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Summary
We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue-specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included an increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.
Significance
We conducted the most comprehensive analysis to date of the molecular effects of ancestry across cancer or normal tissues. We found that, though many ancestry effects were shared by normal tissues, they were profoundly tissue-specific, suggesting ancestry effects have to be considered primarily on a per-tissue basis both among cancers and non-cancer tissues. In tissue-specific analyses of normal tissue especially, more samples from diverse ancestries are required for comprehensive ancestry analyses, and we identified important controls for confounders and artifacts that need to be applied in such studies. Differences between African, European, and East Asian groups in renal and bladder cancers in particular suggest that ancestry should be taken into account when considering routes to disease and response to immunotherapies.
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