Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.
Archambault AN., Su Y-R., Jeon J., Thomas M., Lin Y., Conti DV., Win AK., Sakoda LC., Lansdorp-Vogelaar I., Peterse EFP., Zauber AG., Duggan D., Holowatyj AN., Huyghe JR., Brenner H., Cotterchio M., Bézieau S., Schmit SL., Edlund CK., Southey MC., MacInnis RJ., Campbell PT., Chang-Claude J., Slattery ML., Chan AT., Joshi AD., Song M., Cao Y., Woods MO., White E., Weinstein SJ., Ulrich CM., Hoffmeister M., Bien SA., Harrison TA., Hampe J., Li CI., Schafmayer C., Offit K., Pharoah PD., Moreno V., Lindblom A., Wolk A., Wu AH., Li L., Gunter MJ., Gsur A., Keku TO., Pearlman R., Bishop DT., Castellví-Bel S., Moreira L., Vodicka P., Kampman E., Giles GG., Albanes D., Baron JA., Berndt SI., Brezina S., Buch S., Buchanan DD., Trichopoulou A., Severi G., Chirlaque M-D., Sánchez M-J., Palli D., Kühn T., Murphy N., Cross AJ., Burnett-Hartman AN., Chanock SJ., de la Chapelle A., Easton DF., Elliott F., English DR., Feskens EJM., FitzGerald LM., Goodman PJ., Hopper JL., Hudson TJ., Hunter DJ., Jacobs EJ., Joshu CE., Küry S., Markowitz SD., Milne RL., Platz EA., Rennert G., Rennert HS., Schumacher FR., Sandler RS., Seminara D., Tangen CM., Thibodeau SN., Toland AE., van Duijnhoven FJB., Visvanathan K., Vodickova L., Potter JD., Männistö S., Weigl K., Figueiredo J., Martín V., Larsson SC., Parfrey PS., Huang W-Y., Lenz H-J., Castelao JE., Gago-Dominguez M., Muñoz-Garzón V., Mancao C., Haiman CA., Wilkens LR., Siegel E., Barry E., Younghusband B., Van Guelpen B., Harlid S., Zeleniuch-Jacquotte A., Liang PS., Du M., Casey G., Lindor NM., Le Marchand L., Gallinger SJ., Jenkins MA., Newcomb PA., Gruber SB., Schoen RE., Hampel H., Corley DA., Hsu L., Peters U., Hayes RB.
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.