Cancer is a common but complex disease with a number of unresolved issues surrounding its underlying
genetic basis. Recent work suggests that some phenotypically distinct cancers may arise due to similar
genetic factors. We propose to evaluate this potential pleiotropy using existing genetic measures in the large,
well-characterized Kaiser Permanente Research Program in Genes, Environment and Health cohort. This
cohort includes over 110,266 individuals with a genome-wide array data, and 22,575 of these individuals will
have been diagnosed with cancer by the start of this project. We will leverage this information to undertake a
comprehensive evaluation of the shared genetic basis underlying cancers. In particular, our initial aim will
evaluate the heritability and overall shared genetic basis of different cancers sites. Then we will investigate
whether specific genetic variants impact risk of different cancers, incorporating into our analyses information
about cancer organ systems and exposures that may modify the genetic associations (e.g., smoking). Our third
aim will decipher the genetic basis of multiple cancers occurring in the same individual, including exome
sequencing of the approximately 1,800 individuals diagnosed with multiple cancers in the cohort and their
family members as available. Based on our findings from these aims, we will evaluate the potential biological
and functional relevance of genetic variants exhibiting carcinogenic pleiotropy. Taken together, this project
provides a unique, innovative, and efficient opportunity to detect pleotropic associations across a range of
cancer sites in a single, large cohort. he individual-level data from an essentially population-based study
allows us to evaluate novel hypotheses about the shared genetic basis of multiple cancers, and nicely
complements existing meta-analyses efforts across different GWAS of the most common cancer sites.
Understanding such potential carcinogenic pleiotropy may help clarify the biological basis of this disease,
explain and predict the occurrence of multiple cancers, and insights into possible treatment strategies among
patients with seemingly distinct cancers.
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