The predictive value of genes of the TGF-beta1 pathway in multimodally treated squamous cell carcinoma of the esophagus.

BACKGROUND AND AIM: Pretherapeutic identification of esophageal squamous cell carcinomas (ESCCs) that are likely to respond to neoadjuvant chemoradiotherapy is important in the attempt to improve the prognosis for patients. In the present study, expression of members of the transforming growth factor-beta1 (TGF-beta1) signaling pathway was investigated in pretherapeutic biopsies from 97 ESCCs (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (45 Gy plus cisplatin and 5-fluorouracil) and subsequent esophagectomy in the setting of a single-center prospective treatment trial. MATERIALS AND METHODS: Expression of TGF-beta1 and its downstream effectors Smad4 and Smad7 was assessed using quantitative reverse transcription polymerase chain reaction from RNA prepared from pretherapeutic tumor biopsies. The presence of phosphorylated Smad2 was assessed immunohistochemically. RESULTS: Expression of TGF-beta1 (mean 7.8; range 0.0-25.7 arb. units), Smad4 (mean 0.1; range 0.0-0.4 arb. units), and Smad7 (mean 1.6; range 0.4-16.1 arb. units) varied substantially between the patients. Tumors with total or subtotal regression, as determined by histopathological examination after neoadjuvant chemoradiotherapy, showed significantly higher levels of Smad4 mRNA expression than tumors with minor or no regression (P = 0.032). TGF-beta1 and Smad7 mRNA expression as well as Smad2 protein expression were of no prognostic value. Expression of the four genes under analysis also showed no impact on the overall survival. In contrast, the overall survival correlated significantly with histopathological regression (P < 0.0001) and to a minor degree also with clinical regression grading (P = 0.0254). INTERPRETATION: Among the parameters analyzed, only Smad4 was found to have possible predictive value for esophageal squamous cell carcinoma in patients receiving neoadjuvant chemoradiotherapy.

c-myc amplification is frequent in esophageal adenocarcinoma and correlated with the upregulation of VEGF-A expression.

BACKGROUND: Deregulation of c-myc plays a major role in the carcinogenesis of human malignancies. We investigated the amplification of the c-myc gene in a surgical series of Barrett cancers. METHODS: Primary resected esophageal (Barrett) adenocarcinomas (n = 84) were investigated for c-myc amplification using chromogene in situ hybridization. Tumor samples were assembled in a tissue microarray. c-myc gene dosage was correlated with clinicopathologic parameters, including the survival and gene expression of cyclooxygenases (COX-1 and COX-2) and proangiogenic growth factors (VEGF-A and VEGF-C). RESULTS: The majority (70 of 84; 83.3%) exhibited amplification of the c-myc gene. There were low-level amplifications in 63 (75.0%) cases and high-level amplifications in 7 (8.3%) cases. No amplification was found in 14 (16.7%) cases. Tumors without c-myc amplification had lower VEGF-A, VEGF-C, and COX-2 expression levels than tumors with low-level and high-level c-myc amplification (statistically significant for VEGF-A; P = .0348). c-myc amplification was not correlated with clinicopathological parameters or survival. Only diffuse and mixed-type tumors, according to Lauren classification, exhibited c-myc amplifications more frequently (P = .0466). CONCLUSIONS: Amplifications of the c-myc gene are frequent in Barrett cancer. c-myc may be involved in the regulation of angiogenesis.

Lack of prognostic impact of p53 gene mutation and p53 phosphorylation at serine 15 in multimodally treated adenocarcinomas of the gastroesophageal junction.

PURPOSE: As inactivation of p53 may be correlated with poor response of tumors to chemo- and/or radiotherapy the presence of p53 mutations in exons 5-8 was determined in adenocarcinomas of the gastroesophageal junction (GEJ). As p53 protein phosphorylation at serine 15 indicates stabilization and protection against mdm-2 the presence of this phosphorylation state was subsequently evaluated. METHODS: Mutations in exons 5-8 were analyzed by denaturing high pressure liquid chromatography (DHPLC) and subsequent sequence analysis in pretherapeutic biopsies of 38 adenocarcinomas of the GEJ that had undergone multimodal treatment in the course of a prospective multicentric phase III trial. The presence of p53 protein phosphorylation at serine 15 was evaluated by immunohistochemistry. RESULTS: Mutations in the DNA binding region were found in 23 samples and were only weakly associated with worse 2-year survival (P=0.083). Phosphorylation at serine 15 of p53 was detected in 14 samples, being neither associated with p53 mutation nor with patient's survival. CONCLUSION: This allows the conclusion that the determination of these two parameters does not help to select patients who do profit from multimodal treatment for adenocarcinomas of the GEJ.