Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Alexi N Archambault, Yu-Ru Su, Jihyoun Jeon, Minta Thomas, Yi Lin, David V Conti, Aung Ko Win, Lori C Sakoda, Iris Lansdorp-Vogelaar, Elisabeth F P Peterse, Ann G Zauber, David Duggan, Andreana N Holowatyj, Jeroen R Huyghe, Hermann Brenner, Michelle Cotterchio, Stéphane Bézieau, Stephanie L Schmit, Christopher K Edlund, Melissa C SoutheyRobert J MacInnis, Peter T Campbell, Jenny Chang-Claude, Martha L Slattery, Andrew T Chan, Amit D Joshi, Mingyang Song, Yin Cao, Michael O Woods, Emily White, Stephanie J Weinstein, Cornelia M Ulrich, Michael Hoffmeister, Stephanie A Bien, Tabitha A Harrison, Jochen Hampe, Christopher I Li, Clemens Schafmayer, Kenneth Offit, Paul D Pharoah, Victor Moreno, Annika Lindblom, Alicja Wolk, Anna H Wu, Li Li, Marc J Gunter, Andrea Gsur, Temitope O Keku, Rachel Pearlman, D Timothy Bishop, Sergi Castellví-Bel, Leticia Moreira, Pavel Vodicka, Ellen Kampman, Graham G Giles, Demetrius Albanes, John A Baron, Sonja I Berndt, Stefanie Brezina, Stephan Buch, Daniel D Buchanan, Antonia Trichopoulou, Gianluca Severi, María-Dolores Chirlaque, Maria-José Sánchez, Domenico Palli, Tilman Kühn, Neil Murphy, Amanda J Cross, Andrea N Burnett-Hartman, Stephen J Chanock, Albert de la Chapelle, Douglas F Easton, Faye Elliott, Dallas R English, Edith J M Feskens, Liesel M FitzGerald, Phyllis J Goodman, John L Hopper, Thomas J Hudson, David J Hunter, Eric J Jacobs, Corinne E Joshu, Sébastien Küry, Sanford D Markowitz, Roger L Milne, Elizabeth A Platz, Gad Rennert, Hedy S Rennert, Fredrick R Schumacher, Robert S Sandler, Daniela Seminara, Catherine M Tangen, Stephen N Thibodeau, Amanda E Toland, Franzel J B van Duijnhoven, Kala Visvanathan, Ludmila Vodickova, John D Potter, Satu Männistö, Korbinian Weigl, Jane Figueiredo, Vicente Martín, Susanna C Larsson, Patrick S Parfrey, Wen-Yi Huang, Heinz-Josef Lenz, Jose E Castelao, Manuela Gago-Dominguez, Victor Muñoz-Garzón, Christoph Mancao, Christopher A Haiman, Lynne R Wilkens, Erin Siegel, Elizabeth Barry, Ban Younghusband, Bethany Van Guelpen, Sophia Harlid, Anne Zeleniuch-Jacquotte, Peter S Liang, Mengmeng Du, Graham Casey, Noralane M Lindor, Loic Le Marchand, Steven J Gallinger, Mark A Jenkins, Polly A Newcomb, Stephen B Gruber, Robert E Schoen, Heather Hampel, Douglas A Corley, Li Hsu, Ulrike Peters, Richard B Hayes

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.

RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.

CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Original languageEnglish
Pages (from-to)1274-1286.e12
Issue number5
Early online date19 Dec 2019
Publication statusPublished - Apr 2020

Bibliographical note

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.


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