Scarisbrick Julia J, Woolford Alison J, Calonje Eduardo, Photiou Andrew, Ferreira Sylvia, Orchard Guy, Russell-Jones Robin, Whittaker Sean J
Skin Tumor Unit, St. John's Institute Dermatology, St. Thomas' Hospital, Lambeth Palace Road., London, UK.
J Invest Dermatol. 2002 Mar;118(3):493-9. doi: 10.1046/j.0022-202x.2001.01682.x.
There are few data on the molecular pathogenesis of cutaneous T cell lymphomas. A recent allelotyping study by our group identified frequent allelic loss on 9p, 10q, and 17p including losses on 9p21 in 16% of patients with mycosis fungoides and 46% with Sezary syndrome. The P15 and P16 genes are intricately linked on 9p21 and can be inactivated in melanoma and non-Hodgkin's lymphoma. We have therefore studied 76 patients with either mycosis fungoides or Sezary syndrome for abnormalities of these genes. DNA samples were analyzed for loss of heterozygosity, homozygous deletion, intragenic mutations, and promoter methylation. In addition P15 and P16 protein expression was assessed. Microsatellite analysis was informative in 73 of 76 cases: allelic loss on 9p21 was identified in 18 patients (25%), including 12 of 57 with mycosis fungoides (21%) and six of 16 with Sezary syndrome (37%). Single strand conformation polymorphism analysis of the entire coding regions of both genes did not identify any mutations, although two polymorphisms were identified including C613A, which has not previously been described. P15 and P16 gene promoter methylation was found in 45% and 29% of patients, respectively. Furthermore aberrant P15 protein expression was detected in 85% of patients analyzed with P15 gene abnormalities and abnormal P16 expression in 59% with P16 gene abnormalities. These abnormalities were not dependent on cutaneous stage of disease. This study suggests that abnormalities of the P15 and P16 genes are common in both early and advanced stages of mycosis fungoides and Sezary syndrome and that these genes may be inactivated by allelic loss and aberrant promoter methylation.
关于皮肤T细胞淋巴瘤的分子发病机制，相关数据较少。我们团队最近进行的一项等位基因分型研究发现，9p、10q和17p存在频繁的等位基因缺失，其中蕈样肉芽肿患者中有16%、塞扎里综合征患者中有46%存在9p21缺失。P15和P16基因紧密连锁于9p21，在黑色素瘤和非霍奇金淋巴瘤中可能失活。因此，我们研究了76例蕈样肉芽肿或塞扎里综合征患者这些基因的异常情况。对DNA样本进行杂合性缺失、纯合性缺失、基因内突变和启动子甲基化分析。此外，还评估了P15和P16蛋白表达。76例中有73例微卫星分析结果有效：18例患者（25%）检测到9p21等位基因缺失，其中蕈样肉芽肿57例中有12例（21%），塞扎里综合征16例中有6例（37%）。对两个基因的整个编码区进行单链构象多态性分析未发现任何突变，不过发现了两个多态性，包括之前未描述过的C613A。分别在45%和29%的患者中发现P15和P16基因启动子甲基化。此外，在分析的P15基因异常患者中，85%检测到P15蛋白表达异常；在P16基因异常患者中，59%检测到P16表达异常。这些异常与疾病的皮肤分期无关。这项研究表明，P15和P16基因异常在蕈样肉芽肿和塞扎里综合征的早期和晚期都很常见，这些基因可能通过等位基因缺失和异常的启动子甲基化而失活。
