Alterations of the p16/Rb/cyclin-D1 pathway in vulvar carcinoma, vulvar intraepithelial neoplasia, and lichen sclerosus.

Three different alterations in the p16/pRb/cyclin-D1 pathway (p16(INK4a)-promoter hypermethylation and expression of pRb and cyclin-D1) were investigated in a series of 38 cases of vulvar carcinoma (VC), 13 cases of vulvar intraepithelial neoplasia (VIN), and 21 cases of lichen sclerosus (LS). Paraffin blocks from 72 patients were selected for investigation of DNA methylation patterns in the CpG island of p16(INK4a) by methylation-specific polymerase chain reaction. Immunohistochemical studies for pRb and cyclin-D1 were performed using the standard avidin-biotin-peroxidase complex method. Epigenetic silencing of p16(INK4a) was detected in 68% of VC, 69.2% of VIN, and 42.8% of LS cases. Lack of pRb protein was found in 21% of VC, 0% of VIN, and 0% of LS cases. Overexpression of cyclin-D1 was found in 21% of VC, 30.8% of VIN, and 0% of LS cases. We conclude (1) that p16(INK4a) epigenetic inactivation most likely represents an early event, insufficient for malignant transformation, that may occur in clinically benign lesions such as LS; (2) that lack of pRb was only detected in fewer than one quarter of the carcinomas and could be considered a late secondary event; and (3) that cyclin-D1, which was overexpressed in VC and VIN, could contribute to the malignant transformation in association with p16 hypermethylation.

Lerma E ，Esteller M ，Herman JG ，Prat J ... -  《HUMAN PATHOLOGY》

Cyclin D1 and retinoblastoma protein in vulvar cancer and adjacent lesions.

Rolfe KJ ，Crow JC ，Benjamin E ，Reid WM ，Maclean AB ，Perrett CW ... -  《INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER》

Alterations of the cyclin D1/pRb/p16(INK4A) pathway in multiple myeloma.

Krämer A ，Schultheis B ，Bergmann J ，Willer A ，Hegenbart U ，Ho AD ，Goldschmidt H ，Hehlmann R ... -  《LEUKEMIA》

The role of pRB, p16 and cyclin D1 in colonic carcinogenesis.

Ayhan S ，Isisag A ，Saruc M ，Nese N ，Demir MA ，Kucukmetin NT ... -  《hepato-gastroenterology》

Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance.

Inactivation of the Rb pathway in non-small cell lung carcinoma (NSCLC) occurs mostly through inactivation of the cyclin-dependent kinase inhibitor p16(INK4A) and/or up-regulation of cyclin D1. In order to assess the frequency and the prognostic value of these abnormalities in NSCLC, immunohistochemical analysis of Rb, p16(INK4), and cyclin D1 has been performed on 168 cases of NSCLC including 77 squamous cell carcinomas, 43 adenocarcinomas, and 48 basaloid carcinomas. The reduced survival rate of basaloid carcinoma (stage I-II) compared with other histological types of NSCLC was confirmed (p = 0.008). Loss of protein expression of Rb and p16(INK4A) was observed in 12 per cent and 58 per cent of NSCLC cases respectively and cyclin D1 overexpression in 43 per cent. There was an inverse correlation between Rb and p16 expression ( p < 0.0001) and a direct correlation between Rb and cyclin D1 expression ( p = 0.0007). In univariate analysis, Rb-negative adenocarcinomas at stages I-II had a significantly shorter survival than Rb-positive cases ( p = 0.04) and stages I-II p16-positive cases had a shorter survival than p16-negative cases ( p = 0.02), which was more significant in basaloid carcinoma ( p = 0.003). p16 status retained its influence on survival in multivariate analysis at stage I-II for all cases ( p = 0.01) and for basaloid carcinoma ( p = 0.005). Cyclin D1 overexpression did not influence survival. Combined Rb/p16/cyclin D1 phenotypes in univariate analysis showed a shorter survival for Rb-negative/p16-positive/cyclin D1-negative tumours ( p = 0.002). These results, linked to previous data, indicate that the Rb pathway of G1 arrest is initially disrupted in the vast majority of NSCLCs (83 per cent), but could not confirm an unfavourable role for each individual event (p16(INK4A) loss or cyclin D1 up-regulation) in prognosis.

Brambilla E ，Moro D ，Gazzeri S ，Brambilla C ... -  《JOURNAL OF PATHOLOGY》