Vorechovský I, Undén A B, Sandstedt B, Toftgård R, Ståhle-Bäckdahl M
Karolinska Institute, Department of Biosciences at Novum, Huddinge, Sweden.
Cancer Res. 1997 Nov 1;57(21):4677-81.
The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility. NBCCS is caused by mutations in the human homologue (PTCH) of the Drosophila patched gene, a developmental regulator implicated in signaling of hedgehog and smoothened. The PTCH gene was found to contain somatic mutations also in sporadic basal cell carcinomas and medulloblastomas, tumors seen in NBCCS, consistent with PTCH acting as a tumor suppressor. Because basal cell carcinomas have been observed to develop in association with benign trichoepitheliomas (TEs) in the same lesions, patients, and families and may share the same cell of origin, we have analyzed PTCH for mutations and expression in TEs. We report frameshift and in-frame somatic deletions in this gene and a consistent overexpression of PTCH mRNA in TEs. These findings provide the first evidence of a gene mutation in TEs and identify a common pathogenic pathway for histopathologically similar but prognostically distinct skin tumors. Moreover, these results support the presence of a gatekeeper mechanism in multistep skin tumorigenesis exerted by the altered PTCH signaling pathway.
痣样基底细胞癌（Gorlin）综合征（NBCCS）是一种常染色体显性疾病，其特征为多种发育缺陷和癌症易感性。NBCCS由果蝇patched基因的人类同源物（PTCH）发生突变引起，patched基因是一种参与刺猬信号通路和平滑蛋白信号传导的发育调节因子。人们发现，在散发性基底细胞癌和髓母细胞瘤（NBCCS中出现的肿瘤）中，PTCH基因也存在体细胞突变，这与PTCH作为肿瘤抑制因子的作用相符。由于已观察到基底细胞癌与同一病变、患者及家族中的良性毛发上皮瘤（TE）相关联，且可能具有相同的起源细胞，因此我们分析了TE中PTCH的突变和表达情况。我们报告了该基因中的移码突变和框内体细胞缺失，以及TE中PTCH mRNA的持续过表达。这些发现提供了TE中基因突变的首个证据，并确定了组织病理学相似但预后不同的皮肤肿瘤的共同致病途径。此外，这些结果支持在多步骤皮肤肿瘤发生过程中，由改变的PTCH信号通路发挥的守门机制的存在。
