Derivation of genetic biomarkers for cancer risk stratification in Barrett’s oesophagus: a prospective cohort study

Abstract

Objective The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC, and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver-operating-characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain, and aneusomy, were significantly associated with progression on univariate analysis. We defined an ‘Abnormal Marker Count’ that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI, 2.6 to 29.8) increased hazard ratio compared with the low-risk group, with an area under the curve of 0.76 (95% CI, 0.66 to 0.86). Conclusion A prediction model based on age, Barrett's length, and the markers p16, MYC, and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

Localization of specialized intestinal metaplasia and the molecular alterations in Barrett esophagus in a Japanese population: an analysis of biopsy samples based on the “Seattle” biopsy protocol

“…Our findings showed that all of the molecular alterations investigated were more frequently detected in the EAC group compared to the BE group, suggesting that CpG hypermethylation at all genes is closely associated with EAC, as previously reported [15-22]. Among these DNA alterations, only APC hypermethylation was an independent predictive marker for EAC development it.…”

“…To date, many reviews regarding molecular biomarkers, including DNA methylation, that are associated with an increased risk of neoplastic progression (HGD or EAC) have been reported [15-22]. A genome-wide profiling of CpG methylation in esophageal tissue samples found that there was a substantial difference in the methylation pattern between normal esophagus samples and those with BE or EAC, but that the difference between BE and EAC was still unclear [21].…”

“…A genome-wide profiling of CpG methylation in esophageal tissue samples found that there was a substantial difference in the methylation pattern between normal esophagus samples and those with BE or EAC, but that the difference between BE and EAC was still unclear [21]. The previous studies also had some limitations; all of the BE samples were obtained from patients who developed HGD or EAC, as opposed to the vast majority of cases of BE that do not progress [19-22]. …”

Improved diagnostic stratification of digitised Barrett's oesophagus biopsies by p53 immunohistochemical staining

“…To optimise the panel (consensus) diagnosis, we wanted to investigate the use of an adjunct diagnostic marker. Earlier studies have shown that aberrant nuclear immunohistochemical staining of the protein encoded by the tumour suppressor gene TP53 (p53) may improve the histological assessment of BO . TP53 is a tumour suppressor gene acting as the guardian of genetic stability.…”

Etiology and Prevention of Esophageal Cancer

“…Recent studies have shown that molecular biomarkers in biopsy or exfoliative cells are potential solutions for this problem. Multiple techniques have been used for this purpose and shown great promise, such as fluorescence in situ hybridization for several marker genes [70], gene arrays for expression patterns of 90 genes [71] and genome sequencing [68]. …”