Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer

Jian Carrot-Zhang; Nyasha Chambwe; Jeffrey S Damrauer; Theo A Knijnenburg; A Gordon Robertson; Christina Yau; Wanding Zhou; Ashton C Berger; Kuan-Lin Huang; Justin Y Newberg; R Jay Mashl; Alessandro Romanel; Rosalyn W Sayaman; Francesca Demichelis; Ina Felau; Garrett M Frampton; Seunghun Han; Katherine A Hoadley; Anab Kemal; Peter W Laird; Alexander J Lazar; Xiuning Le; Ninad Oak; Hui Shen; Christopher K Wong; Jean C Zenklusen; Elad Ziv; Cancer Genome Atlas Analysis Network; Andrew D Cherniack; Rameen Beroukhim

doi:10.1016/j.ccell.2020.04.012

Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer

Cancer Cell. 2020 May 11;37(5):639-654.e6. doi: 10.1016/j.ccell.2020.04.012.

Authors

Jian Carrot-Zhang¹, Nyasha Chambwe², Jeffrey S Damrauer³, Theo A Knijnenburg², A Gordon Robertson⁴, Christina Yau⁵, Wanding Zhou⁶, Ashton C Berger⁷, Kuan-Lin Huang⁸, Justin Y Newberg⁹, R Jay Mashl¹⁰, Alessandro Romanel¹¹, Rosalyn W Sayaman¹², Francesca Demichelis¹¹, Ina Felau¹³, Garrett M Frampton⁹, Seunghun Han¹⁴, Katherine A Hoadley³, Anab Kemal¹³, Peter W Laird⁶, Alexander J Lazar¹⁵, Xiuning Le¹⁶, Ninad Oak¹⁷, Hui Shen⁶, Christopher K Wong¹⁸, Jean C Zenklusen¹³, Elad Ziv¹⁹; Cancer Genome Atlas Analysis Network; Andrew D Cherniack²², Rameen Beroukhim²³

Collaborators

Cancer Genome Atlas Analysis Network:
Francois Aguet²⁰, Li Ding⁹, John A Demchok¹³, Michael K A Mensah¹³, Samantha Caesar-Johnson¹³, Roy Tarnuzzer¹³, Zhining Wang¹³, Liming Yang¹³, Jessica Alfoldi²⁰, Konrad J Karczewski²⁰, Daniel G MacArthur²⁰, Matthew Meyerson¹, Christopher Benz²¹, Joshua M Stuart¹⁸

Affiliations

¹ The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
² Institute for Systems Biology, Seattle, WA 98109, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ British Columbia Cancer Agency, Genome Sciences Centre, Vancouver, BC V5Z4S6, Canada.
⁵ Buck Institute for Research on Aging, Novato, CA 94945, USA; Department of Surgery, University of California, San Francisco, San Francisco, CA 94115, USA.
⁶ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁷ The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Foundation Medicine, Cambridge, MA 02141, USA.
¹⁰ Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
¹¹ Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy.
¹² Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
¹³ National Cancer Institute, Bethesda, MD 20892, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Departments of Pathology, Genomic Medicine, and Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Department of Thoracic and Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
¹⁷ Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁸ UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
¹⁹ Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
²⁰ The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
²¹ Buck Institute for Research on Aging, Novato, CA 94945, USA.
²² The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: achernia@broadinstitute.org.
²³ The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: rameen_beroukhim@dfci.harvard.edu.

Abstract

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.

Keywords: TCGA; admixture; ancestry; cancer; eQTL; genomics; mRNA; methylation; miRNA; mutation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation*
DNA-Binding Proteins / genetics
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
MicroRNAs / genetics*
Mutation*
Neoplasm Proteins / genetics*
Neoplasms / ethnology
Neoplasms / genetics*
Neoplasms / pathology
Transcription Factors / genetics
Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

DNA-Binding Proteins
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
MicroRNAs
Neoplasm Proteins
PBRM1 protein, human
Transcription Factors
Von Hippel-Lindau Tumor Suppressor Protein
VHL protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding