Aneuploidy in Targeted Endoscopic Biopsies Outperforms Other Tissue Biomarkers in the Prediction of Histologic Progression of Barrett's Oesophagus: A Multi-Centre Prospective Cohort Study

Abstract

Introduction: The cancer risk in Barrett’s oesophagus (BO) is difficult to estimate. Confirmed histologic dysplasia has strong predictive power, but can be missed by random biopsies, while other clinical parameters have limited utility for risk stratification. We aimed to assess the utility of a large panel of molecular biomarkers on targeted biopsies to predict neoplastic progression of BO. Methods: In a prospective study in three tertiary centres, 203 patients with BO were tested for 9 biomarkers (p53 and cyclin A expression; aneuploidy and tetraploidy; CDKN2A (encoding for p16), RUNX3 and HPP1 hypermethylation; 9p and 17p loss of heterozygosity) on autofluorescence-targeted biopsies taken at index endoscopy and followed-up as per clinical standard. Data comparing progressors to non-progressors were evaluated by univariate and multivariate analyses using survival curves, Cox-proportional hazards and logistic regression models. Findings: 127 patients with no high-grade dysplasia (HGD) or early oesophageal adenocarcinoma (OAC) were included, of which 42 had evidence of any histologic progression over time. Aneuploidy was the only predictor of progression from non-dysplastic BO (NDBO) to any grade of neoplasia (p=0.013) and HGD/OAC (p=0.002). Aberrant p53 expression correlated with the risk of short-term progression within 12 months, with an odds ratio for histologically missed dysplasia of 6.0 (95% CI: 3.1-11.2). A biomarker panel comprising aneuploidy and p53 had an area under the ROC curve of 0.68 (95% CI: 0.59-0.77) for prediction of any histologic progression. Interpretation: In our study, aneuploidy is the only biomarker that predicts neoplastic progression of NDBO. Aberrant p53 expression suggests prevalent dysplasia, which might have been missed by random biopsies, and warrants early follow up. Funding Statement: This study was funded by a Medical Research Council Program Grant to RCF and by a Lister Institute for Preventive Medicine prize to RCF, with additional clinical research infrastructure support from the Experimental Cancer Medicine Centre and the Cambridge Biomedical Research Centre. Declaration of Interests: KR reports grants, personal fees and non-financial support from Olympus, outside the submitted work. JJGHMB reports grants from Olympus Endoscopy, outside the submitted work. Other authors declare no conflicts of interest. Ethics Approval Statement: This was a prospective study approved by the Cambridgeshire 2 Research Ethics Committee (09/H0308/118) and the Amsterdam University Medical Centre (AUMC) Medical Ethics Committee (MEC 09/073). This was a National Institute of Health research (NIHR) portfolio study (UKCRN ID 7561).