenia and breast cancer (rg = 0.16, p = 0.003) as well as a negative genetic correlation between adiposity and breast cancer (rg = -0.25, p = 0.01). However, these genetic correlations were not statistically significant after adjustment for number of tests performed. In functional enrichment analysis across all cancers, we observed a 17-fold (se: 2.9) enrichment of heritability located within conserved regions. In addition, transcription factor binding sites (TFBS), super-enhancers and histone marks showed 6.6- (se: 1.2), 2.5- (se: 0.2) and 2.0-fold enrichments, respectively. This is the first study to estimate the genetic correlation between these five common cancers in a population of unrelated individuals. Although we observe only modest evidence of a shared heritability of these cancers, the standard errors were large; larger samples will be needed to find modest, true genetic correlations. In addition, we found that conserved genetic regions are enriched for cancer heritability and future studies seeking to discover genetic variants associated with these cancers should focus on these regions. Note: This abstract was not presented at the meeting. Citation Format: Sara Lindstrom, Hilary Finucane, Brendan Bulik-Sullivan, Fredrick Schumacher, Christopher Amos, Stephen Gruber, Brian Henderson, David Hunter, Thomas Sellers, Benjamin Neale, Alkes Price, Peter Kraft, GAME-ON Consortium. Quantification and functional characterization of the shared heritability across multiple cancer sites: results from the GAME-ON Consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4611. doi:10.1158/1538-7445.AM2015-4611