A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Mathieu Lemire; Conghui Qu; Lenora W.M. Loo; Syed H.E. Zaidi; Hansong Wang; Sonja I. Berndt; Stéphane Bézieau; Hermann Brenner; Peter T. Campbell; Andrew T. Chan; Jenny Chang-Claude; Mengmeng Du; Christopher K. Edlund; Steven Gallinger; Robert W. Haile; Tabitha A. Harrison; Michael Hoffmeister; John L. Hopper; Lifang Hou; Li Hsu; Eric J. Jacobs; Mark A. Jenkins; Jihyoun Jeon; Sébastien Küry; Li Li; Noralane M. Lindor; Polly A. Newcomb; John D. Potter; Gad Rennert; Anja Rudolph; Robert E. Schoen; Fredrick R. Schumacher; Daniela Seminara; Gianluca Severi; Martha L. Slattery; Emily White; Michael O. Woods; Michelle Cotterchio; Loïc Le Marchand; Graham Casey; Stephen B. Gruber; Ulrike Peters; Thomas J. Hudson

doi:10.1007/s00439-015-1598-6

A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Mathieu Lemire^*, Conghui Qu, Lenora W.M. Loo, Syed H.E. Zaidi, Hansong Wang, Sonja I. Berndt, Stéphane Bézieau, Hermann Brenner, Peter T. Campbell, Andrew T. Chan, Jenny Chang-Claude, Mengmeng Du, Christopher K. Edlund, Steven Gallinger, Robert W. Haile, Tabitha A. Harrison, Michael Hoffmeister, John L. Hopper, Lifang Hou, Li HsuEric J. Jacobs, Mark A. Jenkins, Jihyoun Jeon, Sébastien Küry, Li Li, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Gad Rennert, Anja Rudolph, Robert E. Schoen, Fredrick R. Schumacher, Daniela Seminara, Gianluca Severi, Martha L. Slattery, Emily White, Michael O. Woods, Michelle Cotterchio, Loïc Le Marchand, Graham Casey, Stephen B. Gruber, Ulrike Peters, Thomas J. Hudson

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Preventive Medicine

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Abstract

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10⁻¹⁰; odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83–0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77–0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10⁻⁸).

Original language	English (US)
Pages (from-to)	1249-1262
Number of pages	14
Journal	Human Genetics
Volume	134
Issue number	11-12
DOIs	https://doi.org/10.1007/s00439-015-1598-6
State	Published - Sep 24 2015

Funding

ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Fran\u00E7aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G\u00E9n\u00E9tique and the Ligue R\u00E9gionale Contre le Cancer (LRCC). OFCCR: National Institutes of Health, 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. CANCER PREVENTION STUDY II: CPS-II is supported by the American Cancer Society (ACS). We would like to thank the CPS-II participants and the CPS-II Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. 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. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007 May;39(5):645\u20139), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009 Sep;41(9):986\u201390, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar;42(3):224\u20138), and the Lung Cancer and Smoking study (Landi MT, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009 Nov;85(5):679\u201391). The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource ( http://cgems.cancer.gov/data/ ) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website ( http://www.ncbi.nlm.nih.gov/gap ) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. CCFR: This work was supported by grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with the following CCFR centers: Australasian Colorectal Cancer Family Registry (U01 CA074778 and U01/U24 CA097735), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (U01/U24 CA074794), USC Consortium Colorectal Cancer Family Registry U01/U24 CA074799). The Colon CFR GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (U01 CA122839 and R01 CA143237 to Graham Casey). CRC tumor and normal tissues used for the gene expression study were made available by The Jeremy Jass Memorial Pathology Bank. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR. DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to M. L. Slattery); HPFS is supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993 and P50 CA127003), NHS by the National Institutes of Health (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003,) and PHS by the National Institutes of Health (R01 CA042182).

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Genetics
Genetics(clinical)

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Cite this

Lemire, M., Qu, C., Loo, L. W. M., Zaidi, S. H. E., Wang, H., Berndt, S. I., Bézieau, S., Brenner, H., Campbell, P. T., Chan, A. T., Chang-Claude, J., Du, M., Edlund, C. K., Gallinger, S., Haile, R. W., Harrison, T. A., Hoffmeister, M., Hopper, J. L., Hou, L., ... Hudson, T. J. (2015). A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1. Human Genetics, 134(11-12), 1249-1262. https://doi.org/10.1007/s00439-015-1598-6

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title = "A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1",

abstract = "Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10−10; odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83–0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77–0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10−8).",

author = "Mathieu Lemire and Conghui Qu and Loo, {Lenora W.M.} and Zaidi, {Syed H.E.} and Hansong Wang and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Hermann Brenner and Campbell, {Peter T.} and Chan, {Andrew T.} and Jenny Chang-Claude and Mengmeng Du and Edlund, {Christopher K.} and Steven Gallinger and Haile, {Robert W.} and Harrison, {Tabitha A.} and Michael Hoffmeister and Hopper, {John L.} and Lifang Hou and Li Hsu and Jacobs, {Eric J.} and Jenkins, {Mark A.} and Jihyoun Jeon and S{\'e}bastien K{\"u}ry and Li Li and Lindor, {Noralane M.} and Newcomb, {Polly A.} and Potter, {John D.} and Gad Rennert and Anja Rudolph and Schoen, {Robert E.} and Schumacher, {Fredrick R.} and Daniela Seminara and Gianluca Severi and Slattery, {Martha L.} and Emily White and Woods, {Michael O.} and Michelle Cotterchio and {Le Marchand}, Lo{\"i}c and Graham Casey and Gruber, {Stephen B.} and Ulrike Peters and Hudson, {Thomas J.}",

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year = "2015",

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doi = "10.1007/s00439-015-1598-6",

language = "English (US)",

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Lemire, M, Qu, C, Loo, LWM, Zaidi, SHE, Wang, H, Berndt, SI, Bézieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Du, M, Edlund, CK, Gallinger, S, Haile, RW, Harrison, TA, Hoffmeister, M, Hopper, JL, Hou, L, Hsu, L, Jacobs, EJ, Jenkins, MA, Jeon, J, Küry, S, Li, L, Lindor, NM, Newcomb, PA, Potter, JD, Rennert, G, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Severi, G, Slattery, ML, White, E, Woods, MO, Cotterchio, M, Le Marchand, L, Casey, G, Gruber, SB, Peters, U & Hudson, TJ 2015, 'A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1', Human Genetics, vol. 134, no. 11-12, pp. 1249-1262. https://doi.org/10.1007/s00439-015-1598-6

TY - JOUR

T1 - A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

AU - Lemire, Mathieu

AU - Qu, Conghui

AU - Loo, Lenora W.M.

AU - Zaidi, Syed H.E.

AU - Wang, Hansong

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Brenner, Hermann

AU - Campbell, Peter T.

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Du, Mengmeng

AU - Edlund, Christopher K.

AU - Gallinger, Steven

AU - Haile, Robert W.

AU - Harrison, Tabitha A.

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Hou, Lifang

AU - Hsu, Li

AU - Jacobs, Eric J.

AU - Jenkins, Mark A.

AU - Jeon, Jihyoun

AU - Küry, Sébastien

AU - Li, Li

AU - Lindor, Noralane M.

AU - Newcomb, Polly A.

AU - Potter, John D.

AU - Rennert, Gad

AU - Rudolph, Anja

AU - Schoen, Robert E.

AU - Schumacher, Fredrick R.

AU - Seminara, Daniela

AU - Severi, Gianluca

AU - Slattery, Martha L.

AU - White, Emily

AU - Woods, Michael O.

AU - Cotterchio, Michelle

AU - Le Marchand, Loïc

AU - Casey, Graham

AU - Gruber, Stephen B.

AU - Peters, Ulrike

AU - Hudson, Thomas J.

PY - 2015/9/24

Y1 - 2015/9/24

N2 - Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10−10; odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83–0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77–0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10−8).

AB - Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10−10; odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83–0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77–0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10−8).

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ER -

A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

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