Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts

Sara R Rashkin; Rebecca E Graff; Linda Kachuri; Khanh K Thai; Stacey E Alexeeff; Maruta A Blatchins; Taylor B Cavazos; Douglas A Corley; Nima C Emami; Joshua D Hoffman; Eric Jorgenson; Lawrence H Kushi; Travis J Meyers; Stephen K Van Den Eeden; Elad Ziv; Laurel A Habel; Thomas J Hoffmann; Lori C Sakoda; John S Witte

doi:10.1038/s41467-020-18246-6

Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts

Nat Commun. 2020 Sep 4;11(1):4423. doi: 10.1038/s41467-020-18246-6.

Authors

Sara R Rashkin^#¹, Rebecca E Graff^#^{1

2}, Linda Kachuri¹, Khanh K Thai², Stacey E Alexeeff², Maruta A Blatchins², Taylor B Cavazos^{1

3}, Douglas A Corley², Nima C Emami^{1

3}, Joshua D Hoffman¹, Eric Jorgenson², Lawrence H Kushi², Travis J Meyers¹, Stephen K Van Den Eeden^{2

4}, Elad Ziv^{5

6

7}, Laurel A Habel², Thomas J Hoffmann^{1

2

5}, Lori C Sakoda⁸, John S Witte^{9

10

11

12}

Affiliations

¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
² Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
³ Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
⁵ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁷ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁸ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA. lori.sakoda@kp.org.
⁹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.
¹⁰ Department of Urology, University of California, San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.
¹¹ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.
¹² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.

^# Contributed equally.

Abstract

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.

Publication types

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

MeSH terms

Adult
Aged
Carcinogenesis / genetics*
Case-Control Studies
Female
Genetic Pleiotropy
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Middle Aged
Neoplasms / epidemiology
Neoplasms / genetics*
Polymorphism, Single Nucleotide
Risk Assessment
Risk Factors
White People / genetics

Abstract

Publication types

MeSH terms

Grants and funding