Institute of Legal Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.
Virchows Arch. 2011 Feb;458(2):221-9. doi: 10.1007/s00428-010-1007-4. Epub 2010 Nov 18.
Alterations in the p16/cyclinD1/Rb and ARF/Mdm2/p53 pathways are frequent events in the pathogenesis of squamous cell carcinomas. Different mechanisms of p16 regulation have been described for penile carcinomas so far. Therefore, expression of p16 and p53 was immunohistochemically detected with monoclonal antibodies in 52 primary invasive penile squamous cell carcinomas. The carcinomas were analyzed for allelic loss (LOH) in p16(INK4A) and p53, as well as for mutations in the p16(INK4A) and the p53 gene. In addition, we examined the promoter status of p16(INK4A) by methylation-specific PCR. The presence of human papilloma virus (HPV) 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Data were compared to clinical data. Concerning p16, 26 (50%) tumors showed positive immunohistochemistry, 32 (62%) tumors showed allelic loss and 22 tumors (42%) showed promoter hypermethylation. All tumors with negative p16 immunohistochemistry showed LOH near the p16(INK4A) locus and/or hypermethylation of the p16(INK4A) promoter. HPV 16 DNA was detected in 17 tumors, ten of them with positive p16 immunostaining. The remaining seven tumors with negative p16 staining showed allelic loss and/or promoter hypermethylation. Evidence of lymph node metastasis was significantly associated with negative p16 immunohistochemistry as well as with combined LOH and promoter hypermethylation (p = 0.003 and p = 0.018, respectively). Allelic loss around p53 was found in 22 tumors (42%), and seven mutations of the p53 gene could be demonstrated in our tumors. No correlations could be found between any p53 alteration and clinical parameters.
p16/cyclinD1/Rb 和 ARF/Mdm2/p53 通路的改变是鳞状细胞癌发病机制中的常见事件。迄今为止，已经描述了阴茎癌中 p16 调节的不同机制。因此，使用单克隆抗体通过免疫组织化学检测了 52 例原发性侵袭性阴茎鳞状细胞癌中的 p16 和 p53 的表达。分析了 p16(INK4A)和 p53 的等位基因缺失 (LOH)以及 p16(INK4A)和 p53 基因的突变。此外，我们通过甲基化特异性 PCR 检查了 p16(INK4A)的启动子状态。通过 PCR 分析了人乳头瘤病毒 (HPV) 6/11、HPV 16 和 HPV 18 DNA 的存在。将数据与临床数据进行了比较。关于 p16，26 例（50%）肿瘤的免疫组化呈阳性，32 例（62%）肿瘤存在等位基因缺失，22 例（42%）肿瘤存在启动子高甲基化。所有 p16 免疫组化呈阴性的肿瘤均显示 p16(INK4A)基因座附近的 LOH 和/或 p16(INK4A)启动子的高甲基化。在 17 例肿瘤中检测到 HPV 16 DNA，其中 10 例 p16 免疫染色阳性。其余 7 例 p16 染色阴性的肿瘤表现出等位基因缺失和/或启动子高甲基化。淋巴结转移的证据与 p16 免疫组化阴性以及联合 LOH 和启动子高甲基化显著相关（p=0.003 和 p=0.018）。在 22 例肿瘤中发现 p53 周围的等位基因缺失（42%），并且可以在我们的肿瘤中证明 p53 基因的 7 个突变。任何 p53 改变与临床参数之间均未发现相关性。
