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Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.
Characterizing the Shared Genetic Basis of Common Cancers
The goal of our proposed research is to characterize pleiotropic loci in order to gain new insight into common carcinogenic mechanisms, shared etiology of multiple cancers, and treatment for cancer patients with seemingly distinct diseases. The UK cohort currently holds 80K subjects across multiple malignant cancer types. We propose to comprehensively assess the shared genetic basis underlying these different cancers within the UK cohort through the following aims: 1) Assess the co-inheritance of cancers due to common variation. 2) Evaluate locus-specific pleiotropy across different cancers. The detection and characterization of pleiotropy is key to understanding the biological and clinical underpinnings of cancer. While any single pleiotropic variant may have modest impact on disease, combinations of multiple variants can provide increasingly accurate prediction and be important for individualized risk counseling as well as for cancer screening and surveillance. Even where there already exist clinically relevant findings for individual cancers, our efforts to detect pleiotropy may provide an avenue for informing the successful development and application of treatments across cancers. Genotyping of all cancer subjects on the Affymetrix array is close to completion for the UK biobank subjects, and data on per subject cancer type is already available. We will use these data to determine genome-wide heritability for the most common cancers in the UK cohort, and calculate the co-inheritance and overall shared genomic basis among these cancers using complex statistical analysis methods. We request the full genotyped cohort.