Aims: Several studies have reported that dysregulation of b catenin or k-ras mutation promotes cyclin D1 expression. This study investigated the relation between cyclin D1 expression and clinicopathological parameters in carcinoma of the ampulla of Vater (CAV), and also assessed the relation between increased cyclin D1 expression and b catenin/k-ras status in this series. Methods: Thirty CAVs were evaluated for cyclin D1 expression by immunohistochemistry in relation to patient clinicopathological features. Aberrant b catenin expression and k-ras mutation were also investigated by immunostaining and direct sequencing, and related to cyclin D1 expression. Results: Increased cyclin D1 expression was seen in 17 of 30 CAVs and was significantly correlated with tumour cell proliferation and disease free survival time (p = 0.018, p = 0.018, respectively). Nuclear accumulation of b catenin was found in nine of 30 cases, including four cases with missense mutations in exon 3 of CTNNB-1, and was significantly correlated with increased cyclin D1 expression (p = 0.003). kras gene mutation was detected in 12 of 30 cases, and was also significantly correlated with increased cyclin D1 expression (p = 0.026). Overall, 14 of 17 CAVs with increased cyclin D1 expression showed nuclear accumulation of b catenin and/or k-ras mutation. Conclusions: Increased cyclin D1 expression appears to be associated with tumour proliferation and poorer clinical outcome in CAV. It is also associated with both aberrant b catenin expression and k-ras mutation. These results are consistent with the in vitro data that cyclin D1 can be transactivated by activated b catenin-T cell factor/LEF and k-ras pathways.
Human papilloma virus (HPV) is regarded as a causative carcinogenic agent in anogenital squamous cell carcinoma (SCC), but there is controversy about its etiologic role in esophageal SCC (ESCC). In this study, we attempted to clarify whether HPV infection plays a crucial role in the development of ESCC by analysis of multiple factors. These included: detection of HPV DNA; evaluation of immunohistochemical assays for HPV-related cell cycle regulators and apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method; and genetic analysis of the p53 gene. Twenty of the 48 ESCC examined (42%) were found to be positive for the HPV genome by polymerase chain reaction. They comprised 16 cases with the HPV16 subtype, three with the HPV18 subtype, and one with both HPV16 and 18. Immunohistochemical analysis revealed that the expression of p21/WAF-1 was significantly decreased in HPV-positive cases (chi2 = 9.2614; P = 0.0023). Furthermore, the 10 apoptosis-negative (< or =10%) cases of HPV-positive SCC were almost exclusively p21/WAF-1-negative (chi2 = 12.1406; P = 0.0005), indicating the significance of the relationship between HPV infection and the phenotype that is expected from HPV-induced inhibition of p53. Although 14 cases possessed missense and deletion mutations of the p53 gene (of which four mutations were found in HPV-positive ESCC), no accumulation of the mutation was defined in the phenotype, suggesting that distinct mutation processes might be involved in HPV-negative and -positive ESCC. The data provide significant support for the hypothesis that HPV infection may play a crucial role in the oncogenesis of some ESCC.
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