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Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer


Archambault, AN and Su, YR and Jeon, J and Thomas, M and Lin, Y and Conti, DV and Win, AK and Sakoda, LC and Lansdorp-Vogelaar, I and Peterse, EF and Zauber, AG and Duggan, D and Holowatyj, AN and Huyghe, JR and Brenner, H and Cotterchio, M and Bezieau, S and Schmit, SL and Edlund, CK and Southey, MC and MacInnis, RJ and Campbell, PT and Chang-Claude, J and Slattery, ML and Chan, AT and Joshi, AD and Song, M and Cao, Y and Woods, MO and White, E and Weinstein, SJ and Ulrich, CM and Hoffmeister, M and Bien, SA and Harrison, TA and Hampe, J and Li, CI and Schafmayer, C and Offit, K and Pharoah, PD and Moreno, V and Lindblom, A and Wolk, A and Wu, AH and Li, L and Gunter, MJ and Gsur, A and Keku, TO and Pearlman, R and Bishop, DT and Castellvi-Bel, S and Moreira, L and Vodicka, P and Kampman, E and Giles, GG and Albanes, D and Baron, JA and Berndt, SI and Brezina, S and Buch, S and Buchanan, DD and Trichopoulou, A and Severi, G and Chirlaque, MD and Sanchez, MJ and Palli, D and Kuhn, T and Murphy, N and Cross, AJ and Burnett-Hartman, AN and Chanock, SJ and Chapelle, ADL and Easton, DF and Elliott, F and English, DR and Feskens, EJ and Fitzgerald, LM and Goodman, PJ and Hopper, JL and Hudson, TJ and Hunter, DJ and Jacobs, EJ and Joshu, CE and Kury, S and Markowitz, SD and Milne, RL and Platz, EA and Rennert, G and Rennert, HS and Schumacher, FR and Sandler, RS and Seminara, D and Tangen, CM and Thibodeau, SN and Toland, AE and van Duijnhoven, FJ and Visvanathan, K and Vodickova, L and Potter, JD and Mannisto, S and Weigl, K and Figueiredo, J and Martin, V and Larsson, SC and Parfrey, PS and Huang, WY and Lenz, HJ and Castelao, JE and Gago-Dominguez, M and Munoz-Garzon, V and Mancao, C and Haiman, CA and Wilkens, LR and Siegel, E and Barry, E and Younghusband, B and Van Guelpen, B and Harlid, S and Zeleniuch-Jacquotte, A and Liang, PS and Du, M and Casey, G and Lindor, NM and Le Marchand, L and Gallinger, SJ and Jenkins, MA and Newcomb, PA and Gruber, SB and Schoen, RE and Hampel, H and Corley, DA and Hsu, L and Peters, U and Hayes, RB, Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer, Gastroenterology, 158, (5) pp. 1274-1286. ISSN 0016-5085 (2020) [Refereed Article]

Copyright Statement

© 2020 by the AGA Institute

DOI: doi:10.1053/j.gastro.2019.12.012


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.


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.


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=5.61x10–5). 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.


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 preventative measures.

Item Details

Item Type:Refereed Article
Keywords:colon cancer, SNP, penetrance, EOCRC
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Cancer genetics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Fitzgerald, LM (Dr Liesel FitzGerald)
ID Code:136335
Year Published:2020
Web of Science® Times Cited:70
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-12-16
Last Modified:2022-08-29

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