A Genome-wide Association Study Identifies New Susceptibility Loci for Esophageal Adenocarcinoma and Barrett's Esophagus

Overview

Journal Nat Genet

Specialty Genetics

Date 2013 Oct 15

PMID 24121790

Citations 111

Authors

David M Levine

Weronica E Ek

Rui Zhang

Xinxue Liu

Lynn Onstad

Cassandra Sather

Pierre Lao-Sirieix

Marilie D Gammon

Douglas A Corley

Nicholas J Shaheen

Nigel C Bird

Laura J Hardie

Liam J Murray

Brian J Reid

Wong-Ho Chow

Harvey A Risch

Olof Nyren

Weimin Ye

Geoffrey Liu

Yvonne Romero

Leslie Bernstein

Anna H Wu

Alan G Casson

Stephen J Chanock

Patricia Harrington

Isabel Caldas

Irene Debiram-Beecham

Carlos Caldas

Nicholas K Hayward

Paul D Pharoah

Rebecca C Fitzgerald

Stuart Macgregor

David C Whiteman

Thomas L Vaughan

Affiliations

Soon will be listed here.

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.

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References

Trudgill N, Kapur K, Riley S . Familial clustering of reflux symptoms. Am J Gastroenterol. 1999; 94(5):1172-8. DOI: 10.1111/j.1572-0241.1999.01060.x. View

Menke V, Pot R, Moons L, van Zoest K, Hansen B, van Dekken H . Functional single-nucleotide polymorphism of epidermal growth factor is associated with the development of Barrett's esophagus and esophageal adenocarcinoma. J Hum Genet. 2011; 57(1):26-32. DOI: 10.1038/jhg.2011.124. View

Peiffer D, Le J, Steemers F, Chang W, Jenniges T, Garcia F . High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res. 2006; 16(9):1136-48. PMC: 1557768. DOI: 10.1101/gr.5402306. View

Chak A, Faulx A, Kinnard M, Brock W, Willis J, Wiesner G . Identification of Barrett's esophagus in relatives by endoscopic screening. Am J Gastroenterol. 2004; 99(11):2107-14. DOI: 10.1111/j.1572-0241.2004.40464.x. View

Venturi S, Venturi M . Iodine in evolution of salivary glands and in oral health. Nutr Health. 2009; 20(2):119-34. DOI: 10.1177/026010600902000204. View

Fitzgerald R . Complex diseases in gastroenterology and hepatology: GERD, Barrett's, and esophageal adenocarcinoma. Clin Gastroenterol Hepatol. 2005; 3(6):529-37. DOI: 10.1016/s1542-3565(05)00248-x. View

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

Price A, Patterson N, Plenge R, Weinblatt M, Shadick N, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8):904-9. DOI: 10.1038/ng1847. View

Woo J, Miletich I, Kim B, Sharpe P, Shivdasani R . Barx1-mediated inhibition of Wnt signaling in the mouse thoracic foregut controls tracheo-esophageal septation and epithelial differentiation. PLoS One. 2011; 6(7):e22493. PMC: 3142160. DOI: 10.1371/journal.pone.0022493. View

10.

Koon H, Ippolito G, Banham A, Tucker P . FOXP1: a potential therapeutic target in cancer. Expert Opin Ther Targets. 2007; 11(7):955-65. PMC: 4282158. DOI: 10.1517/14728222.11.7.955. View

11.

Dura P, van Veen E, Salomon J, Te Morsche R, Roelofs H, Kristinsson J . Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk. Int J Cancer. 2013; 133(7):1751-5. DOI: 10.1002/ijc.28160. View

12.

Cheung L, Hennessy B, Li J, Yu S, Myers A, Djordjevic B . High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011; 1(2):170-85. PMC: 3187555. DOI: 10.1158/2159-8290.CD-11-0039. View

13.

Zheng X, Levine D, Shen J, Gogarten S, Laurie C, Weir B . A high-performance computing toolset for relatedness and principal component analysis of SNP data. Bioinformatics. 2012; 28(24):3326-8. PMC: 3519454. DOI: 10.1093/bioinformatics/bts606. View

14.

Jochem V, Fuerst P, Fromkes J . Familial Barrett's esophagus associated with adenocarcinoma. Gastroenterology. 1992; 102(4 Pt 1):1400-2. View

15.

Lanuti M, Liu G, Goodwin J, Zhai R, Fuchs B, Asomaning K . A functional epidermal growth factor (EGF) polymorphism, EGF serum levels, and esophageal adenocarcinoma risk and outcome. Clin Cancer Res. 2008; 14(10):3216-22. PMC: 2572712. DOI: 10.1158/1078-0432.CCR-07-4932. View

16.

Altarejos J, Goebel N, Conkright M, Inoue H, Xie J, Arias C . The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nat Med. 2008; 14(10):1112-7. PMC: 2667698. DOI: 10.1038/nm.1866. View

17.

Montgomery S, Sammeth M, Gutierrez-Arcelus M, Lach R, Ingle C, Nisbett J . Transcriptome genetics using second generation sequencing in a Caucasian population. Nature. 2010; 464(7289):773-7. PMC: 3836232. DOI: 10.1038/nature08903. View

18.

Li Y, Willer C, Ding J, Scheet P, Abecasis G . MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010; 34(8):816-34. PMC: 3175618. DOI: 10.1002/gepi.20533. View

19.

Jankowski J, Hopwood D, Wormsley K . Expression of epidermal growth factor, transforming growth factor alpha and their receptor in gastro-oesophageal diseases. Dig Dis. 1993; 11(1):1-11. DOI: 10.1159/000171396. View

20.

Poynton A, Walsh T, OSullivan G, Hennessy T . Carcinoma arising in familial Barrett's esophagus. Am J Gastroenterol. 1996; 91(9):1855-6. View