Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression

Reid, Brian J.; Prevo, Laura J.; Galipeau, Patricia C.; Sanchez, Carissa A.; Longton, Gary; Levine, Douglas S.; Blount, Patricia L.; Rabinovitch, Peter S.

doi:10.1111/j.1572-0241.2001.04236.x

Cited by 334 publications

(157 citation statements)

References 72 publications

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“…both), 51 and loss of heterozygosity for 17p, 52 further implicating the p53 tumor suppressor gene in the molecular pathogenesis of esophageal adenocarcinoma. 39 With further validation, it is likely that such biomarkers (in particular, cell nuclear DNA content or ploidy) soon will be incorporated into routine clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma

Casson

Zheng

Evans

et al. 2005

Cancer

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Section: Discussionmentioning

confidence: 99%

Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma

Casson

Zheng

Evans

et al. 2005

Cancer

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“…In previous studies, aneuploidy and LOH at chromosome 17p defined patients at high risk for developing EAC in prospective trials, respresenting Phase 4 biomarker development studies (Teodori et al, 1998;Barrett et al, 1999;Rabinovitch et al, 2001;Reid et al, 2001). In addition, inactivation of p16 was shown to be an early and frequent event in EAC (Suzuki et al, 1995;Barrett et al, 1996Barrett et al, , 1999Maley et al, 2004).…”

Section: Runx3 Mrna Expression Runx3 Msp Value (Nmv)mentioning

confidence: 99%

“…For example, loss of heterozygosity (LOH) at chromosome 17p (17p-LOH) and ploidy status define the risk of developing EAC in prospective trials (Teodori et al, 1998;Barrett et al, 1999;Rabinovitch et al, 2001;Reid et al, 2001). Aneuploid subclones were detectable prior to the p53 inactivation (Neshat et al, 1994;Galipeau et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk

et al. 2005

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Patients with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EAC). Clinical neoplastic progression risk factors, such as age and the length of the esophageal BE segment, have been identified. However, improved molecular biomarkers predicting increased progression risk are needed for improved risk assessment and stratification. Using realtime quantitative methylation-specific PCR, we screened 10 genes (HPP1, RUNX3, RIZ1, CRBP1, 3-OST-2, APC, TIMP3, p16, MGMT, p14) for promoter hypermethylation in 77 EAC, 93 BE, and 64 normal esophagus (NE) specimens. A subset of genes manifesting significant differences in methylation frequencies between BE and EAC was then analysed in 20 dysplastic specimens. All 10 genes except p14 were frequently methylated in EACs, with RUNX3, HPP1, CRBP1, RIZ1, and OST-2 representing novel methylation targets in EAC and/or BE. p16, RUNX3, and HPP1 displayed increasing methylation frequencies in BE vs EAC. Furthermore, these increases in methylation occurred early, at the interface between BE and low-grade dysplasia (LGD). To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2 0 -deoxycytidine (Aza-C) treatment. Real-time RT-PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA. Hypermethylation of a subset of six genes (APC, TIMP3, CRBP1, p16, RUNX3, and HPP1) was then tested in a retrospective longitudinal study of 99 BE and nine LGD specimens obtained from 53 BE patients undergoing surveillance endoscopy. Only highgrade dysplasia (HGD) or EAC were defined as progression end points. Two patient groups were compared: eight progressors (P) and 45 nonprogressors (NP), using Cox proportional hazards models to determine the relative progression risks of age, BE segment length, and methylation events. Multivariate analyses revealed that only hypermethylation of p16 (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.33-2.20), RUNX3 (OR 1.80, 95% CI 1.08-2.81), and HPP1 (OR 1.77, 95% CI 1.06-2.81) were independently associated with an increased risk of progression, whereas age, BE segment length, and hypermethylation of TIMP3, APC, or CRBP1 were not independent risk factors. In combined analyses, risk was detectable up to, but not earlier than, 2 years preceding neoplastic progression. Hypermethylation of p16, RUNX3, and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC. These findings have implications regarding risk stratification, early EAC detection, and the appropriate endoscopic surveillance interval for patients with BE.

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“…In a large, prospective trial of patients with Barrett esophagus, 17p LOH in biopsy tissues was found to predict cancer progression at 5 years. 79 Moreover, p53 antibodies have been detected in the sera of Barrett patients who later progressed to dysplasia and cancer. 80 Studies investigating the prognostic significance of 17p LOH and p53 antibodies in gastric cardia tumors have not been done.…”

Section: Resistance Of Growth-inhibitory Signalsmentioning

confidence: 99%

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

Souza

Spechler

2005

CA: A Cancer Journal for Clinicians

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For decades, the incidence rates for squamous cell carcinoma of the esophagus and adenocarcinoma of the distal stomach have been declining while the rates for adenocarcinomas of the esophagus and gastric cardia have increased profoundly. Recent studies have shown that the gastroesophageal junction (GEJ) is regularly exposed to concentrated gastric acid and to a variety of nitrosating species, noxious agents that may contribute to carcinogenesis in this region. For adenocarcinomas that straddle the GEJ, it can be difficult to determine whether the tumor originated in the esophagus or in the gastric cardia. This classification problem hampers studies on the epidemiology and pathogenesis of GEJ tumors. Current concepts in the prevention of cancers of the distal esophagus and proximal stomach have emerged from advances in our understanding of the specific molecular events that occur during the evolution of these tumors. This report reviews those events and focuses on current concepts in the prevention of adenocarcinomas at the GEJ. The similarities and differences in risk factors, molecular pathogenesis, and in preventive strategies for adenocarcinomas of the esophagus and gastric cardia are highlighted. (CA Cancer J Clin 2005;55:334-351.)

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Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression

Cited by 334 publications

References 72 publications

Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma

Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma

Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

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