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Clonal Expansions and Short Telomeres Are Associated with Neoplasia in Early-onset, but not Late-onset, Ulcerative Colitis

Salk, Jesse J. MD, PhD*,†; Bansal, Aasthaa PhD; Lai, Lisa A. PhD†,§; Crispin, David A. BS*,†; Ussakli, Cigdem H. MD*; Horwitz, Marshall S. MD, PhD*; Bronner, Mary P. MD; Brentnall, Teresa A. MD†,§; Loeb, Lawrence A. MD, PhD*; Rabinovitch, Peter S. MD, PhD*,¶; Risques, Rosa Ana PhD*

doi: 10.1097/MIB.0b013e3182a87640
Original Clinical Articles

Background: Patients with ulcerative colitis (UC) are at risk of developing colorectal cancer. We have previously reported that cancer progression is associated with the presence of clonal expansions and shorter telomeres in nondysplastic mucosa. We sought to validate these findings in an independent case–control study.

Methods: This study included 33 patients with UC: 14 progressors (patients with high-grade dysplasia or cancer) and 19 nonprogressors. For each patient, a mean of 5 nondysplastic biopsies from proximal, mid, and distal colon were assessed for clonal expansions, as determined by clonal length altering mutations in polyguanine tracts, and telomere length, as measured by quantitative PCR. Both parameters were compared with individual clinicopathological characteristics.

Results: Clonal expansions and shorter telomeres were more frequent in nondysplastic biopsies from UC progressors than nonprogressors, but only for patients with early-onset of UC (diagnosis at younger than 50 years of age). Late-onset progressor patients had very few or no clonal expansions and longer telomeres. A few nonprogressors exhibited clonal expansions, which were associated with older age and shorter telomeres. In progressors, clonal expansions were associated with proximity to dysplasia. The mean percentage of clonally expanded mutations distinguished early-onset progressors from nonprogressors with 100% sensitivity and 80% specificity.

Conclusions: Early-onset progressors develop cancer in a field of clonally expanded epithelium with shorter telomeres. The detection of these clones in a few random nondysplastic colon biopsies is a promising cancer biomarker in early-onset UC. Curiously, patients with late-onset UC seem to develop cancer without the involvement of such fields.

Article first published online 3 October 2013

*Department of Pathology,

Department of Medicine,

Department of Biostatistics, and

§Division of Gastroenterology, University of Washington, School of Medicine, Seattle, Washington;

Division of Anatomic Pathology, University of Utah, Salt Lake City, Utah; and

Division of Public Health Science, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Reprints: Rosa Ana Risques, PhD, Department of Pathology, University of Washington, Box 357705, 1959 Northeast Pacific Street, K-081 HSB, Seattle, WA 98195-7705 (e-mail: rrisques@u.washington.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).

Supported by the National Institutes of Health under award numbers K07 CA137136 (to R.A.R), R01 CA160674 (to L.A.L.), R01 CA068124 to (T.A.B.), P30 AG13280 to (P.S.R.), UL1 TR000423 to (A.B.), and the Crohn's and Colitis Foundation of America.

The authors have no conflicts of interest to disclose.

Received July 02, 2013

Accepted August 07, 2013

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