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Gene Signature Distinguishes Patients with Chronic Ulcerative Colitis Harboring Remote Neoplastic Lesions

Pekow, Joel MD*; Dougherty, Urszula MS*; Huang, Yong PhD*; Gometz, Edward MD*; Nathanson, Jeff MD*; Cohen, Greg MD*; Levy, Shawn PhD; Kocherginsky, Masha PhD; Venu, Nanda MD*; Westerhoff, Maria MD§; Hart, John MD§; Noffsinger, Amy E. MD§; Hanauer, Stephen B. MD*; Hurst, Roger D. MD; Fichera, Alessandro MD; Joseph, Loren J.§; Liu, Qiang MD§; Bissonnette, Marc MD*

doi: 10.1097/MIB.0b013e3182802bac
Original Basic Science Articles

Background: Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer. The standard method of surveillance for neoplasia in UC by colonoscopy is invasive and can miss flat lesions. We sought to identify a gene expression signature in nondysplastic mucosa without active inflammation that could serve as a marker for remote neoplastic lesions.

Methods: Gene expression was analyzed by complementary DNA microarray in 5 normal controls, 4 UC patients without dysplasia, and 11 UC patients harboring remote neoplasia. Common gene ontology pathways of significantly differentially expressed genes were identified. Expression of genes which were progressively and significantly upregulated from controls to UC without neoplasia, to UC with remote neoplasia were evaluated by real-time polymerase chain reaction. Several gene products were also examined by immunohistochemistry.

Results: Four hundred and sixty-eight genes were significantly upregulated, and 541 genes were significantly downregulated in UC patients with neoplasia compared with UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly upregulated from controls to nondysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increased expression of S100A9 and REG1α in UC-associated cancer and in nondysplastic tissue from UC patients harboring remote neoplasia compared with UC patients without neoplasia and controls.

Conclusions: Gene expression changes occurring as a field effect in the distal colon of patients with chronic UC identify patients harboring remote neoplastic lesions. These markers may lead to a more accurate and less invasive method of detection of neoplasia in patients with inflammatory bowel disease.

Supplemental Digital Content is Available in the Text.Article first published online 6 February 2013

*Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago, Chicago, Illinois

Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee

Departments of Health Studies

§Pathology

Surgery, University of Chicago, Chicago, Illinois.

Reprints: Joel Pekow, MD, 900 East 57th Street, MB#9, Chicago, IL 60637 (e-mail: jpekow@medicine.bsd.uchicago.edu).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

The authors have no conflicts of interest to disclose.

Supported by the International Organization for the Study of Inflammatory Bowel Disease (M.B. and G.C.), the Crohn’s and Colitis Foundation of America (J.P.), and National Institutes of Health Grant K08DK090152 (J.P).

Received June 21, 2012

Accepted July 03, 2012

© Crohn's & Colitis Foundation of America, Inc.
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