Cross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts

Rebecca E. Graff, Taylor B. Cavazos, Khanh K. Thai, Linda Kachuri, Sara R. Rashkin, Joshua D. Hoffman, Stacey E. Alexeeff, Maruta Blatchins, Travis J. Meyers, Lancelote Leong, Caroline G. Tai, Nima C. Emami, Douglas A. Corley, Lawrence H. Kushi, Elad Ziv, Stephen K. Eeden, Eric Jorgenson, Thomas J. Hoffmann, Laurel A. Habel, John S. Witte () and Lori C. Sakoda ()
Additional contact information
Rebecca E. Graff: University of California San Francisco
Taylor B. Cavazos: Program in Biological and Medical Informatics, University of California San Francisco
Khanh K. Thai: Kaiser Permanente Northern California
Linda Kachuri: University of California San Francisco
Sara R. Rashkin: University of California San Francisco
Joshua D. Hoffman: University of California San Francisco
Stacey E. Alexeeff: Kaiser Permanente Northern California
Maruta Blatchins: Kaiser Permanente Northern California
Travis J. Meyers: University of California San Francisco
Lancelote Leong: University of California San Francisco
Caroline G. Tai: University of California San Francisco
Nima C. Emami: University of California San Francisco
Douglas A. Corley: Kaiser Permanente Northern California
Lawrence H. Kushi: Kaiser Permanente Northern California
Elad Ziv: University of California San Francisco
Stephen K. Eeden: Kaiser Permanente Northern California
Eric Jorgenson: Kaiser Permanente Northern California
Thomas J. Hoffmann: University of California San Francisco
Laurel A. Habel: Kaiser Permanente Northern California
John S. Witte: University of California San Francisco
Lori C. Sakoda: Kaiser Permanente Northern California

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.

Date: 2021
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DOI: 10.1038/s41467-021-21288-z

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