Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies
Authors: Cavazos Taylor B. , Kachuri Linda , Graff Rebecca E. , Nierenberg Jovia L. , Thai Khanh K. , Alexeeff Stacey , Van Den Eeden Stephen , Corley Douglas A. , Kushi Lawrence H. ,   Regeneron Genetics Center, Abecasis Goncalo , Baras Aris , Cantor Michael , Coppola Giovanni , Deubler Andrew , Economides Aris , Karalis Katia , Lotta Luca A. , Overton John D. , Reid Jeffrey G. , Siminovitch Katherine , Shuldiner Alan , Beechert Christina , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Overton John D. , Padilla Maria Sotiropoulos , Pradhan Manasi , Manoochehri Kia , Schleicher Thomas D. , Widom Louis , Wolf Sarah E. , Ulloa Ricardo H. , Averitt Amelia , Banerjee Nilanjana , Cantor Michael , Li Dadong , Malhotra Sameer , Sharma Deepika , Staples Jeffrey , Bai Xiaodong , Balasubramanian Suganthi , Bao Suying , Boutkov Boris , Chen Siying , Eom Gisu , Habegger Lukas , Hawes Alicia , Khalid Shareef , Krasheninina Olga , Lanche Rouel , Mansfield Adam J. , Maxwell Evan K. , Mitra George , Nafde Mona , O’Keeffe Sean , Orelus Max , Panea Razvan , Polanco Tommy , Rasool Ayesha , Reid Jeffrey G. , Salerno William , Staples Jeffrey C. , Sun Kathie , Xin Jiwen , Abecasis Goncalo , Backman Joshua , Damask Amy , Dobbyn Lee , Ferreira Manuel Allen Revez , Ghosh Arkopravo , Gillies Christopher , Gurski Lauren , Jorgenson Eric , Kang Hyun Min , Kessler Michael , Kosmicki Jack , Li Alexander , Lin Nan , Liu Daren , Locke Adam , Marchini Jonathan , Marcketta Anthony , Mbatchou Joelle , Moscati Arden , Paulding Charles , Sidore Carlo , Stahl Eli , Watanabe Kyoko , Ye Bin , Zhang Blair , Ziyatdinov Andrey , Jones Marcus B. , Mighty Jason , Mitnaul Lyndon J. , Hoffmann Thomas J. , Ziv Elad , Habel Laurel A. , Jorgenson Eric , Sakoda Lori C. , Witte John S. 
Published: October 2022

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.