Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.
Age of Onset
Case-Control Studies
Cohort Studies
Colorectal Neoplasms
/ genetics
DNA Mutational Analysis
Datasets as Topic
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotyping Techniques
Humans
Life Style
Male
Medical History Taking
Middle Aged
Mutation Rate
Polymorphism, Single Nucleotide
Risk Factors
Whole Genome Sequencing
Colon Cancer
EOCRC
Penetrance
SNP
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
18
07
2019
revised:
22
11
2019
accepted:
09
12
2019
pubmed:
24
12
2019
medline:
11
7
2020
entrez:
24
12
2019
Statut:
ppublish
Résumé
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 = 5.61 × 10 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.
Sections du résumé
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
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.
Identifiants
pubmed: 31866242
pii: S0016-5085(19)41937-9
doi: 10.1053/j.gastro.2019.12.012
pmc: PMC7103489
mid: NIHMS1547252
pii:
doi:
Types de publication
Journal Article
Multicenter Study
Observational Study
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1274-1286.e12Subventions
Organisme : NCI NIH HHS
ID : R01 CA067941
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004446
Pays : United States
Organisme : NCI NIH HHS
ID : K05 CA154337
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148107
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA067941
Pays : United States
Organisme : Cancer Research UK
ID : 10589
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : HHSN268201100001I
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197350
Pays : United States
Organisme : Cancer Research UK
ID : 10124
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA076366
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197735
Pays : United States
Organisme : NIA NIH HHS
ID : RC2 AG036607
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : AHRQ HHS
ID : T32 HS026120
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004438
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074799
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA037429
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA182883
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA087969
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201000035C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201000006C
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100004I
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074783
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA055075
Pays : United States
Organisme : NCI NIH HHS
ID : N01 CN067009
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA189974
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA151993
Pays : United States
Organisme : Cancer Research UK
ID : 19167
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA206279
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100046C
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034987
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA150964
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA048998
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA182934
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA189184
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167552
Pays : United States
Organisme : WHI NIH HHS
ID : HHSN268201100003C
Pays : United States
Organisme : Medical Research Council
ID : MR/N003284/1
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : Z01 CP010200
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074794
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA164930
Pays : United States
Organisme : NCI NIH HHS
ID : N01PC35137
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA066635
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074806
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA206110
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA137178
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA097735
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074794
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : CCR NIH HHS
ID : HHSN261201300011C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201300012I
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014089
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA230162
Pays : United States
Organisme : Medical Research Council
ID : G0401527
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA081488
Pays : United States
Organisme : NCI NIH HHS
ID : N01PC35142
Pays : United States
Organisme : NIA NIH HHS
ID : HHSN271201100004C
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201407
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA063464
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA033619
Pays : United States
Organisme : NCI NIH HHS
ID : P20 CA233216
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186107
Pays : United States
Organisme : WHI NIH HHS
ID : HHSN268201100002C
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207371
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201300021C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201000035I
Pays : United States
Organisme : Medical Research Council
ID : G1000143
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 16561
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA042182
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA063464
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA060987
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA097735
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES013678
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136726
Pays : United States
Organisme : Cancer Research UK
ID : 25004
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Organisme : Cancer Research UK
ID : 14136
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R03 CA215775
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA167552
Pays : United States
Organisme : NCI NIH HHS
ID : P20 CA252728
Pays : United States
Organisme : CCR NIH HHS
ID : N01RC37004
Pays : United States
Organisme : NCI NIH HHS
ID : K07 CA188142
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA122839
Pays : United States
Organisme : NIH HHS
ID : S10 OD020069
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100003I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100002I
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074783
Pays : United States
Organisme : Medical Research Council
ID : MR/L01629X/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : N01 CN045165
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074799
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196569
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074806
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074800
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127003
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA182883
Pays : United States
Organisme : NCI NIH HHS
ID : K07 CA190673
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA071789
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201000121C
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA054281
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074800
Pays : United States
Organisme : WHI NIH HHS
ID : HHSN268201100001C
Pays : United States
Organisme : WHI NIH HHS
ID : HHSN268201100004C
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA042014
Pays : United States
Organisme : Cancer Research UK
ID : 10119
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
Références
Sci Rep. 2015 Sep 11;5:14060
pubmed: 26358404
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Genomics. 2011 Aug;98(2):79-89
pubmed: 21565264
CA Cancer J Clin. 2018 Jul;68(4):250-281
pubmed: 29846947
Cancer Epidemiol Biomarkers Prev. 2019 Jan;28(1):83-90
pubmed: 30530848
Biostatistics. 2008 Oct;9(4):621-34
pubmed: 18310059
J Natl Cancer Inst. 2017 Aug 1;109(8):
pubmed: 29117391
N Engl J Med. 2005 May 5;352(18):1851-60
pubmed: 15872200
Sci Rep. 2017 Jan 13;7:40644
pubmed: 28084440
Gastroenterology. 2018 Dec;155(6):1716-1719.e4
pubmed: 30165046
Gastroenterology. 2018 Oct;155(4):947-949
pubmed: 30193780
Br J Cancer. 2010 Aug 10;103(4):575-80
pubmed: 20648012
Br J Cancer. 2006 Sep 18;95(6):752-6
pubmed: 16940983
Hum Mol Genet. 2014 Jul 15;23(14):3898-905
pubmed: 24562164
Future Oncol. 2016 Feb;12(4):503-13
pubmed: 26846999
Gastroenterology. 2013 Apr;144(4):799-807.e24
pubmed: 23266556
Gut. 2019 Dec;68(12):2179-2185
pubmed: 31488504
Genetics. 2015 Aug;200(4):1051-60
pubmed: 26092718
Gut. 2013 Jun;62(6):871-81
pubmed: 22490517
JAMA. 2016 Jun 21;315(23):2595-609
pubmed: 27305518
Genetics. 2015 Aug;200(4):1285-95
pubmed: 26092716
PLoS Biol. 2011 Jan 18;9(1):e1000579
pubmed: 21267061
Carcinogenesis. 2012 Mar;33(3):613-9
pubmed: 22235025
Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):3062-7
pubmed: 19843678
Hum Genet. 2012 Oct;131(10):1655-64
pubmed: 22821350
Clin Colorectal Cancer. 2017 Dec;16(4):293-299.e6
pubmed: 29033218
Gastroenterology. 2015 Jun;148(7):1330-9.e14
pubmed: 25683114
Prev Med. 2017 Dec;105:345-349
pubmed: 28987338
Nat Commun. 2015 Jul 07;6:7138
pubmed: 26151821
Hum Mol Genet. 2013 Dec 15;22(24):5075-82
pubmed: 23904454
Gastroenterology. 2018 Jun;154(8):2152-2164.e19
pubmed: 29458155
Gastroenterology. 2018 Oct;155(4):950-954
pubmed: 30138614
Nat Genet. 2019 Jan;51(1):76-87
pubmed: 30510241
JAMA Surg. 2015 Jan;150(1):17-22
pubmed: 25372703
CA Cancer J Clin. 2016 Jan-Feb;66(1):7-30
pubmed: 26742998
J Clin Oncol. 2008 Dec 10;26(35):5783-8
pubmed: 18809606
Cancer Epidemiol Biomarkers Prev. 2011 Jan;20(1):70-81
pubmed: 21071539
Ann Intern Med. 2009 Jun 16;150(12):849-57, W152
pubmed: 19528563
Cancer. 2006 Sep 1;107(5 Suppl):1142-52
pubmed: 16835912
JAMA Oncol. 2017 Apr 1;3(4):464-471
pubmed: 27978560
Gastroenterology. 2017 Jul;153(1):307-323
pubmed: 28600072
JAMA. 2016 Jun 21;315(23):2564-2575
pubmed: 27304597
Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1695-8
pubmed: 19505901
Med Care. 2007 Feb;45(2):160-7
pubmed: 17224779
Gastroenterology. 2010 Jun;138(6):2044-58
pubmed: 20420945