Vanin Katrina, Scurry James, Thorne Heather, Yuen Kally, Ramsay Robert G
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne, Australia.
J Invest Dermatol. 2002 Nov;119(5):1027-33. doi: 10.1046/j.1523-1747.2002.19513.x.
Human papillomavirus is a risk factor for vulvar cancer, whereas human papillomavirus-negative late onset vulvar carcinoma is associated with the dermatologic condition, lichen sclerosus. Human papillomavirus E6 protein targets TP53 for degradation and by inference it has been assumed that human papillomavirus-negative vulvar cancer is dependent upon the acquisition of p53 somatic mutations and subsequent allelic loss. To investigate this, TP53 expression, loss of heterozygosity, and p53 genomic sequence were examined in 29 cases of human papillomavirus-negative vulvar carcinoma with adjacent lichen sclerosus. We examined 37 cases of lichen sclerosus without vulvar carcinoma, 10 cases of nongenital lichen sclerosus, and 12 cases of normal vulvar epithelium served as controls. TP53 was evident in 72% of vulvar carcinoma, 48% in epithelium adjacent to vulvar carcinoma, but was minimal in normal samples. When lichen sclerosus cases were selected to exclude samples with absolutely no TP53 expression through probable failed antigen retrieval or homozygous p53 loss the number of epithelial cells expressing TP53 increased progressively from nongenital lichen sclerosus to lichen sclerosus without vulvar carcinoma, then to lichen sclerosus with vulvar carcinoma (p<0.0001). These data suggest elevated TP53 is a feature of vulvar lichen sclerosus. Seventy-four percent of vulvar carcinoma had chromosome 17p-linked loss of heterozygosity, whereas 47% of adjacent lichen sclerosus featured loss of heterozygosity, but only 31% of vulvar carcinoma had p53 mutations, a frequency less than reported previously. Seven percent of adjacent lichen sclerosus had mutations, showing for the first time the presence of an identical mutation to the matched vulvar carcinoma. These data, however, implicate p53 mutations as a later event in vulvar carcinoma and in marked contrast to the original expectation, our loss of heterozygosity data are consistent with loss of another locus (not p53) on 17p operating as a tumor suppressor in lichen sclerosus destined to develop vulvar carcinoma.
人乳头瘤病毒是外阴癌的一个风险因素，而人乳头瘤病毒阴性的晚发性外阴癌与皮肤病性疾病硬化性苔藓相关。人乳头瘤病毒E6蛋白靶向TP53进行降解，由此推断，人乳头瘤病毒阴性的外阴癌依赖于p53体细胞突变的获得及随后的等位基因缺失。为对此进行研究，我们检测了29例伴有相邻硬化性苔藓的人乳头瘤病毒阴性外阴癌病例的TP53表达、杂合性缺失及p53基因组序列。我们检测了37例无外阴癌的硬化性苔藓病例、10例非生殖器硬化性苔藓病例以及12例正常外阴上皮作为对照。TP53在外阴癌中72%呈阳性，在外阴癌相邻上皮中48%呈阳性，但在正常样本中含量极少。当选择硬化性苔藓病例以排除因抗原修复可能失败或p53纯合缺失而绝对无TP53表达的样本时，表达TP53的上皮细胞数量从非生殖器硬化性苔藓到无外阴癌的硬化性苔藓，再到伴有外阴癌的硬化性苔藓逐渐增加（p<0.0001）。这些数据表明TP53升高是外阴硬化性苔藓的一个特征。74%的外阴癌有17号染色体p臂连锁的杂合性缺失，而47%的相邻硬化性苔藓有杂合性缺失，但只有31%的外阴癌有p53突变，该频率低于先前报道。7%的相邻硬化性苔藓有突变，首次显示出与匹配的外阴癌存在相同突变。然而，这些数据表明p53突变是外阴癌中的一个后期事件，与最初的预期形成鲜明对比的是我们的杂合性缺失数据与17号染色体p臂上另一个位点（非p53）的缺失一致，该位点在注定发展为外阴癌的硬化性苔藓中作为肿瘤抑制因子发挥作用。
