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; Regeneron Genetics Center; Thomas J Hoffmann; Elad Ziv; Laurel A Habel; Eric Jorgenson; Lori C Sakoda; John S Witte

doi:10.1186/s12916-022-02535-6

Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies

BMC Med. 2022 Oct 6;20(1):332. doi: 10.1186/s12916-022-02535-6.

Authors

Taylor B Cavazos¹, Linda Kachuri^{2

3}, Rebecca E Graff^{2

4}, Jovia L Nierenberg^{2

5}, Khanh K Thai⁴, Stacey Alexeeff⁴, Stephen Van Den Eeden⁴, Douglas A Corley⁴, Lawrence H Kushi⁴; Regeneron Genetics Center; Thomas J Hoffmann², Elad Ziv⁵, Laurel A Habel⁴, Eric Jorgenson⁶, Lori C Sakoda^{4

7}, John S Witte^{8

9

10}

Collaborators

Regeneron Genetics Center:
Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Katia Karalis, Luca A Lotta, John D Overton, Jeffrey G Reid, Katherine Siminovitch, Alan 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 C Staples, Kathie Sun, Jiwen Xin, Goncalo Abecasis, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Lauren Gurski, Eric Jorgenson, Hyun Min Kang, Michael Kessler, Jack Kosmicki, Alexander Li, Nan Lin, Daren Liu, Adam Locke, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Eli Stahl, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Marcus B Jones, Jason Mighty, Lyndon J Mitnaul

Affiliations

¹ Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, 94158, USA.
² Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94158, USA.
³ Department of Epidemiology and Population Health, Stanford University, Alway Building, 300 Pasteur Drive, Stanford, CA, 94305, USA.
⁴ Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA.
⁵ Regeneron Genetics Center, Tarrytown, NY, 10591, USA.
⁶ Department of Medicine, University of California San Francisco, San Francisco, CA, 94158, USA.
⁷ Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, 91101, USA.
⁸ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, 94158, USA. jswitte@stanford.edu.
⁹ Department of Epidemiology and Population Health, Stanford University, Alway Building, 300 Pasteur Drive, Stanford, CA, 94305, USA. jswitte@stanford.edu.
¹⁰ Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA. jswitte@stanford.edu.

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.

Keywords: Germline genetics; Multiple primary cancers; Pleiotropy; Whole-exome sequencing.

Publication types

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

MeSH terms

Exome / genetics
Exome Sequencing
Genetic Predisposition to Disease* / genetics
Humans
Neoplasms, Multiple Primary* / genetics
Phenotype

Abstract

Publication types

MeSH terms

Grants and funding