TP53 Gene Mutations Are Rare in Nondysplastic Barrett's Esophagus

Novotna, Kamila; Trková, Marie; Pazdro, A; Smejkal, M; Soukupova, Alzbeta; Kodetová, Daniela; Smejkal, P; Sedláček, Zdeněk

doi:10.1007/s10620-006-3093-3

Cited by 18 publications

(18 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like the primary patient tissues, all were Cytokeratin, EpCam and p53 positive, confirming respectively the epithelial nature of the cells; their derivation from transformed metaplastic columnar-type epithelium (rather than adjacent normal squamous oesophageal epithelium); and neoplastic phenotype, as oesophageal p53 staining is not found in non-dysplastic Barrett's Oesophagus. [11, 12] Trefoil Factor 3 (TFF3) is involved in protection, maintenance and repair of the intestinal mucosa, [13] specific for cells with an intestinal phenotype, [14] and is a reliable marker of metaplastic change in the oesophagus. [15] It was present in all of the primary patient cancer tissue, but absent in the feeder layer culture of the close-to-patient cancer cells, however expression was restored in both the 3D-TGA with mesenchymal support (Figure 1E, 1F) and xenografts (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Individual patient oesophageal cancer 3D models for tailored treatment

et al. 2016

View full text Add to dashboard Cite

BackgroundA model to predict chemotherapy response would provide a marked clinical benefit, enabling tailored treatment of oesophageal cancer, where less than half of patients respond to the routinely administered chemotherapy.MethodsCancer cells were established from tumour biopsies taken from individual patients about to undergo neoadjuvant chemotherapy. A 3D-tumour growth assay (3D-TGA) was developed, in which cancer cells were grown with or without supporting mesenchymal cells, then subjected to chemo-sensitivity testing using the standard chemotherapy administered in clinic, and a novel emerging HDAC inhibitor, Panobinostat.RESULTSIndividual patients cancer cells could be expanded and screened within a clinically applicable timescale of 3 weeks. Incorporating mesenchymal support within the 3D-TGA significantly enhanced both the growth and drug resistance profiles of the patients cancer cells. The ex vivo drug response in the presence, but not absence, of mesenchymal cells accurately reflected clinical chemo-sensitivity, as measured by tumour regression grade. Combination with Panobinostat enhanced response and proved efficacious in otherwise chemo-resistant tumours.ConclusionsThis novel method of establishing individual patient oesophageal cancers in the laboratory, from small endoscopic biopsies, enables clinically-relevant chemo-sensitivity testing, and reduces use of animals by providing more refined in vitro models for pre-screening of drugs. The 3D-TGA accurately predicted chemo-sensitivity in patients, and could be developed to guide tailored patient treatment. The incorporation of mesenchymal cells as the stromal cell component of the tumour micro-environment had a significant effect upon enhancing chemotherapy drug resistance in oesophageal cancer, and could prove a useful target for future drug development.

show abstract

Section: Resultsmentioning

confidence: 99%

Individual patient oesophageal cancer 3D models for tailored treatment

et al. 2016

View full text Add to dashboard Cite

show abstract

“…This suggested that the p53 mutation was an important step in the progression toward adenocarcinoma. Although p53 mutations are common in adenocarcinoma, they are relatively uncommon in nondysplastic Barrett's esophagus (52).…”

Section: Studies Of P53 and Barrett's Esophagusmentioning

confidence: 99%

Clinical Use of p53 in Barrett's Esophagus

Keswani¹,

Noffsinger

Waxman³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Barrett's esophagus is an established precursor to esophageal adenocarcinoma. Whereas most patients with Barrett's esophagus do not progress to adenocarcinoma, patients with progression have a poor prognosis. Current management strategies use frequent endoscopic surveillance and multiple nontargeted biopsies. This approach, however, may miss dysplastic areas. Furthermore, given the relatively high prevalence of Barrett's esophagus but low incidence of progression, this invasive and expensive approach has not been shown to be cost-effective. Thus, there is intense interest in using biomarkers to identify patients at increased risk of progressing to adenocarcinoma. This has included examination of mutations in the tumor suppressor gene, p53. In this report, we discuss the biology of p53 and the incidence of p53 mutations in Barrett's esophagus and review relevant studies regarding the ability of p53 to predict neoplastic progression. Additionally, we report our results of the expression of p53 by immunohistochemistry in a group of 18 patients that have undergone endoscopic esophageal mucosal resection for dysplasia. Although the presence of a p53 mutation increases the risk of neoplastic progression, the absence of this mutation does not abrogate the risk. Continuing efforts, therefore, are needed to define and prospectively validate a panel of biomarkers to risk-stratify patients with Barrett's esophagus. Determination of p53 mutational status may ultimately be a component of such a panel. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1243 -9)

show abstract

“…Recently, Novotna et al, by direct sequencing of exons 5 to 9 of the p53 gene, reported lack of p53 mutations in 24 BE cases in the absence of dysplasia. 24 These data suggest that p53 mutation is rare, if present at all, before the development of dysplasia in BE. Downregulation of APC expression was observed in HGD stage, and was markedly decreased in EC.…”

Section: Discussionmentioning

confidence: 79%

Genomic Instability in Precancerous Lesions before Inactivation of Tumor Suppressors p53 and APC in Patients

Yang¹,

Fruehauf²,

Xiang³

et al. 2006

Cell Cycle

View full text Add to dashboard Cite

The etiology and significance of genomic instability (GIN), a hallmark of human cancers, remains controversial. The paradigm that inactivation of tumor suppressors [e.g. p53 or adenomatous polyposis coli (APC) genes] leads to GIN is largely based on experiments in vitro and in animal models. It remains unclear whether GIN is a cause or a result of cancer, particularly in patients. Precancerous Barrett's esophagus (BE) provides a clinical model to investigate GIN in cancer progression. We analyzed specimens from endoscopic biopsies or esophagectomies in patients with BE (ten cases, including five cases with multilayered epithelium (ME)), BE-associated esophageal adenocarcinoma (ten cases), or with normal gastro-esophageal junction (five cases). Chromosomal enumeration probe Cep 7, 11, 12, 17 and 18 were detected by fluorescence in situ hybridization (FISH). Expression of p53 and APC were determined by immunohistochemistry. Increased p53 expression, a measurement of p53 mutations, was observed in BE with high grade dysplasia (HGD) and in BE-associated esophageal cancer (EC). The expression of wild type APC was decreased in BE with HGD and in advanced EC. Chromosomal abnormalities were found in all EC samples. Numeric changes of chromosome 7, 11 and 12 were observed in BE in 14%, 64% and 43% of cases, respectively. Aneusomy of chromosome 11 and 12 were found in ME and in BE without dysplasia, in the presence of normal expression pattern of p53 and APC. Our results suggest that GIN is an early event that occurs at precancerous stages prior to changes in tumor suppressor genes (p53 and APC) in BE-associated tumorigenesis in patients, suggesting that GIN may serve as a causative link between chronic inflammation and cancer.

show abstract

TP53 Gene Mutations Are Rare in Nondysplastic Barrett's Esophagus

Cited by 18 publications

References 19 publications

Individual patient oesophageal cancer 3D models for tailored treatment

Individual patient oesophageal cancer 3D models for tailored treatment

Clinical Use of p53 in Barrett's Esophagus

Genomic Instability in Precancerous Lesions before Inactivation of Tumor Suppressors p53 and APC in Patients

Contact Info

Product

Resources

About