Abstract 1310: Identification of pleiotropic cancer susceptibility variants from genome-wide association studies reveals functional characteristics
Authors: Wu Yi-Hsuan , Graff Rebecca E. , Passarelli Michael N. , Hoffmann Thomas J. , Ziv Elad , Witte John S. 
Published: July 2017

Abstract
Background: There exists compelling evidence that some genetic variants are associated with the risk of multiple cancers (i.e., pleiotropy). However, the biological mechanisms of the pleiotropic effects are unclear. Thus, we investigated the functional effects for genetic variants associated with the risk of multiple cancers.
Methods: The National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) GWAS Catalog contains 28,643 variant-trait associations with p &lt; 10-5. We utilized the Experimental Factor Ontology (EFO) to classify cancer traits and obtained all associations between variants and cancer risk. Based on pairwise linkage disequilibrium (LD) determined from the European (EUR) population of Phase 3 of the 1000 Genomes Project in LDlink, correlated variants (R-squared ≥ 0.8) were clustered into groups. Variant groups associated with the risk of multiple cancers were annotated using the Ensembl Variant Effect Predictor (VEP), and tested for functional enrichment using the DAVID Functional Annotation Tool.
Results: We identified 1,456 variant-cancer risk associations. The majority (57.1%) of the associations were discovered in European ancestry populations, 19.0% in East Asians, 7.9% in an African Americans or Afro-Caribbeans, and 7.1% in Hispanics or Latin Americans. Removing duplicates, we found 1,034 unique variant-cancer risk associations for 1,005 unique variants and 27 unique cancer sites. After clustering correlated variants, we identified 29 pleiotropic variant groups, of which 2 were associated with risk of five different cancer sites. Variant group rs10936599 and rs12696304 within the MYNN gene (7.8 kb from the TERC gene) was associated with leukemia, multiple myeloma, and colorectal, skin, and bladder cancer. Variant group rs31489, rs31490, rs401681, and rs4975616 within the CLPTM1L gene (22.8 kb from the TERT gene) was associated with leukemia, and lung, pancreatic, skin, and bladder cancer. Among the 42 unique variants that composed the 29 pleiotropic variant groups, 41 variants were within a known gene, and only 1 variant was in an intergenic region. The 41 variants mapped to 26 genes, which were enriched in cellular response to hypoxia (p= 0.0071), establishment of protein localization to telomere (p= 0.0071), and ubl conjugation (p= 0.0072).
Conclusion: This study identified and functionally characterized genetic variants showing pleiotropic effects on cancer risk. Our findings improve the understanding of shared biological mechanisms common to different cancers. Clinical implications could include the classification of cancers based on etiology, genetic testing for multiple cancers, and repurposing cancer treatments.
Citation Format: Yi-Hsuan Wu, Rebecca E. Graff, Michael N. Passarelli, Thomas J. Hoffmann, Elad Ziv, John S. Witte. Identification of pleiotropic cancer susceptibility variants from genome-wide association studies reveals functional characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1310. doi:10.1158/1538-7445.AM2017-1310