Abstract
Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10-10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10-9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10-9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1487-1493 |
| Number of pages | 7 |
| Journal | Nature Genetics |
| Volume | 45 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2013 |
ASJC Scopus subject areas
- Genetics
MD Anderson CCSG core facilities
- Clinical Trials Office
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In: Nature Genetics, Vol. 45, No. 12, 12.2013, p. 1487-1493.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus
AU - Levine, David M.
AU - Ek, Weronica E.
AU - Zhang, Rui
AU - Liu, Xinxue
AU - Onstad, Lynn
AU - Sather, Cassandra
AU - Lao-Sirieix, Pierre
AU - Gammon, Marilie D.
AU - Corley, Douglas A.
AU - Shaheen, Nicholas J.
AU - Bird, Nigel C.
AU - Hardie, Laura J.
AU - Murray, Liam J.
AU - Reid, Brian J.
AU - Chow, Wong Ho
AU - Risch, Harvey A.
AU - Nyrén, Olof
AU - Ye, Weimin
AU - Liu, Geoffrey
AU - Romero, Yvonne
AU - Bernstein, Leslie
AU - Wu, Anna H.
AU - Casson, Alan G.
AU - Chanock, Stephen J.
AU - Harrington, Patricia
AU - Caldas, Isabel
AU - Debiram-Beecham, Irene
AU - Caldas, Carlos
AU - Hayward, Nicholas K.
AU - Pharoah, Paul D.
AU - Fitzgerald, Rebecca C.
AU - MacGregor, Stuart
AU - Whiteman, David C.
AU - Vaughan, Thomas L.
N1 - Funding Information: We thank P. Christopherson, P. Hansen, L. Nolan and T. Watson for their efforts in project management and the organization of biospecimens and data, and we thank Cathy Laurie, Cecelia Laurie and B. Weir for helpful suggestions regarding analyses. This work was primarily funded by a US National Institutes of Health (NIH) grant (R01CA136725) to T.L.V. and D.C.W. T.L.V. is also supported by grant K05CA124911. D.C.W. is supported by a Future Fellowship (FT0990987) from the Australian Research Council. S.M. is supported by an Australian National Health and Medical Research Council (NHMRC) Career Development Award. N.K.H. is supported by Research Fellowships from the NHMRC of Australia. Y.R. is supported in part by a grant from the US NIH (NIDDK 02956), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program and the Fraternal Order of the Eagles. Funding Information: The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute and the Swedish Cancer Society (4559-B01-01XAA and 4758-B02-01XAB). The Kaiser-Permanente Study was supported by grants from the US NIH (R01DK63616 and R01CA59636) and from the California Tobacco-Related Research Program (3RT-0122 and 10RT-0251). The UK Barrett’s oesophagus gene study was funded by a Medical Research Council Programme grant, and the UK SOCS study was funded by Cancer Research UK as well as by the Cambridge National Institute for Health Research Biomedical Research Centre and the Cambridge Experimental Cancer Medicine Centre. The SEARCH grant was funded by Cancer Research UK grants C490/A10119 and C490/A10124. Genotyping of MD Anderson controls (C. Amos, PI) was performed through the University of Texas MD Anderson Cancer Center (UTMDACC) and the Johns Hopkins University Center for Inherited Disease Research (CIDR), supported in part by US NIH grants R01CA100264, P30CA016672 and R01CA133996 and the UTMDACC NIH SPORE in Melanoma 2P50CA093459, as well as by the Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096C from the US NIH. This study made use of data generated by the Wellcome Trust Case Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs). The Romero Registry is supported in part by the American Digestive Health Foundation Endoscopic Research Award, the American College of Gastroenterology Junior Faculty Development Award, the Glaxo Wellcome, Inc., Institute for Digestive Health Clinical Research Award and the Miles and Shirley Fiterman Center for Digestive Diseases at the Mayo Clinic (Rochester, Minnesota). The Romero Registry also receives charitable gifts from five industry partners (Affymetrix, AstraZeneca, Santarus, Takeda and Wyeth). The US Multicenter Study was funded by grants U01CA57949, U01CA57983 and U01CA57923 from the US NIH. Members of the Romero Registry: Sami R. Achem (Mayo Clinic, Jacksonville, Florida, USA), Yvonne Romero (Mayo Clinic, Rochester, Minnesota, USA), David A. Ahlquist (Mayo Clinic, Rochester, Minnesota, USA), Steven R. Alberts (Mayo Clinic, Rochester, Minnesota, USA), Jeffrey A. Alexander (Mayo Clinic, Rochester, Minnesota, USA), Mark S. Allen (Mayo Clinic, Rochester, Minnesota, USA), Amindra S. Arora (Mayo Clinic, Rochester, Minnesota, USA), Jonathan B. Ashman (Mayo Clinic, Phoenix, Arizona, USA), Pamela J. Atherton (Mayo Clinic, Rochester, Minnesota, USA), Lisa A. Boardman (Mayo Clinic, Rochester, Minnesota, USA), Ernest P. Bouras (Mayo Clinic, Jacksonville, Florida, USA), Vicki A. Bryhn (Mayo Clinic, Rochester, Minnesota, USA), Patrick A. Burch (Mayo Clinic, Rochester, Minnesota, USA), George E. Burdick (Mayo Clinic, Rochester, Minnesota, USA), Navtej S. Buttar (Mayo Clinic, Rochester, Minnesota, USA), John K. Camoriano (Mayo Clinic, Phoenix, Arizona, USA), John R. Cangemi (Mayo Clinic, Jacksonville, Florida, USA), Stephen D. Cassivi (Mayo Clinic, Rochester, Minnesota, USA), Frances K. Cayer (Mayo Clinic, Jacksonville, Florida, USA), Amy C. Clayton (Mayo Clinic, Rochester, Minnesota, USA), Michael D. Crowell (Mayo Clinic, Phoenix, Arizona, USA), Julie M. Cunningham (Mayo Clinic, Rochester, Minnesota, USA), Mariza de Andrade (Mayo Clinic, Rochester, Minnesota, USA), Piet de Groen (Mayo Clinic, Rochester, Minnesota, USA), Giovani De Petris (Mayo Clinic, Phoenix, Arizona, USA), Claude Deschamps (Mayo Clinic, Rochester, Minnesota, USA), Kenneth R. DeVault (Mayo Clinic, Jacksonville, Florida, USA), Robert B. Diasio (Mayo Clinic, Rochester, Minnesota, USA), John K. DiBaise (Mayo Clinic, Phoenix, Arizona, USA), Eric S. Edell (Mayo Clinic, Rochester, Minnesota, USA), Sharon Elcombe (Mayo Clinic, Rochester, Minnesota, USA), Charles Erlichman (Mayo Clinic, Rochester, Minnesota, USA), Douglas O. Faigel (Mayo Clinic, Phoenix, Arizona, USA), Tom R. Fitch (Mayo Clinic, Phoenix, Arizona, USA), David E. Fleischer (Mayo Clinic, Phoenix, Arizona, USA), Jean C. Fox (Mayo Clinic, Rochester, Minnesota, USA), Amy E. Foxx-Orenstein (Mayo Clinic, Rochester, Minnesota, USA), Dawn Francis (Mayo Clinic, Rochester, Minnesota, USA), Mary B. Fredericksen (Mayo Clinic, Rochester, Minnesota, USA), Evanthia Galanis (Mayo Clinic, Rochester, Minnesota, USA), Debra M. Geno (Mayo Clinic, Rochester, Minnesota, USA), Axel Grothey (Mayo Clinic, Rochester, Minnesota, USA), Michael G. Haddock (Mayo Clinic, Rochester, Minnesota, USA), Kevin C. Halling (Mayo Clinic, Rochester, Minnesota, USA), Denise M. Harnois (Mayo Clinic, Jacksonville, Florida, USA), Tracy W. Hilton (Mayo Clinic, Jacksonville, Florida, USA), Timothy Hobday (Mayo Clinic, Rochester, Minnesota, USA), Lesley A. Houghton (Mayo Clinic, Jacksonville, Florida, USA), Prasad A. Iyer (Mayo Clinic, Rochester, Minnesota, USA), Dawn E. Jaroszewski (Mayo Clinic, Phoenix, Arizona, USA), Aminah Jatoi (Mayo Clinic, Rochester, Minnesota, USA), Robert B. Jenkins (Mayo Clinic, Rochester, Minnesota, USA), Elizabeth A. Johnson (Mayo Clinic, Jacksonville, Florida, USA), Rajni Katipamula (Mayo Clinic, Rochester, Minnesota, USA), David A. Katzka (Mayo Clinic, Rochester, Minnesota, USA), Sharon F. Kaufman (Mayo Clinic, Rochester, Minnesota, USA), Andrew P. Keaveny (Mayo Clinic, Jacksonville, Florida, USA), Daniel A. Keller (Mayo Clinic, Rochester, Minnesota, USA), George P. Kim (Mayo Clinic, Jacksonville, Florida, USA), Benjamin R. Kipp (Mayo Clinic, Rochester, Minnesota, USA), Dora M. Lam-Himlin (Mayo Clinic, Rochester, Minnesota, USA), Stephen M. Lange (Mayo Clinic, Jacksonville, Florida, USA), Louis Lanza (Mayo Clinic, Phoenix, Arizona, USA), Shauna N. Legrand (Mayo Clinic, Jacksonville, Florida, USA), Paul J. Limburg (Mayo Clinic, Rochester, Minnesota, USA), Wilma L. Lingle (Mayo Clinic, Rochester, Minnesota, USA), Wanguo Liu (Mayo Clinic,
PY - 2013/12
Y1 - 2013/12
N2 - Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10-10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10-9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10-9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.
AB - Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10-10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10-9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10-9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.
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UR - http://www.scopus.com/inward/citedby.url?scp=84888320412&partnerID=8YFLogxK
U2 - 10.1038/ng.2796
DO - 10.1038/ng.2796
M3 - Article
C2 - 24121790
AN - SCOPUS:84888320412
SN - 1061-4036
VL - 45
SP - 1487
EP - 1493
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -