Gastroenterology

Gastroenterology

Volume 143, Issue 4, October 2012, Pages 927-935.e3
Gastroenterology

Original Research
Clinical—Alimentary Tract
Population-Based Study Reveals New Risk-Stratification Biomarker Panel for Barrett's Esophagus

https://doi.org/10.1053/j.gastro.2012.06.041Get rights and content

Background & Aims

The risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is low and difficult to calculate. Accurate tools to determine risk are needed to optimize surveillance and intervention. We assessed the ability of candidate biomarkers to predict which cases of BE will progress to EAC or high-grade dysplasia and identified those that can be measured in formalin-fixed tissues.

Methods

We analyzed data from a nested case-control study performed using the population-based Northern Ireland BE Register (1993–2005). Cases who progressed to EAC (n = 89) or high-grade dysplasia ≥6 months after diagnosis with BE were matched to controls (nonprogressors, n = 291), for age, sex, and year of BE diagnosis. Established biomarkers (abnormal DNA content, p53, and cyclin A expression) and new biomarkers (levels of sialyl Lewisa, Lewisx, and Aspergillus oryzae lectin [AOL] and binding of wheat germ agglutinin) were assessed in paraffin-embedded tissue samples from patients with a first diagnosis of BE. Conditional logistic regression analysis was applied to assess odds of progression for patients with dysplastic and nondysplastic BE, based on biomarker status.

Results

Low-grade dysplasia and all biomarkers tested, other than Lewisx, were associated with risk of EAC or high-grade dysplasia. In backward selection, a panel comprising low-grade dysplasia, abnormal DNA ploidy, and AOL most accurately identified progressors and nonprogressors. The adjusted odds ratio for progression of patients with BE with low-grade dysplasia was 3.74 (95% confidence interval, 2.43–5.79) for each additional biomarker and the risk increased by 2.99 for each additional factor (95% confidence interval, 1.72–5.20) in patients without dysplasia.

Conclusions

Low-grade dysplasia, abnormal DNA ploidy, and AOL can be used to identify patients with BE most likely to develop EAC or high-grade dysplasia.

Section snippets

Study Design

A nested case-control study was conducted within the NIBR.5, 19, 20 The NIBR is a population-based register of all 9329 adults diagnosed with columnar-lined esophagus between 1993 and 2005 throughout Northern Ireland. Within the NIBR, 4306 patients with a visible columnar-lined segment displayed specialized intestinal metaplasia on biopsy and, for the purposes of this study, this definition was used for diagnosis of BE. Cases were BE patients from the NIBR who developed EAC, gastric cardia

Patient Demographics

After a mean (±standard deviation) follow-up period of 6.7 years (±3.3 y), 56 EAC, 13 gastric cardia cancers, and 25 HGD cases were diagnosed within the cohort. After review by 2 expert pathologists, 5 cases (2 EAC, 1 gastric cardia cancer, and 2 HGD cases) were found to have evidence of HGD or EAC at their initial BE diagnosis and therefore were excluded from analysis, leaving 89 cases. Table 1 shows the characteristics of these 89 cases and their 291 matched controls. Cases and controls did

Discussion

This population-based, phase 3, biomarker study has revealed a new combination panel for assessment of risk to progression from BE (±LGD) to EAC. The combination panel of 7 biomarkers represents a significant step to individualize patient risk and is advantageous owing to the use of relatively simple techniques that can be applied to formalin-fixed tissue. Furthermore, analysis of a simplified 3-biomarker panel model showed a significant stepwise increase risk of progression for AOL, DNA

Acknowledgments

The authors would like to extend their thanks for the input of all staff in the Centre for Public Health at Queen's University Belfast, past and present, who have contributed to the development of the Northern Ireland Barrett's esophagus register.

Elizabeth Bird–Lieberman, Jason Dunn, and Helen Coleman contributed equally to this work.

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    Conflicts of interest The authors disclose no conflicts.

    Funding This work was funded by a grant from the Medical Research Council and was supported by the University College London Experimental Cancer Medicine Centre, the Cambridge Experimental Cancer Medicine Centre (Cambridge and University College London), and the National Institute for Health Research Cambridge Biomedical Research Centre. Work undertaken at University College London Hospital/ University College London received a portion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The work also was supported by funding from a research fellowship from GlaxoSmithKline (E.B.-L.). The Northern Ireland Barrett's esophagus register has received financial support from the Ulster Cancer Foundation and the Health and Social Care Research and Development Office, Northern Ireland.

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