• Taylor B Cavazos, Linda Kachuri, Rebecca E Graff, Jovia L Nierenberg, Khanh K Thai, Stacey Alexeeff, Stephen Van Den Eeden, Douglas A Corley, Lawrence H Kushi, Regeneron Genetics Center, Thomas J Hoffmann, Elad Ziv, Laurel A Habel, Eric Jorgenson, Lori C Sakoda, and John S Witte.
• Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, 94158, USA.
• Bmc Med. 2022 Oct 6; 20 (1): 332332.

BackgroundUp to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.MethodsTo characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers.ResultsWe identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer.ConclusionsOverall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.© 2022. The Author(s).

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