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Comparison of Cancer-Associated Genetic Abnormalities in Columnar-Lined Esophagus Tissues With and Without Goblet Cells

Bandla, Santhoshi PhD*; Peters, Jeffrey H. MD*; Ruff, David PhD; Chen, Shiaw-Min PhD; Li, Chieh-Yuan BS; Song, Kunchang MD; Thoms, Kimberly BS*; Litle, Virginia R. MD§; Watson, Thomas MD*; Chapurin, Nikita BS*; Lada, Michal MD*; Pennathur, Arjun MD; Luketich, James D. MD; Peterson, Derick PhD; Dulak, Austin PhD**; Lin, Lin PhD††; Bass, Adam MD**; Beer, David G. PhD††; Godfrey, Tony E. PhD§; Zhou, Zhongren MD, PhD

doi: 10.1097/SLA.0000000000000424
Original Articles

Objective: To determine and compare the frequency of cancer-associated genetic abnormalities in esophageal metaplasia biopsies with and without goblet cells.

Background: Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma (EAC), but the appropriate histologic definition of Barrett's esophagus is debated. Intestinal metaplasia (IM) is defined by the presence of goblet cells whereas nongoblet cell metaplasia (NGM) lacks goblet cells. Both have been implicated in EAC risk but this is controversial. Although IM is known to harbor genetic changes associated with EAC, little is known about NGM. We hypothesized that if NGM and IM infer similar EAC risk, then they would harbor similar genetic aberrations in genes associated with EAC.

Methods: Ninety frozen NGM, IM, and normal tissues from 45 subjects were studied. DNA copy number abnormalities were identified using microarrays and fluorescence in situ hybridization. Targeted sequencing of all exons from 20 EAC-associated genes was performed on metaplasia biopsies using Ion AmpliSeq DNA sequencing.

Results: Frequent copy number abnormalities targeting cancer-associated genes were found in IM whereas no such changes were observed in NGM. In 1 subject, fluorescence in situ hybridization confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy. Targeted sequencing revealed 11 nonsynonymous mutations in 16 IM samples and 2 mutations in 19 NGM samples.

Conclusions: This study reports the largest and most comprehensive comparison of DNA aberrations in IM and NGM genomes. Our results show that IM has a much higher frequency of cancer-associated mutations than NGM.

Supplemental Digital Content is Available in the Text.Intestinal metaplasia and nongoblet cell metaplasia (NGM) are implicated in esophageal adenocarcinoma risk though little is known about genetic changes in NGM. This is the largest and most comprehensive comparison of DNA aberrations in both intestinal metaplasia and NGM genomes. We report that intestinal metaplasia tissues show more frequent cancer-associated mutations than NGM tissues.

*Departments of Surgery

Pathology, and

Biostatistics, University of Rochester Medical Center, Strong Memorial Hospital, Rochester, NY

Life Technologies, Foster City, CA

**Dana Farber Cancer Center, Boston, MA

††University of Michigan, Ann Arbor, MI

University of Pittsburgh, Pittsburgh, PA; and

§Department of Surgery, Boston University, Boston, MA.

Reprints: Tony E Godfrey, PhD, Surgery and Computational Biomedicine, Boston University Medical Center, 700 Albany St, W408, Boston, MA 02118. or Zhongren Zhou, MD, PhD, Pathology and Laboratory Medicine, University of Rochester, 601 Elmwood Ave, Box 626, Rochester, NY 14642. E-mail:

Disclosure: Supported in part by NIH grant R01 CA130853 to TEG.

The authors declare no conflicts of interest.

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 (

© 2014 by Lippincott Williams & Wilkins.