Mario Sarbia

p53 protein expression and prognosis in squamous cell carcinoma of the esophagus.

Background. The p53 gene product is known to regulate cell growth and proliferation. Whereas the wild‐type p53 protein suppresses cell growth, the mutated p53 protein acts as an oncogene. Mutations in the p53 gene usually result in p53 protein stabilization and accumulation; so that the gene product can be detected by immunohistochemistry. Recently, the immunohistochemical detection of the p53 protein was associated with prognosis in breast, colorectal, and other types of cancer. However, its prognostic role in esophageal cancer remains to be elucidated.

Expression of cyclin B1 in the metaplasia-dysplasia-carcinoma sequence of Barrett esophagus

It is known that proliferation is deregulated progressively during carcinogenesis in Barrett esophagus (BE). Cyclin B1 is a key protein for the regulation of G2‐M‐phase transition during the cell cycle and is essential for initiation of mitosis.

Basaloid squamous cell carcinoma of the esophagus

Basaloid squamous cell carcinoma (BSCC) is a recently recognized, poorly differentiated variant of squamous cell carcinoma (SCC), which is located predominantly in the upper aerodigestive tract.

Prognostic significance of cyclin D1 in esophageal squamous cell carcinoma patients treated with surgery alone or combined therapy modalities.

In the present study, the expression of cyclin D1, as detected by immunohistochemistry, was compared with other prognostic variables and its prognostic impact was evaluated in a group of 172 patients with squamous cell carcinoma (SCC) of the esophagus who underwent potentially curative resection therapy and in a second group of 38 patients with SCC of the esophagus who were treated by combined modality therapy (radiochemotherapy ± surgery). Expression of cyclin D1 in surgically treated carcinomas correlated negatively with tumor differentiation (p = 0.026) but positively with mitotic activity (p = 0.0199) and nodal status (p = 0.040). There were no significant correlations with pT category. Patients with cyclin D1‐positive carcinomas showed significantly worse overall survival than patients with cyclin D1‐negative carcinomas, both in univariate (p = 0.0016) and in multivariate survival analyses (p = 0.0038). Expression of cyclin D1 in carcinomas with multimodal treatment was correlated with poor response to chemotherapy (p = 0.026) but not with overall survival. We thus consider expression of cyclin D1 to be an important parameter, predicting an unfavorable overall survival of surgically treated esophageal cancer patients. Int. J. Cancer (Pred. Oncol.) 84:86–91, 1999.

ASSOCIATION OF CYCLIN D1 (G870A) POLYMORPHISM WITH SUSCEPTIBILITY TO ESOPHAGEAL AND GASTRIC CARDIAC CARCINOMA IN A NORTHERN CHINESE POPULATION

Our aim was to investigate the association of cyclin D1 (G870A) single nucleotide polymorphism with susceptibility to esophageal and cardiac carcinoma in a northern Chinese population. By polymerase chain reaction‐single strand conformation polymorphism analysis, cyclin D1 (G870A) genotyping was carried out among 120 patients with esophageal squamous cell carcinoma (ESCC), 87 patients with gastric cardiac adenocarcinoma (CAC), and 183 age‐ and gender‐matched controls. The cyclin D1 genotype distribution among ESCC patients was significantly different from that among healthy controls (χ2 = 7.372, p = 0.025). The G/G genotype was significantly less frequent among ESCC patients (9.2%) than among healthy controls (20.8%) (χ2 = 7.192, p = 0.007). The G/G genotype significantly reduced risk for the development of ESCC compared to the combination of G/A and A/A genotypes (adjusted odds ratio [OR] = 0.37, 95% confidence interval [CI] = 0.16–0.83). After stratification according to smoking status, the A/A frequency among smoking ESCC (34.3%) and CAC patients (35.7%) was significantly higher than that among smoking healthy controls (18.6%) (χ2 = 5.426 and 5.599, p = 0.020 and 0.018, respectively). Smokers with the A/A genotype had an about 2‐fold increased risk for both of ESCC and CAC compared to the G/A and G/G genotypes, with an adjusted OR of 2.26 in ESCC (95% CI = 1.14–4.49) and of 2.42 in CAC (95% CI = 1.17–4.98). No correlation between the cyclin D1 genotype and development of ESCC or CAC was found among nonsmokers. Determination of the cyclin D1 (G870A) single nucleotide polymorphism may be suitable to identify individuals with increased risk for ESCC or CAC in the northern Chinese population.

Gene Amplification and Protein Overexpression of c-erb-b2 in Barrett Carcinoma and Its Precursor Lesions

We examined 39 samples of metaplastic specialized epithelium (SE), 27 of low-grade dysplasia (LGD), 27 of high-grade dysplasia (HGD), and 46 of adenocarcinoma (CA) derived from Barrett esophagus for c-erb-b2 gene amplification using differential polymerase chain reaction and for overexpression of c-erb-b2 protein using immunohistochemical analysis. Amplification of the c-erb-b2 gene was as follows: SE, 0.0%; LGD, 0.0%; HGD, 11.1%; and CA, 13.6%; and protein overexpression was as follows: SE, 0.0%; LGD, 7.4%; HGD, 18.5%; and CA, 21.7%. In 8 (89%) of 9 samples, c-erb-b2 gene amplification correlated with protein overexpression. The reverse was true in 8 (47%) of 17 samples: c-erb-b2 protein overexpression was proved with simultaneous gene amplification. Amplification of c-erb-b2 is a late event in the carcinogenesis of Barrett esophagus. In contrast, protein overexpression appears more often and earlier Besides gene amplification, other mechanisms to induce protein overexpression must exist.

Expression of Bcl-2 and amplification of c-myc are frequent in basaloid squamous cell carcinomas of the esophagus

Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare, poorly differentiated variant of typical esophageal squamous cell carcinoma (SCC) characterized by high proliferative activity and frequent spontaneous apoptoses. In the present study, we investigated the expression of the apoptosis-suppressing protein Bcl-2 in 23 BSCC of the esophagus and 23 stage-matched typical esophageal SCC by means of immunohistochemistry. In addition, amplification of the apoptosis- and proliferation-inducing gene c-myc was determined by means of differential polymerase chain reaction. Bcl-2 expression was found significantly more often in BSCC than in SCC (86.9% vs. 17.4%, P < 0.0001). Amplification of c-myc was nearly twice as common in BSCC as in SCC (47.8% vs. 26.1%, not significant). Bcl-2 protein expression together with c-myc amplification was detected in 43.5% of the BSCC but in none of the typical SCC (P < 0.0001). Taken together, our findings indicate that the molecular pathogenesis of esophageal BSCC differs from that of typical SCC and frequently involves coactivation of c-myc and Bcl-2.

Methylation of RAS association domain family protein 1A as a biomarker of lung cancer

Promoter hypermethylation is an important mechanism for silencing tumor‐suppressor genes in cancer and a promising tool for development of molecular biomarkers. This study aimed to determine the prevalence of RAS association domain family protein 1A (RASSF1A) promoter hypermethylation in bronchial aspirates of patients with suspected lung cancer and to test whether this type of methylation assay could be used as a diagnostic adjunct to conventional cytology.

Prognostic value of histopathologic parameters of esophageal squamous cell carcinoma

Background. The grading of squamous cell carcinoma (SCC) of the esophagus as proposed by the World Health Organization (WHO) has not yet proved to be prognostically significant. Therefore, the prognostic impact of various histologic parameters was investigated and compared with that of the WHO grading.

bcl-2 expression and prognosis in squamous-cell carcinomas of the esophagus

The bcl‐2 proto‐oncogene is a known inhibitor of apoptosis and may be an important regulator of tumor growth. In the present study, bcl‐2‐protein expression was investigated by immunohistochemistry and correlated with prognosis in a series of 150 potentially curatively resected squamous‐cell carcinomas of the esophagus. For comparison bcl‐2‐protein expression was analyzed in normal esophageal mucosa, severe squamous dysplasias and carcinomas in situ. bcl‐2 immunoreactivity was found in 48 out of 150 invasive squamous‐cell carcinomas; the remaining carcinomas were completely negative. bcl‐2‐protein expression was found more frequently among poorly differentiated than among well‐differentiated tumors (p < 0.0001). No correlation was found between bcl‐2‐protein expression and the parameters tumor size, depth of invasion and nodal status. Moreover bcl‐2‐protein expression had no significant influence on overall survival. Whereas in normal mucosa bcl‐2 immunoreactivity was restricted to the basal‐cell layer, in 9 out of 15 severe squamous dysplasias and in 7 out of 14 carcinomas in situ bcl‐2 staining was detected in all epithelial layers. Thus bcl‐2‐protein is frequently expressed in invasive squamous‐cell carcinomas of the esophagus and in precursor lesions of esophageal cancer but has no significant impact on the outcome of esophageal cancer.