Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies
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, Gonçalo R. Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris N. Economides, Katia Karalis, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Katherine Siminovitch, Alan R. Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, John D. Overton, Maria Sotiropoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D. Schleicher, Louis Widom, Sarah E. Wolf, Ricardo H. Ulloa, Amelia Averitt, Nilanjana Banerjee, Michael Cantor, Dadong Li, Sameer Malhotra, Deepika Sharma, Jeffrey Staples, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, George Mitra, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, Jeffrey G. Reid, William Salerno, Jeffrey Staples, Kathie Sun, Jiwen Xin, Gonçalo R. Abecasis, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher E. Gillies, Lauren Gurski, Eric Jorgenson, Hyun Min Kang, Michael D. Kessler, Jack A. Kosmicki, Alexander Li, Nan Lin, Daren Liu, Adam E. Locke, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Eli A. Stahl, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Marcus B. Jones, Jason Mighty, Lyndon J. Mitnaul, Thomas J. Hoffmann, Elad Ziv, Laurel A. Habel
Abstract
BACKGROUND: Up 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. METHODS: To 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. RESULTS: We 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. CONCLUSIONS: Overall, 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.