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