Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma

Mohammed Orloff, Charissa Peterson, Xin He, Shireen Ganapathi, Brandie Heald, Yi Ran Yang, Gurkan Bebek, Todd Romigh, Jee Hoon Song, Wenjing Wu, Stefan David, Yulan Cheng, Stephen Meltzer, Charis Eng

Research output: Contribution to journalArticle

Abstract

Context: Barrett esophagus (BE) occurs in 1% to 10% of the general population and is believed to be the precursor of esophageal adenocarcinoma (EAC). The incidence of EAC has increased 350% in the last 3 decades without clear etiology. Finding pre-disposition genes may improve premorbid risk assessment, genetic counseling, and management. Genome-wide multiplatform approaches may lead to the identification of genes important in BE/EAC development. Objective: To identify risk alleles or mutated genes associated with BE/EAC. Design, Setting, and Patients: Model-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005-2006). Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007-2010) were validated and fine mapped. Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 "priority" candidate genes for mutation analysis (2010). Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010). Main Outcome Measures: Identification of germline mutations in genes associated with BE/EAC cases. Functional interrogation of the most commonly mutated gene. Results: Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/ EAC (all PT (p.R293X). An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95% CI, 0.004-0.120; P=.09). MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate. Immunohistochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expression of CCND1. Conclusion: MSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases.

LanguageEnglish (US)
Pages410-419
Number of pages10
JournalJournal of the American Medical Association
Volume306
Issue number4
DOIs
StatePublished - Jul 27 2011

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Barrett Esophagus
Germ-Line Mutation
Adenocarcinoma
Genes
Mutation
Siblings
Genetic Counseling
Genetic Association Studies
Up-Regulation
Immunohistochemistry
Alleles
Outcome Assessment (Health Care)
Genome
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

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Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. / Orloff, Mohammed; Peterson, Charissa; He, Xin; Ganapathi, Shireen; Heald, Brandie; Yang, Yi Ran; Bebek, Gurkan; Romigh, Todd; Song, Jee Hoon; Wu, Wenjing; David, Stefan; Cheng, Yulan; Meltzer, Stephen; Eng, Charis.

In: Journal of the American Medical Association, Vol. 306, No. 4, 27.07.2011, p. 410-419.

Research output: Contribution to journalArticle

Orloff, M, Peterson, C, He, X, Ganapathi, S, Heald, B, Yang, YR, Bebek, G, Romigh, T, Song, JH, Wu, W, David, S, Cheng, Y, Meltzer, S & Eng, C 2011, 'Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma' Journal of the American Medical Association, vol. 306, no. 4, pp. 410-419. https://doi.org/10.1001/jama.2011.1029
Orloff, Mohammed ; Peterson, Charissa ; He, Xin ; Ganapathi, Shireen ; Heald, Brandie ; Yang, Yi Ran ; Bebek, Gurkan ; Romigh, Todd ; Song, Jee Hoon ; Wu, Wenjing ; David, Stefan ; Cheng, Yulan ; Meltzer, Stephen ; Eng, Charis. / Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. In: Journal of the American Medical Association. 2011 ; Vol. 306, No. 4. pp. 410-419.
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AU - Orloff, Mohammed

AU - Peterson, Charissa

AU - He, Xin

AU - Ganapathi, Shireen

AU - Heald, Brandie

AU - Yang, Yi Ran

AU - Bebek, Gurkan

AU - Romigh, Todd

AU - Song, Jee Hoon

AU - Wu, Wenjing

AU - David, Stefan

AU - Cheng, Yulan

AU - Meltzer, Stephen

AU - Eng, Charis

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