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

21 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

Keywords

Colon Cancer
EOCRC
Penetrance
SNP

ASJC Scopus subject areas

Hepatology
Gastroenterology

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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{247dcd4eeda7468abce394e40b7eebd3,

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 = "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.

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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