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. Southey; Robert 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

doi:10.1053/j.gastro.2019.12.012

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 journal › Article › peer-review

88 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	1274-1286.e12
Journal	Gastroenterology
Volume	158
Issue number	5
DOIs	https://doi.org/10.1053/j.gastro.2019.12.012
State	Published - Apr 2020
Externally published	Yes

Keywords

Colon Cancer
EOCRC
Penetrance
SNP

ASJC Scopus subject areas

Hepatology
Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1053/j.gastro.2019.12.012

Cite this

Archambault, A. N., Su, Y. R., Jeon, J., Thomas, M., Lin, Y., Conti, D. V., Win, A. K., Sakoda, L. C., Lansdorp-Vogelaar, I., Peterse, E. F. P., Zauber, A. G., Duggan, D., Holowatyj, A. N., Huyghe, J. R., Brenner, H., Cotterchio, M., Bézieau, S., Schmit, S. L., Edlund, C. K., ... Hayes, R. B. (2020). Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer. Gastroenterology, 158(5), 1274-1286.e12. https://doi.org/10.1053/j.gastro.2019.12.012

Archambault, AN, Su, YR, 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, MD, Sánchez, MJ, 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, WY, Lenz, HJ, 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 2020, 'Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer', Gastroenterology, vol. 158, no. 5, pp. 1274-1286.e12. https://doi.org/10.1053/j.gastro.2019.12.012

@article{f49474ec9b07453db5da41861c7c8896,

title = "Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer",

abstract = "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.",

keywords = "Colon Cancer, EOCRC, Penetrance, SNP",

author = "Archambault, {Alexi N.} and Su, {Yu Ru} and Jihyoun Jeon and Minta Thomas and Yi Lin and Conti, {David V.} and Win, {Aung Ko} and Sakoda, {Lori C.} and Iris Lansdorp-Vogelaar and Peterse, {Elisabeth F.P.} and Zauber, {Ann G.} and David Duggan and Holowatyj, {Andreana N.} and Huyghe, {Jeroen R.} and Hermann Brenner and Michelle Cotterchio and St{\'e}phane B{\'e}zieau and Schmit, {Stephanie L.} and Edlund, {Christopher K.} and Southey, {Melissa C.} and MacInnis, {Robert J.} and Campbell, {Peter T.} and Jenny Chang-Claude and Slattery, {Martha L.} and Chan, {Andrew T.} and Joshi, {Amit D.} and Mingyang Song and Yin Cao and Woods, {Michael O.} and Emily White and Weinstein, {Stephanie J.} and Ulrich, {Cornelia M.} and Michael Hoffmeister and Bien, {Stephanie A.} and Harrison, {Tabitha A.} and Jochen Hampe and Li, {Christopher I.} and Clemens Schafmayer and Kenneth Offit and Pharoah, {Paul D.} and Victor Moreno and Annika Lindblom and Alicja Wolk and Wu, {Anna H.} and Li Li and Gunter, {Marc J.} and Andrea Gsur and Keku, {Temitope O.} and Rachel Pearlman and Bishop, {D. Timothy} and Sergi Castellv{\'i}-Bel and Leticia Moreira and Pavel Vodicka and Ellen Kampman and Giles, {Graham G.} and Demetrius Albanes and Baron, {John A.} and Berndt, {Sonja I.} and Stefanie Brezina and Stephan Buch and Buchanan, {Daniel D.} and Antonia Trichopoulou and Gianluca Severi and Chirlaque, {Mar{\'i}a Dolores} and S{\'a}nchez, {Maria Jos{\'e}} and Domenico Palli and Tilman K{\"u}hn and Neil Murphy and Cross, {Amanda J.} and Burnett-Hartman, {Andrea N.} and Chanock, {Stephen J.} and {de la Chapelle}, Albert and Easton, {Douglas F.} and Faye Elliott and English, {Dallas R.} and Feskens, {Edith J.M.} and FitzGerald, {Liesel M.} and Goodman, {Phyllis J.} and Hopper, {John L.} and Hudson, {Thomas J.} and Hunter, {David J.} and Jacobs, {Eric J.} and Joshu, {Corinne E.} and S{\'e}bastien K{\"u}ry and Markowitz, {Sanford D.} and Milne, {Roger L.} and Platz, {Elizabeth A.} and Gad Rennert and Rennert, {Hedy S.} and Schumacher, {Fredrick R.} and Sandler, {Robert S.} and Daniela Seminara and Tangen, {Catherine M.} and Thibodeau, {Stephen N.} and Toland, {Amanda E.} and {van Duijnhoven}, {Franzel J.B.} and Kala Visvanathan and Ludmila Vodickova and Potter, {John D.} and Satu M{\"a}nnist{\"o} and Korbinian Weigl and Jane Figueiredo and Vicente Mart{\'i}n and Larsson, {Susanna C.} and Parfrey, {Patrick S.} and Huang, {Wen Yi} and Lenz, {Heinz Josef} and Castelao, {Jose E.} and Manuela Gago-Dominguez and Victor Mu{\~n}oz-Garz{\'o}n and Christoph Mancao and Haiman, {Christopher A.} and Wilkens, {Lynne R.} and Erin Siegel and Elizabeth Barry and Ban Younghusband and {Van Guelpen}, Bethany and Sophia Harlid and Anne Zeleniuch-Jacquotte and Liang, {Peter S.} and Mengmeng Du and Graham Casey and Lindor, {Noralane M.} and {Le Marchand}, Loic and Gallinger, {Steven J.} and Jenkins, {Mark A.} and Newcomb, {Polly A.} and Gruber, {Stephen B.} and Schoen, {Robert E.} and Heather Hampel and Corley, {Douglas A.} and Li Hsu and Ulrike Peters and Hayes, {Richard B.}",

note = "Funding Information: NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from the County Council of V{\"a}sterbotten, Sweden; Wallenberg Centre for Molecular Medicine at Ume{\aa} University; Lion{\textquoteright}s Cancer Research Foundation at Ume{\aa} University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Ume{\aa} University, Ume{\aa}, Sweden. Funding Information: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. Funding Information: COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d{\textquoteright}Huzes and the Dutch Cancer Society (UM 2012–5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The NQplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant no. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public–private partnership on pre-competitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. Funding Information: CORSA: This study was funded by FFG BRIDGE (grant 829675, to Andrea Gsur), the “Herzfelder'sche Familienstiftung” (grant to Andrea Gsur) and was supported by COST Actions BM1206 and CA17118. Funding Information: MECC: This work was supported by the NIH, U.S. Department of Health and Human Services (R01 CA81488 to SBG and GR). Funding Information: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the NIH (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the NIH (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003) and PHS by the NIH (R01 CA042182). Funding Information: Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institut{\'e}s Distinguished Professor Award to Alicja Wolk. Funding Information: EPIC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G{\'e}n{\'e}rale de l{\textquoteright}Education Nationale, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andaluc{\'i}a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Sk{\aa}ne and V{\"a}sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). Funding Information: Kentucky: This work was supported by the following grant support: 1) Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8) and 2) NCI R01CA136726; and, we would like to acknowledge the staff at the Kentucky Cancer Registry Funding Information: NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the NIH, US Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Montr{\'e}al, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. Funding Information: Funding This study was supported by National Cancer Institute, National Institutes of Health Grants R03-CA215775?01A1, R01-CA206279?03. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding Information: CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), and Junta de Castilla y Le{\'o}n (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d{\textquoteright}Oncolog{\'i}a de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: OFCCR: NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Funding Information: Funding This study was supported by National Cancer Institute , National Institutes of Health Grants R03-CA215775–01A1 , R01-CA206279–03 . Funding Information: RPGEH: Data used in this study were provided by the Kaiser Permanente Research Bank (KPRB) from the KPRB collection, which includes the Kaiser Permanente RPGEH and the Genetic Epidemiology Research on Adult Health and Aging (GERA) data, funded by the NIH [RC2 AG036607 (Schaefer and Risch)], The Ellison Medical Foundation, and the Kaiser Permanente Community Benefits Program. Access to data used in this study may be obtained by application to the KPRB via ResearchBankAccess@kp.org . Funding Information: NCCCS I & II: We acknowledge funding support for this project from the NIH, R01 CA66635 and P30 DK034987. Funding Information: Czech Republic CCS: This work was supported by the Grant Agency of the Czech Republic (grants CZ GA CR: GAP304/10/1286 and 1585) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants AZV 15-27580A and AZV 17-30920A). Funding Information: EPICOLON: This work was supported by grants from Fondo de Investigaci{\'o}n Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, P111/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, Acci{\'o}n Transversal de C{\'a}ncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola contra el C{\'a}ncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncolog{\'i}a” AEG (Asociaci{\'o}n Espa{\~n}ola de Gastroenterolog{\'i}a), Fundaci{\'o}n Privada Olga Torres, FP7 CHIBCHA Consortium, Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d{\textquoteright}Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Action BM1206. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, NIH, U.S. Department of Health and Human Services (U01 CA164930, R01 CA201407). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-W{\"u}rttemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish research council; K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2 and the Stockholm County Council (ALF project). Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: Kiel: This work was supported by institutional funds from the Medical Faculties of the Christian-Albrechts University Kiel and the Technical University Dresden. Funding Information: Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by NCI/NIH, US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350,; P01 CA196569; R01 CA201407) and National Institutes of Environmental Health Sciences, NIH (grant number T32 ES013678). Funding Information: MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the NIH (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). Publisher Copyright: {\textcopyright} 2020 AGA Institute",

year = "2020",

month = apr,

doi = "10.1053/j.gastro.2019.12.012",

language = "English (US)",

volume = "158",

pages = "1274--1286.e12",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "5",

}

TY - JOUR

T1 - Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

AU - Archambault, Alexi N.

AU - Su, Yu Ru

AU - Jeon, Jihyoun

AU - Thomas, Minta

AU - Lin, Yi

AU - Conti, David V.

AU - Win, Aung Ko

AU - Sakoda, Lori C.

AU - Lansdorp-Vogelaar, Iris

AU - Peterse, Elisabeth F.P.

AU - Zauber, Ann G.

AU - Duggan, David

AU - Holowatyj, Andreana N.

AU - Huyghe, Jeroen R.

AU - Brenner, Hermann

AU - Cotterchio, Michelle

AU - Bézieau, Stéphane

AU - Schmit, Stephanie L.

AU - Edlund, Christopher K.

AU - Southey, Melissa C.

AU - MacInnis, Robert J.

AU - Campbell, Peter T.

AU - Chang-Claude, Jenny

AU - Slattery, Martha L.

AU - Chan, Andrew T.

AU - Joshi, Amit D.

AU - Song, Mingyang

AU - Cao, Yin

AU - Woods, Michael O.

AU - White, Emily

AU - Weinstein, Stephanie J.

AU - Ulrich, Cornelia M.

AU - Hoffmeister, Michael

AU - Bien, Stephanie A.

AU - Harrison, Tabitha A.

AU - Hampe, Jochen

AU - Li, Christopher I.

AU - Schafmayer, Clemens

AU - Offit, Kenneth

AU - Pharoah, Paul D.

AU - Moreno, Victor

AU - Lindblom, Annika

AU - Wolk, Alicja

AU - Wu, Anna H.

AU - Li, Li

AU - Gunter, Marc J.

AU - Gsur, Andrea

AU - Keku, Temitope O.

AU - Pearlman, Rachel

AU - Bishop, D. Timothy

AU - Castellví-Bel, Sergi

AU - Moreira, Leticia

AU - Vodicka, Pavel

AU - Kampman, Ellen

AU - Giles, Graham G.

AU - Albanes, Demetrius

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Brezina, Stefanie

AU - Buch, Stephan

AU - Buchanan, Daniel D.

AU - Trichopoulou, Antonia

AU - Severi, Gianluca

AU - Chirlaque, María Dolores

AU - Sánchez, Maria José

AU - Palli, Domenico

AU - Kühn, Tilman

AU - Murphy, Neil

AU - Cross, Amanda J.

AU - Burnett-Hartman, Andrea N.

AU - Chanock, Stephen J.

AU - de la Chapelle, Albert

AU - Easton, Douglas F.

AU - Elliott, Faye

AU - English, Dallas R.

AU - Feskens, Edith J.M.

AU - FitzGerald, Liesel M.

AU - Goodman, Phyllis J.

AU - Hopper, John L.

AU - Hudson, Thomas J.

AU - Hunter, David J.

AU - Jacobs, Eric J.

AU - Joshu, Corinne E.

AU - Küry, Sébastien

AU - Markowitz, Sanford D.

AU - Milne, Roger L.

AU - Platz, Elizabeth A.

AU - Rennert, Gad

AU - Rennert, Hedy S.

AU - Schumacher, Fredrick R.

AU - Sandler, Robert S.

AU - Seminara, Daniela

AU - Tangen, Catherine M.

AU - Thibodeau, Stephen N.

AU - Toland, Amanda E.

AU - van Duijnhoven, Franzel J.B.

AU - Visvanathan, Kala

AU - Vodickova, Ludmila

AU - Potter, John D.

AU - Männistö, Satu

AU - Weigl, Korbinian

AU - Figueiredo, Jane

AU - Martín, Vicente

AU - Larsson, Susanna C.

AU - Parfrey, Patrick S.

AU - Huang, Wen Yi

AU - Lenz, Heinz Josef

AU - Castelao, Jose E.

AU - Gago-Dominguez, Manuela

AU - Muñoz-Garzón, Victor

AU - Mancao, Christoph

AU - Haiman, Christopher A.

AU - Wilkens, Lynne R.

AU - Siegel, Erin

AU - Barry, Elizabeth

AU - Younghusband, Ban

AU - Van Guelpen, Bethany

AU - Harlid, Sophia

AU - Zeleniuch-Jacquotte, Anne

AU - Liang, Peter S.

AU - Du, Mengmeng

AU - Casey, Graham

AU - Lindor, Noralane M.

AU - Le Marchand, Loic

AU - Gallinger, Steven J.

AU - Jenkins, Mark A.

AU - Newcomb, Polly A.

AU - Gruber, Stephen B.

AU - Schoen, Robert E.

AU - Hampel, Heather

AU - Corley, Douglas A.

AU - Hsu, Li

AU - Peters, Ulrike

AU - Hayes, Richard B.

N1 - Funding Information: NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from the County Council of Västerbotten, Sweden; Wallenberg Centre for Molecular Medicine at Umeå University; Lion’s Cancer Research Foundation at Umeå University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Umeå University, Umeå, Sweden. Funding Information: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. Funding Information: COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d’Huzes and the Dutch Cancer Society (UM 2012–5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The NQplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant no. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public–private partnership on pre-competitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. Funding Information: CORSA: This study was funded by FFG BRIDGE (grant 829675, to Andrea Gsur), the “Herzfelder'sche Familienstiftung” (grant to Andrea Gsur) and was supported by COST Actions BM1206 and CA17118. Funding Information: MECC: This work was supported by the NIH, U.S. Department of Health and Human Services (R01 CA81488 to SBG and GR). Funding Information: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the NIH (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the NIH (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003) and PHS by the NIH (R01 CA042182). Funding Information: Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institutés Distinguished Professor Award to Alicja Wolk. Funding Information: EPIC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). Funding Information: Kentucky: This work was supported by the following grant support: 1) Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8) and 2) NCI R01CA136726; and, we would like to acknowledge the staff at the Kentucky Cancer Registry Funding Information: NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the NIH, US Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. Funding Information: Funding This study was supported by National Cancer Institute, National Institutes of Health Grants R03-CA215775?01A1, R01-CA206279?03. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding Information: CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), and Junta de Castilla y León (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: OFCCR: NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Funding Information: Funding This study was supported by National Cancer Institute , National Institutes of Health Grants R03-CA215775–01A1 , R01-CA206279–03 . Funding Information: RPGEH: Data used in this study were provided by the Kaiser Permanente Research Bank (KPRB) from the KPRB collection, which includes the Kaiser Permanente RPGEH and the Genetic Epidemiology Research on Adult Health and Aging (GERA) data, funded by the NIH [RC2 AG036607 (Schaefer and Risch)], The Ellison Medical Foundation, and the Kaiser Permanente Community Benefits Program. Access to data used in this study may be obtained by application to the KPRB via ResearchBankAccess@kp.org . Funding Information: NCCCS I & II: We acknowledge funding support for this project from the NIH, R01 CA66635 and P30 DK034987. Funding Information: Czech Republic CCS: This work was supported by the Grant Agency of the Czech Republic (grants CZ GA CR: GAP304/10/1286 and 1585) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants AZV 15-27580A and AZV 17-30920A). Funding Information: EPICOLON: This work was supported by grants from Fondo de Investigación Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, P111/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, Acción Transversal de Cáncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología), Fundación Privada Olga Torres, FP7 CHIBCHA Consortium, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d’Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Action BM1206. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, NIH, U.S. Department of Health and Human Services (U01 CA164930, R01 CA201407). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish research council; K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2 and the Stockholm County Council (ALF project). Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: Kiel: This work was supported by institutional funds from the Medical Faculties of the Christian-Albrechts University Kiel and the Technical University Dresden. Funding Information: Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by NCI/NIH, US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350,; P01 CA196569; R01 CA201407) and National Institutes of Environmental Health Sciences, NIH (grant number T32 ES013678). Funding Information: MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the NIH (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). Publisher Copyright: © 2020 AGA Institute

PY - 2020/4

Y1 - 2020/4

N2 - 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.

AB - 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.

KW - Colon Cancer

KW - EOCRC

KW - Penetrance

KW - SNP

UR - http://www.scopus.com/inward/record.url?scp=85081984635&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85081984635&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2019.12.012

DO - 10.1053/j.gastro.2019.12.012

M3 - Article

C2 - 31866242

AN - SCOPUS:85081984635

SN - 0016-5085

VL - 158

SP - 1274-1286.e12

JO - Gastroenterology

JF - Gastroenterology

IS - 5

ER -

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

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