P53 mutational status improves estimation of prognosis in patients with curatively resected adenocarcinoma in Barrett's esophagus.

The incidence of adenocarcinomas in Barrett's esophagus has been rising in the last two decades in the United States and Western Europe for yet unknown reasons. We reported previously a large multi-institutional trial implicating p53 mutations as being involved in the pathogenesis of Barrett's cancer and representing an early marker for the malignant potential of Barrett's epithelium. A prospective study was performed to evaluate the prognostic impact of p53 mutations on survival in 59 patients with Barrett's cancer. Tissue for DNA analysis was obtained by endoscopic biopsy or immediately after surgical resections from the tumor, Barrett's epithelium, and normal stomach and esophagus. p53 mutation analysis was performed by PCR-single strand conformational polymorphism screening of exons 5-9 and DNA sequencing to unequivocally prove the presence of a mutation. p53 mutations were identified in 30 of 59 (50.8%) patients. The presence of a p53 mutation in the tumor had a significant impact on survival after curative resections (RO-resections) with cumulative 5-year survival probabilities of 68.8+/-9.7% for mutation-negative tumors and 24.3+/-9.9% for mutation-positive tumors (log rank: P < 0.001). By Cox proportional hazard analysis, including the parameters of gender, age, Union International Contre Cancer tumor stage, grading, and p53 mutation status, only Union International Contre Cancer tumor stage (P < 0.0001) and p53 mutation status (P < 0.02) were of significant independent prognostic importance. p53 mutation analysis by DNA sequencing is of significant independent prognostic importance next to histopathological tumor stage in patients with curatively resected (RO-resection) Barrett's cancer. It appears that p53 mutational status is a valuable parameter to define low-risk (p53 mutation-negative) and high-risk (p53 mutation-positive) groups for treatment failure after curative resections.

Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer.

A prospective study was performed in patients with non-small cell lung cancer (NSCLC) to evaluate the prognostic importance of multiple molecular marker (p53, c-Ki-ras, c-erbB-2) testing. 103 patients with potentially curative resections (RO resection) for NSCLC in histopathological stages I-IIIA were included. SSCP analysis and DNA sequencing for p53 and c-Ki-ras genes were performed on paired tumour and normal lung tissue samples and immunohistochemistry (c-erbB-2) was done on frozen tissue sections with a specific anti-c-erbB-2 monoclonal antibody. 46/103 (44.6%) NSCLC showed p53 mutations and 17/103 (16.5%) c-Ki-ras mutations including 12/37 (32.4%) adenocarcinomas. Overexpression of c-erbB-2 (p185) was detected in 56/103 (54.4%) tumours. 24/103 (23.3%) NSCLC were negative for alterations in all 3 parameters (c-Ki-ras, p53 and p185) whereas 79/103 (76.7%) were positive for at least one of the 3 parameters. In a regression model including a multiple molecular marker parameter (negative for all 3 markers versus positive for at least one marker), histopathological stage (P<0.00001), respectively the pT (P<0.01) and pN (P<0.00001) categories and the multiple molecular marker parameter (P<0.01) were of significant prognostic importance. This study demonstrates that testing 3 molecular markers (c-Ki-ras, p53 and c-erbB-2) improves estimation of prognosis compared to single marker testing and appears to define low (82.6%+/-7.9% 5-year survival) and high risk (40.2%+/-5.5% 5-year survival) groups for treatment failure in potentially curative (RO) resected NSCLC.

[Frequency and significance of APC gene mutations in malignant degeneration of Barrett esophagus]. / Frequenz und Bedeutung von APC Genmutationen in der malignen Degeneration des Barrett-Osophagus.

The frequency and importance of APC gene mutations in patients with adenocarcinoma in Barrett's esophagus were evaluated. Tissue samples were obtained by endoscopic biopsy or after surgery in 43 patients. DNA analysis was performed with PCR SSCP and DNA sequencing of the mutation cluster region (Exon 15) of the APC gene. Our analysis demonstrated an infrequent occurrence of APC gene mutations in Barrett's cancer (n = 3) and dysplastic Barrett's mucosa (n = 1). Therefore, the functional significance of the frequently observed APC allelic losses (LOH) must be questioned, as a single allelic loss is not sufficient for a complete gene inactivation. It might however be, that a target gene responsible for the molecular pathogenesis of Barrett's cancer is located outside the APC region on chromosome 5q21. 5q allelic losses could however, serve as a marker for the malignant potential of Barrett's epithelium, as they occur with a high frequency in an early stage of carcinogenesis.

[Clinical significance of p53 tumor suppressor gene mutations in adenocarcinoma in Barrett esophagus]. / Klinische Bedeutung von p53 Tumor-Suppressor-Gen Mutationen beim Adenocarcinom im Barrett-Osophagus.

p53 mutations are involved in the pathogenesis of adenocarcinomas in Barrett's esophagus. Our study included patients with histopathologically classified Barrett's cancer and shows that p53 mutations are clinically important for curatively resected (R0) Barrett's cancer. It appears that the p53 mutation status is a promising parameter for the definition of risk groups after potentially curative resections.