Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

Chenjie Zeng; Koichi Matsuda; Wei Hua Jia; Jiang Chang; Sun Seog Kweon; Yong Bing Xiang; Aesun Shin; Sun Ha Jee; Dong Hyun Kim; Ben Zhang; Qiuyin Cai; Xingyi Guo; Jirong Long; Nan Wang; Regina Courtney; Zhi Zhong Pan; Chen Wu; Atsushi Takahashi; Min Ho Shin; Keitaro Matsuo; Fumihiko Matsuda; Yu Tang Gao; Jae Hwan Oh; Soriul Kim; Keum Ji Jung; Yoon Ok Ahn; Zefang Ren; Hong Lan Li; Jie Wu; Jiajun Shi; Wanqing Wen; Gong Yang; Bingshan Li; Bu Tian Ji; Stephen B. Gruber; Fredrick R. Schumacher; Stephanie L. Stenzel; Graham Casey; John L. Hopper; Mark A. Jenkins; Hyeong Rok Kim; Jin Young Jeong; Ji Won Park; Kazuo Tajima; Sang Hee Cho; Michiaki Kubo; Xiao Ou Shu; Dongxin Lin; Yi Xin Zeng; Wei Zheng; Hermann Brenner; Robert E. Schoen; Sébastien Küry; John A. Baron; Sonja I. Berndt; Stéphane Bezieau; Bette J. Caan; Christopher S. Carlson; Andrew T. Chan; Jenny Chang-Claude; Stephen J. Chanock; David V. Conti; Keith Curtis; David Duggan; Charles S. Fuchs; Steven Gallinger; Edward L. Giovannucci; Robert W. Haile; Tabitha A. Harrison; Richard B. Hayes; Michael Hoffmeister; Li Hsu; Thomas J. Hudson; David J. Hunter; Carolyn M. Hutter; Rebecca D. Jackson; Shuo Jiao; Loic Le Marchand; Mathieu Lemire; Noralane M. Lindor; Jing Ma; Polly A. Newcomb; Ulrike Peters; John D. Potter; Conghui Qu; Daniela Seminara; Martha L. Slattery; Stephen N. Thibodeau; Emily White; Brent W. Zanke; Kendra Blalock; Peter T. Campbell; Christopher K. Edlund; Jane Figueiredo; W. James Gauderman; Jian Gong; Roger C. Green; John F. Harju; Eric J. Jacobs; Li Li; Yi Lin; Frank J. Manion; Victor Moreno; Bhramar Mukherjee; Leon Raskin; Gianluca Severi; Duncan C. Thomas

doi:10.1053/j.gastro.2016.02.076

Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

Chenjie Zeng, Koichi Matsuda, Wei Hua Jia, Jiang Chang, Sun Seog Kweon, Yong Bing Xiang, Aesun Shin, Sun Ha Jee, Dong Hyun Kim, Ben Zhang, Qiuyin Cai, Xingyi Guo, Jirong Long, Nan Wang, Regina Courtney, Zhi Zhong Pan, Chen Wu, Atsushi Takahashi, Min Ho Shin, Keitaro MatsuoFumihiko Matsuda, Yu Tang Gao, Jae Hwan Oh, Soriul Kim, Keum Ji Jung, Yoon Ok Ahn, Zefang Ren, Hong Lan Li, Jie Wu, Jiajun Shi, Wanqing Wen, Gong Yang, Bingshan Li, Bu Tian Ji, Stephen B. Gruber, Fredrick R. Schumacher, Stephanie L. Stenzel, Graham Casey, John L. Hopper, Mark A. Jenkins, Hyeong Rok Kim, Jin Young Jeong, Ji Won Park, Kazuo Tajima, Sang Hee Cho, Michiaki Kubo, Xiao Ou Shu, Dongxin Lin, Yi Xin Zeng, Wei Zheng, Hermann Brenner, Robert E. Schoen, Sébastien Küry, John A. Baron, Sonja I. Berndt, Stéphane Bezieau, Bette J. Caan, Christopher S. Carlson, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, David V. Conti, Keith Curtis, David Duggan, Charles S. Fuchs, Steven Gallinger, Edward L. Giovannucci, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, Li Hsu, Thomas J. Hudson, David J. Hunter, Carolyn M. Hutter, Rebecca D. Jackson, Shuo Jiao, Loic Le Marchand, Mathieu Lemire, Noralane M. Lindor, Jing Ma, Polly A. Newcomb, Ulrike Peters, John D. Potter, Conghui Qu, Daniela Seminara, Martha L. Slattery, Stephen N. Thibodeau, Emily White, Brent W. Zanke, Kendra Blalock, Peter T. Campbell, Christopher K. Edlund, Jane Figueiredo, W. James Gauderman, Jian Gong, Roger C. Green, John F. Harju, Eric J. Jacobs, Li Li, Yi Lin, Frank J. Manion, Victor Moreno, Bhramar Mukherjee, Leon Raskin, Gianluca Severi, Duncan C. Thomas

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10^-8 to 1.24 × 10^-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Original language	English (US)
Pages (from-to)	1633-1645
Number of pages	13
Journal	Gastroenterology
Volume	150
Issue number	7
DOIs	https://doi.org/10.1053/j.gastro.2016.02.076
State	Published - Jun 1 2016

Keywords

Colon Cancer
Epidemiology
Single Nucleotide Polymorphisms
eQTL

ASJC Scopus subject areas

Hepatology
Gastroenterology

Access to Document

10.1053/j.gastro.2016.02.076

Cite this

Zeng, C., Matsuda, K., Jia, W. H., Chang, J., Kweon, S. S., Xiang, Y. B., Shin, A., Jee, S. H., Kim, D. H., Zhang, B., Cai, Q., Guo, X., Long, J., Wang, N., Courtney, R., Pan, Z. Z., Wu, C., Takahashi, A., Shin, M. H., ... Thomas, D. C. (2016). Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. Gastroenterology, 150(7), 1633-1645. https://doi.org/10.1053/j.gastro.2016.02.076

Zeng, C, Matsuda, K, Jia, WH, Chang, J, Kweon, SS, Xiang, YB, Shin, A, Jee, SH, Kim, DH, Zhang, B, Cai, Q, Guo, X, Long, J, Wang, N, Courtney, R, Pan, ZZ, Wu, C, Takahashi, A, Shin, MH, Matsuo, K, Matsuda, F, Gao, YT, Oh, JH, Kim, S, Jung, KJ, Ahn, YO, Ren, Z, Li, HL, Wu, J, Shi, J, Wen, W, Yang, G, Li, B, Ji, BT, Gruber, SB, Schumacher, FR, Stenzel, SL, Casey, G, Hopper, JL, Jenkins, MA, Kim, HR, Jeong, JY, Park, JW, Tajima, K, Cho, SH, Kubo, M, Shu, XO, Lin, D, Zeng, YX, Zheng, W, Brenner, H, Schoen, RE, Küry, S, Baron, JA, Berndt, SI, Bezieau, S, Caan, BJ, Carlson, CS, Chan, AT, Chang-Claude, J, Chanock, SJ, Conti, DV, Curtis, K, Duggan, D, Fuchs, CS, Gallinger, S, Giovannucci, EL, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hsu, L, Hudson, TJ, Hunter, DJ, Hutter, CM, Jackson, RD, Jiao, S, Le Marchand, L, Lemire, M, Lindor, NM, Ma, J, Newcomb, PA, Peters, U, Potter, JD, Qu, C, Seminara, D, Slattery, ML, Thibodeau, SN, White, E, Zanke, BW, Blalock, K, Campbell, PT, Edlund, CK, Figueiredo, J, Gauderman, WJ, Gong, J, Green, RC, Harju, JF, Jacobs, EJ, Li, L, Lin, Y, Manion, FJ, Moreno, V, Mukherjee, B, Raskin, L, Severi, G & Thomas, DC 2016, 'Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk', Gastroenterology, vol. 150, no. 7, pp. 1633-1645. https://doi.org/10.1053/j.gastro.2016.02.076

@article{e47cb88c52864066b554d886281cedcd,

title = "Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk",

abstract = "Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10-8 to 1.24 × 10-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.",

keywords = "Colon Cancer, Epidemiology, Single Nucleotide Polymorphisms, eQTL",

author = "Chenjie Zeng and Koichi Matsuda and Jia, {Wei Hua} and Jiang Chang and Kweon, {Sun Seog} and Xiang, {Yong Bing} and Aesun Shin and Jee, {Sun Ha} and Kim, {Dong Hyun} and Ben Zhang and Qiuyin Cai and Xingyi Guo and Jirong Long and Nan Wang and Regina Courtney and Pan, {Zhi Zhong} and Chen Wu and Atsushi Takahashi and Shin, {Min Ho} and Keitaro Matsuo and Fumihiko Matsuda and Gao, {Yu Tang} and Oh, {Jae Hwan} and Soriul Kim and Jung, {Keum Ji} and Ahn, {Yoon Ok} and Zefang Ren and Li, {Hong Lan} and Jie Wu and Jiajun Shi and Wanqing Wen and Gong Yang and Bingshan Li and Ji, {Bu Tian} and Gruber, {Stephen B.} and Schumacher, {Fredrick R.} and Stenzel, {Stephanie L.} and Graham Casey and Hopper, {John L.} and Jenkins, {Mark A.} and Kim, {Hyeong Rok} and Jeong, {Jin Young} and Park, {Ji Won} and Kazuo Tajima and Cho, {Sang Hee} and Michiaki Kubo and Shu, {Xiao Ou} and Dongxin Lin and Zeng, {Yi Xin} and Wei Zheng and Hermann Brenner and Schoen, {Robert E.} and S{\'e}bastien K{\"u}ry and Baron, {John A.} and Berndt, {Sonja I.} and St{\'e}phane Bezieau and Caan, {Bette J.} and Carlson, {Christopher S.} and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Conti, {David V.} and Keith Curtis and David Duggan and Fuchs, {Charles S.} and Steven Gallinger and Giovannucci, {Edward L.} and Haile, {Robert W.} and Harrison, {Tabitha A.} and Hayes, {Richard B.} and Michael Hoffmeister and Li Hsu and Hudson, {Thomas J.} and Hunter, {David J.} and Hutter, {Carolyn M.} and Jackson, {Rebecca D.} and Shuo Jiao and {Le Marchand}, Loic and Mathieu Lemire and Lindor, {Noralane M.} and Jing Ma and Newcomb, {Polly A.} and Ulrike Peters and Potter, {John D.} and Conghui Qu and Daniela Seminara and Slattery, {Martha L.} and Thibodeau, {Stephen N.} and Emily White and Zanke, {Brent W.} and Kendra Blalock and Campbell, {Peter T.} and Edlund, {Christopher K.} and Jane Figueiredo and Gauderman, {W. James} and Jian Gong and Green, {Roger C.} and Harju, {John F.} and Jacobs, {Eric J.} and Li Li and Yi Lin and Manion, {Frank J.} and Victor Moreno and Bhramar Mukherjee and Leon Raskin and Gianluca Severi and Thomas, {Duncan C.}",

note = "Funding Information: Funding The work at the Vanderbilt University School of Medicine was supported by US National Institutes of Health grants R01CA188214, R37CA070867, R01CA124558, P50CA095103, and R01CA148667, as well as Ingram Professorship and Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. The Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH, R37CA070867, UM1CA182910), Shanghai Men's Health Study (US NIH, R01CA082729, UM1CA173640), Shanghai Breast and Endometrial Cancer Studies (US NIH, R01CA064277 and R01CA092585; contributing only controls), Shanghai Colorectal Cancer Study 3 (US NIH, R37CA070867, R01CA188214 and Ingram Professorship funds), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04; National Basic Research Program, 2011CB504303, contributing only controls; Natural Science Foundation of China, 81072383, contributing only controls), Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). The Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, 17015018 and 221S0001), Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276 and 2013R1A1A2A10008260; National Cancer Center Korea, 0910220), and the KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control, 1220180; Seoul R&D Program, 10526). Funding Information: Participating studies (grant support) in the GECCO, CORECT, and CCFR GWAS meta-analysis are GECCO (US NIH, U01CA137088 and R01CA059045), DALS (US NIH, R01CA048998), DACHS (German Federal Ministry of Education and Research, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404 and 01ER0814), HPFS (P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993 and P50 CA127003), NHS (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003), OFCCR (US NIH, U01CA074783), PMH (US NIH, R01CA076366), PHS (US NIH, R01CA042182), VITAL (US NIH, K05CA154337), WHI (US NIH, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C), and PLCO (US NIH, Z01CP 010200, U01HG004446 and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH, U19CA148107) with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, US NIH under RFA CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01CA097735), Familial Colorectal Neoplasia Collaborative Group (US NIH, U01CA074799) (University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01CA074783), Seattle Colorectal Cancer Family Registry (US NIH, U01CA074794). and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The GWAS work was supported by a National Cancer Institute grant (US NIH, U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J. Hudson and B.W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through support from the Ontario Ministry of Economic Development and Innovation. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Fran{\c c}aises dans la Lutte Contre le Cancer (GEFLUC), the Association Anne de Bretagne G{\'e}n{\'e}tique and the Ligue R{\'e}gionale Contre le Cancer (LRCC). PLCO data sets were accessed with approval through dbGaP (CGEMS prostate cancer scan, phs000207.v1.p1 (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645–649); CGEMS pancreatic cancer scan, phs000206.v4.p3 (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41:986–990, 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;42:224–228); and GWAS of Lung Cancer and Smoking, phs000093.v2.p2 (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;85:679–691), which was funded by Z01CP 010200, U01HG004446 and U01HG 004438 from the US NIH). Publisher Copyright: {\textcopyright} 2016 AGA Institute.",

year = "2016",

month = jun,

day = "1",

doi = "10.1053/j.gastro.2016.02.076",

language = "English (US)",

volume = "150",

pages = "1633--1645",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "7",

}

TY - JOUR

T1 - Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

AU - Zeng, Chenjie

AU - Matsuda, Koichi

AU - Jia, Wei Hua

AU - Chang, Jiang

AU - Kweon, Sun Seog

AU - Xiang, Yong Bing

AU - Shin, Aesun

AU - Jee, Sun Ha

AU - Kim, Dong Hyun

AU - Zhang, Ben

AU - Cai, Qiuyin

AU - Guo, Xingyi

AU - Long, Jirong

AU - Wang, Nan

AU - Courtney, Regina

AU - Pan, Zhi Zhong

AU - Wu, Chen

AU - Takahashi, Atsushi

AU - Shin, Min Ho

AU - Matsuo, Keitaro

AU - Matsuda, Fumihiko

AU - Gao, Yu Tang

AU - Oh, Jae Hwan

AU - Kim, Soriul

AU - Jung, Keum Ji

AU - Ahn, Yoon Ok

AU - Ren, Zefang

AU - Li, Hong Lan

AU - Wu, Jie

AU - Shi, Jiajun

AU - Wen, Wanqing

AU - Yang, Gong

AU - Li, Bingshan

AU - Ji, Bu Tian

AU - Gruber, Stephen B.

AU - Schumacher, Fredrick R.

AU - Stenzel, Stephanie L.

AU - Casey, Graham

AU - Hopper, John L.

AU - Jenkins, Mark A.

AU - Kim, Hyeong Rok

AU - Jeong, Jin Young

AU - Park, Ji Won

AU - Tajima, Kazuo

AU - Cho, Sang Hee

AU - Kubo, Michiaki

AU - Shu, Xiao Ou

AU - Lin, Dongxin

AU - Zeng, Yi Xin

AU - Zheng, Wei

AU - Brenner, Hermann

AU - Schoen, Robert E.

AU - Küry, Sébastien

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Bezieau, Stéphane

AU - Caan, Bette J.

AU - Carlson, Christopher S.

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Conti, David V.

AU - Curtis, Keith

AU - Duggan, David

AU - Fuchs, Charles S.

AU - Gallinger, Steven

AU - Giovannucci, Edward L.

AU - Haile, Robert W.

AU - Harrison, Tabitha A.

AU - Hayes, Richard B.

AU - Hoffmeister, Michael

AU - Hsu, Li

AU - Hudson, Thomas J.

AU - Hunter, David J.

AU - Hutter, Carolyn M.

AU - Jackson, Rebecca D.

AU - Jiao, Shuo

AU - Le Marchand, Loic

AU - Lemire, Mathieu

AU - Lindor, Noralane M.

AU - Ma, Jing

AU - Newcomb, Polly A.

AU - Peters, Ulrike

AU - Potter, John D.

AU - Qu, Conghui

AU - Seminara, Daniela

AU - Slattery, Martha L.

AU - Thibodeau, Stephen N.

AU - White, Emily

AU - Zanke, Brent W.

AU - Blalock, Kendra

AU - Campbell, Peter T.

AU - Edlund, Christopher K.

AU - Figueiredo, Jane

AU - Gauderman, W. James

AU - Gong, Jian

AU - Green, Roger C.

AU - Harju, John F.

AU - Jacobs, Eric J.

AU - Li, Li

AU - Lin, Yi

AU - Manion, Frank J.

AU - Moreno, Victor

AU - Mukherjee, Bhramar

AU - Raskin, Leon

AU - Severi, Gianluca

AU - Thomas, Duncan C.

N1 - Funding Information: Funding The work at the Vanderbilt University School of Medicine was supported by US National Institutes of Health grants R01CA188214, R37CA070867, R01CA124558, P50CA095103, and R01CA148667, as well as Ingram Professorship and Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. The Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH, R37CA070867, UM1CA182910), Shanghai Men's Health Study (US NIH, R01CA082729, UM1CA173640), Shanghai Breast and Endometrial Cancer Studies (US NIH, R01CA064277 and R01CA092585; contributing only controls), Shanghai Colorectal Cancer Study 3 (US NIH, R37CA070867, R01CA188214 and Ingram Professorship funds), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04; National Basic Research Program, 2011CB504303, contributing only controls; Natural Science Foundation of China, 81072383, contributing only controls), Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). The Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, 17015018 and 221S0001), Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276 and 2013R1A1A2A10008260; National Cancer Center Korea, 0910220), and the KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control, 1220180; Seoul R&D Program, 10526). Funding Information: Participating studies (grant support) in the GECCO, CORECT, and CCFR GWAS meta-analysis are GECCO (US NIH, U01CA137088 and R01CA059045), DALS (US NIH, R01CA048998), DACHS (German Federal Ministry of Education and Research, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404 and 01ER0814), HPFS (P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993 and P50 CA127003), NHS (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003), OFCCR (US NIH, U01CA074783), PMH (US NIH, R01CA076366), PHS (US NIH, R01CA042182), VITAL (US NIH, K05CA154337), WHI (US NIH, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C), and PLCO (US NIH, Z01CP 010200, U01HG004446 and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH, U19CA148107) with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, US NIH under RFA CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01CA097735), Familial Colorectal Neoplasia Collaborative Group (US NIH, U01CA074799) (University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01CA074783), Seattle Colorectal Cancer Family Registry (US NIH, U01CA074794). and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The GWAS work was supported by a National Cancer Institute grant (US NIH, U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J. Hudson and B.W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through support from the Ontario Ministry of Economic Development and Innovation. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte Contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). PLCO data sets were accessed with approval through dbGaP (CGEMS prostate cancer scan, phs000207.v1.p1 (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645–649); CGEMS pancreatic cancer scan, phs000206.v4.p3 (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41:986–990, 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;42:224–228); and GWAS of Lung Cancer and Smoking, phs000093.v2.p2 (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;85:679–691), which was funded by Z01CP 010200, U01HG004446 and U01HG 004438 from the US NIH). Publisher Copyright: © 2016 AGA Institute.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10-8 to 1.24 × 10-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

AB - Background & Aims Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. Methods This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. Results We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10-8 to 1.24 × 10-12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P <.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. Conclusions We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

KW - Colon Cancer

KW - Epidemiology

KW - Single Nucleotide Polymorphisms

KW - eQTL

UR - http://www.scopus.com/inward/record.url?scp=84975841277&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84975841277&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2016.02.076

DO - 10.1053/j.gastro.2016.02.076

M3 - Article

C2 - 26965516

AN - SCOPUS:84975841277

SN - 0016-5085

VL - 150

SP - 1633

EP - 1645

JO - Gastroenterology

JF - Gastroenterology

IS - 7

ER -

Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

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