Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis

Ulrike Peters, Shuo Jiao, Fredrick R. Schumacher, Carolyn M. Hutter, Aaron K. Aragaki, John A. Baron, Sonja I. Berndt, Stéphane Bézieau, Hermann Brenner, Katja Butterbach, Bette J. Caan, Peter T. Campbell, Christopher S. Carlson, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Lin S. Chen, Gerhard A. Coetzee, Simon G. CoetzeeDavid V. Conti, Keith R. Curtis, David Duggan, Todd Edwards, Charles S. Fuchs, Steven Gallinger, Edward L. Giovannucci, Stephanie M. Gogarten, Stephen B. Gruber, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Brian E. Henderson, Michael Hoffmeister, John L. Hopper, Thomas J. Hudson, David J. Hunter, Rebecca D. Jackson, Sun Ha Jee, Mark A. Jenkins, Wei Hua Jia, Laurence N. Kolonel, Charles Kooperberg, Sébastien Küry, Andrea Z. Lacroix, Cathy C. Laurie, Cecelia A. Laurie, Loic Le Marchand, Mathieu Lemire, David Levine, Noralane Morey Lindor, Yan Liu, Jing Ma, Karen W. Makar, Keitaro Matsuo, Polly A. Newcomb, John D. Potter, Ross L. Prentice, Conghui Qu, Thomas Rohan, Stephanie A. Rosse, Robert E. Schoen, Daniela Seminara, Martha Shrubsole, Xiao Ou Shu, Martha L. Slattery, Darin Taverna, Stephen N Thibodeau, Cornelia M. Ulrich, Emily White, Yongbing Xiang, Brent W. Zanke, Yi Xin Zeng, Ben Zhang, Wei Zheng, Li Hsu

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

Background & Aims: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. Methods: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Results: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10 -8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10-8). We also found evidence for 3 additional loci with P values less than 5.0 × 10-7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10-8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10-8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10 -7). Conclusions: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Original languageEnglish (US)
JournalGastroenterology
Volume144
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Genetic Loci
Genetic Predisposition to Disease
Meta-Analysis
Colorectal Neoplasms
Genome
Cyclin D2
Chromosomes
Alleles
Odds Ratio
Genes
Genome-Wide Association Study
Adenoma
Nucleic Acids
Carrier Proteins
Cyclin T
Catenins
Neoplasms
Intergenic DNA
DNA-Binding Proteins
Laminin

Keywords

  • Colon Cancer
  • Genetics
  • Risk Factors
  • SNP

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Peters, U., Jiao, S., Schumacher, F. R., Hutter, C. M., Aragaki, A. K., Baron, J. A., ... Hsu, L. (2013). Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis. Gastroenterology, 144(4). https://doi.org/10.1053/j.gastro.2012.12.020

Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis. / Peters, Ulrike; Jiao, Shuo; Schumacher, Fredrick R.; Hutter, Carolyn M.; Aragaki, Aaron K.; Baron, John A.; Berndt, Sonja I.; Bézieau, Stéphane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Lin S.; Coetzee, Gerhard A.; Coetzee, Simon G.; Conti, David V.; Curtis, Keith R.; Duggan, David; Edwards, Todd; Fuchs, Charles S.; Gallinger, Steven; Giovannucci, Edward L.; Gogarten, Stephanie M.; Gruber, Stephen B.; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Henderson, Brian E.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Hunter, David J.; Jackson, Rebecca D.; Jee, Sun Ha; Jenkins, Mark A.; Jia, Wei Hua; Kolonel, Laurence N.; Kooperberg, Charles; Küry, Sébastien; Lacroix, Andrea Z.; Laurie, Cathy C.; Laurie, Cecelia A.; Le Marchand, Loic; Lemire, Mathieu; Levine, David; Lindor, Noralane Morey; Liu, Yan; Ma, Jing; Makar, Karen W.; Matsuo, Keitaro; Newcomb, Polly A.; Potter, John D.; Prentice, Ross L.; Qu, Conghui; Rohan, Thomas; Rosse, Stephanie A.; Schoen, Robert E.; Seminara, Daniela; Shrubsole, Martha; Shu, Xiao Ou; Slattery, Martha L.; Taverna, Darin; Thibodeau, Stephen N; Ulrich, Cornelia M.; White, Emily; Xiang, Yongbing; Zanke, Brent W.; Zeng, Yi Xin; Zhang, Ben; Zheng, Wei; Hsu, Li.

In: Gastroenterology, Vol. 144, No. 4, 04.2013.

Research output: Contribution to journalArticle

Peters, U, Jiao, S, Schumacher, FR, Hutter, CM, Aragaki, AK, Baron, JA, Berndt, SI, Bézieau, S, Brenner, H, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, LS, Coetzee, GA, Coetzee, SG, Conti, DV, Curtis, KR, Duggan, D, Edwards, T, Fuchs, CS, Gallinger, S, Giovannucci, EL, Gogarten, SM, Gruber, SB, Haile, RW, Harrison, TA, Hayes, RB, Henderson, BE, Hoffmeister, M, Hopper, JL, Hudson, TJ, Hunter, DJ, Jackson, RD, Jee, SH, Jenkins, MA, Jia, WH, Kolonel, LN, Kooperberg, C, Küry, S, Lacroix, AZ, Laurie, CC, Laurie, CA, Le Marchand, L, Lemire, M, Levine, D, Lindor, NM, Liu, Y, Ma, J, Makar, KW, Matsuo, K, Newcomb, PA, Potter, JD, Prentice, RL, Qu, C, Rohan, T, Rosse, SA, Schoen, RE, Seminara, D, Shrubsole, M, Shu, XO, Slattery, ML, Taverna, D, Thibodeau, SN, Ulrich, CM, White, E, Xiang, Y, Zanke, BW, Zeng, YX, Zhang, B, Zheng, W & Hsu, L 2013, 'Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis', Gastroenterology, vol. 144, no. 4. https://doi.org/10.1053/j.gastro.2012.12.020
Peters, Ulrike ; Jiao, Shuo ; Schumacher, Fredrick R. ; Hutter, Carolyn M. ; Aragaki, Aaron K. ; Baron, John A. ; Berndt, Sonja I. ; Bézieau, Stéphane ; Brenner, Hermann ; Butterbach, Katja ; Caan, Bette J. ; Campbell, Peter T. ; Carlson, Christopher S. ; Casey, Graham ; Chan, Andrew T. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Chen, Lin S. ; Coetzee, Gerhard A. ; Coetzee, Simon G. ; Conti, David V. ; Curtis, Keith R. ; Duggan, David ; Edwards, Todd ; Fuchs, Charles S. ; Gallinger, Steven ; Giovannucci, Edward L. ; Gogarten, Stephanie M. ; Gruber, Stephen B. ; Haile, Robert W. ; Harrison, Tabitha A. ; Hayes, Richard B. ; Henderson, Brian E. ; Hoffmeister, Michael ; Hopper, John L. ; Hudson, Thomas J. ; Hunter, David J. ; Jackson, Rebecca D. ; Jee, Sun Ha ; Jenkins, Mark A. ; Jia, Wei Hua ; Kolonel, Laurence N. ; Kooperberg, Charles ; Küry, Sébastien ; Lacroix, Andrea Z. ; Laurie, Cathy C. ; Laurie, Cecelia A. ; Le Marchand, Loic ; Lemire, Mathieu ; Levine, David ; Lindor, Noralane Morey ; Liu, Yan ; Ma, Jing ; Makar, Karen W. ; Matsuo, Keitaro ; Newcomb, Polly A. ; Potter, John D. ; Prentice, Ross L. ; Qu, Conghui ; Rohan, Thomas ; Rosse, Stephanie A. ; Schoen, Robert E. ; Seminara, Daniela ; Shrubsole, Martha ; Shu, Xiao Ou ; Slattery, Martha L. ; Taverna, Darin ; Thibodeau, Stephen N ; Ulrich, Cornelia M. ; White, Emily ; Xiang, Yongbing ; Zanke, Brent W. ; Zeng, Yi Xin ; Zhang, Ben ; Zheng, Wei ; Hsu, Li. / Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis. In: Gastroenterology. 2013 ; Vol. 144, No. 4.
@article{e639ecaeecf84dc2b4d7653e64a25038,
title = "Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis",
abstract = "Background & Aims: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. Methods: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Results: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10 -8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10-8). We also found evidence for 3 additional loci with P values less than 5.0 × 10-7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10-8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10-8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10 -7). Conclusions: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.",
keywords = "Colon Cancer, Genetics, Risk Factors, SNP",
author = "Ulrike Peters and Shuo Jiao and Schumacher, {Fredrick R.} and Hutter, {Carolyn M.} and Aragaki, {Aaron K.} and Baron, {John A.} and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Hermann Brenner and Katja Butterbach and Caan, {Bette J.} and Campbell, {Peter T.} and Carlson, {Christopher S.} and Graham Casey and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Chen, {Lin S.} and Coetzee, {Gerhard A.} and Coetzee, {Simon G.} and Conti, {David V.} and Curtis, {Keith R.} and David Duggan and Todd Edwards and Fuchs, {Charles S.} and Steven Gallinger and Giovannucci, {Edward L.} and Gogarten, {Stephanie M.} and Gruber, {Stephen B.} and Haile, {Robert W.} and Harrison, {Tabitha A.} and Hayes, {Richard B.} and Henderson, {Brian E.} and Michael Hoffmeister and Hopper, {John L.} and Hudson, {Thomas J.} and Hunter, {David J.} and Jackson, {Rebecca D.} and Jee, {Sun Ha} and Jenkins, {Mark A.} and Jia, {Wei Hua} and Kolonel, {Laurence N.} and Charles Kooperberg and S{\'e}bastien K{\"u}ry and Lacroix, {Andrea Z.} and Laurie, {Cathy C.} and Laurie, {Cecelia A.} and {Le Marchand}, Loic and Mathieu Lemire and David Levine and Lindor, {Noralane Morey} and Yan Liu and Jing Ma and Makar, {Karen W.} and Keitaro Matsuo and Newcomb, {Polly A.} and Potter, {John D.} and Prentice, {Ross L.} and Conghui Qu and Thomas Rohan and Rosse, {Stephanie A.} and Schoen, {Robert E.} and Daniela Seminara and Martha Shrubsole and Shu, {Xiao Ou} and Slattery, {Martha L.} and Darin Taverna and Thibodeau, {Stephen N} and Ulrich, {Cornelia M.} and Emily White and Yongbing Xiang and Zanke, {Brent W.} and Zeng, {Yi Xin} and Ben Zhang and Wei Zheng and Li Hsu",
year = "2013",
month = "4",
doi = "10.1053/j.gastro.2012.12.020",
language = "English (US)",
volume = "144",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis

AU - Peters, Ulrike

AU - Jiao, Shuo

AU - Schumacher, Fredrick R.

AU - Hutter, Carolyn M.

AU - Aragaki, Aaron K.

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Brenner, Hermann

AU - Butterbach, Katja

AU - Caan, Bette J.

AU - Campbell, Peter T.

AU - Carlson, Christopher S.

AU - Casey, Graham

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Chen, Lin S.

AU - Coetzee, Gerhard A.

AU - Coetzee, Simon G.

AU - Conti, David V.

AU - Curtis, Keith R.

AU - Duggan, David

AU - Edwards, Todd

AU - Fuchs, Charles S.

AU - Gallinger, Steven

AU - Giovannucci, Edward L.

AU - Gogarten, Stephanie M.

AU - Gruber, Stephen B.

AU - Haile, Robert W.

AU - Harrison, Tabitha A.

AU - Hayes, Richard B.

AU - Henderson, Brian E.

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Hudson, Thomas J.

AU - Hunter, David J.

AU - Jackson, Rebecca D.

AU - Jee, Sun Ha

AU - Jenkins, Mark A.

AU - Jia, Wei Hua

AU - Kolonel, Laurence N.

AU - Kooperberg, Charles

AU - Küry, Sébastien

AU - Lacroix, Andrea Z.

AU - Laurie, Cathy C.

AU - Laurie, Cecelia A.

AU - Le Marchand, Loic

AU - Lemire, Mathieu

AU - Levine, David

AU - Lindor, Noralane Morey

AU - Liu, Yan

AU - Ma, Jing

AU - Makar, Karen W.

AU - Matsuo, Keitaro

AU - Newcomb, Polly A.

AU - Potter, John D.

AU - Prentice, Ross L.

AU - Qu, Conghui

AU - Rohan, Thomas

AU - Rosse, Stephanie A.

AU - Schoen, Robert E.

AU - Seminara, Daniela

AU - Shrubsole, Martha

AU - Shu, Xiao Ou

AU - Slattery, Martha L.

AU - Taverna, Darin

AU - Thibodeau, Stephen N

AU - Ulrich, Cornelia M.

AU - White, Emily

AU - Xiang, Yongbing

AU - Zanke, Brent W.

AU - Zeng, Yi Xin

AU - Zhang, Ben

AU - Zheng, Wei

AU - Hsu, Li

PY - 2013/4

Y1 - 2013/4

N2 - Background & Aims: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. Methods: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Results: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10 -8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10-8). We also found evidence for 3 additional loci with P values less than 5.0 × 10-7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10-8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10-8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10 -7). Conclusions: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

AB - Background & Aims: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. Methods: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Results: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10 -8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10-8). We also found evidence for 3 additional loci with P values less than 5.0 × 10-7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10-8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10-8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10 -7). Conclusions: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

KW - Colon Cancer

KW - Genetics

KW - Risk Factors

KW - SNP

UR - http://www.scopus.com/inward/record.url?scp=84875253066&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875253066&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2012.12.020

DO - 10.1053/j.gastro.2012.12.020

M3 - Article

C2 - 23266556

AN - SCOPUS:84875253066

VL - 144

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -