Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer

• Published in: Cancer cell Vol. 37; no. 5; pp. 639 - 654.e6
• Main Authors: Carrot-Zhang, Jian, Chambwe, Nyasha, Damrauer, Jeffrey S., Knijnenburg, Theo A., Robertson, A. Gordon, Yau, Christina, Zhou, Wanding, Berger, Ashton C., Huang, Kuan-lin, Newberg, Justin Y., Mashl, R. Jay, Romanel, Alessandro, Sayaman, Rosalyn W., Demichelis, Francesca, Felau, Ina, Frampton, Garrett M., Han, Seunghun, Hoadley, Katherine A., Kemal, Anab, Laird, Peter W., Lazar, Alexander J., Le, Xiuning, Oak, Ninad, Shen, Hui, Wong, Christopher K., Zenklusen, Jean C., Ziv, Elad, Aguet, Francois, Ding, Li, Demchok, John A., Mensah, Michael K.A., Caesar-Johnson, Samantha, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Alfoldi, Jessica, Karczewski, Konrad J., MacArthur, Daniel G., Meyerson, Matthew, Benz, Christopher, Stuart, Joshua M., Cherniack, Andrew D., Beroukhim, Rameen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-05-2020
• Subjects: admixture; ancestry; cancer; DNA Methylation; DNA-Binding Proteins - genetics; eQTL; Ethnicity - genetics; F-Box-WD Repeat-Containing Protein 7 - genetics; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genetics, Population; Genome, Human; Genomics; High-Throughput Nucleotide Sequencing; Humans; methylation; MicroRNAs - genetics; miRNA; mRNA; Mutation; Neoplasm Proteins - genetics; Neoplasms - ethnology; Neoplasms - genetics; Neoplasms - pathology; TCGA; Transcription Factors - genetics; Von Hippel-Lindau Tumor Suppressor Protein - genetics; mutation; ancestry; admixture; methylation; genomics; miRNA; cancer; mRNA; eQTL; TCGA
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2020.04.012

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 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.
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•This large analysis identified ancestry correlates in cancer•Ancestry-associated artifacts and confounders were identified•Ancestry effects are profoundly tissue specific•Rates of FBXW7, VHL, and PBRM1 mutations and immune activity vary by ancestry
Analyzing mutation rates, gene and miRNA expression, and DNA methylation across tumor types, Carrot-Zhang et al. separate confounders and identify ancestry-related effects that potentially explain cancer etiology and treatment.