Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China.
Clin Cancer Res. 2010 Jan 15;16(2):442-50. doi: 10.1158/1078-0432.CCR-09-2574. Epub 2010 Jan 12.
PTCH1 has been identified as the gene responsible for nevoid basal cell carcinoma syndrome (NBCCS). Keratocystic odontogenic tumors (KCOT) are aggressive jaw lesions that may occur in isolation or in association with NBCCS. The aim of this study was to investigate the genetic and/or epigenetic mechanisms of inactivation of the PTCH1 gene in patients with NBCCS and related sporadic KCOTs.
Loss of heterozygosity was analyzed in 44 patients (15 NBCCS-related and 29 sporadic KCOTs), all of whom were previously analyzed for PTCH1 mutations. Allelic location was established in tumors carrying two coincident mutations. PTCH1 mRNA expression and promoter methylation status were analyzed in a panel of KCOTs to define the possible role of epigenetic effects on PTCH1 inactivation.
Although mutations and loss of heterozygosity of PTCH1 were frequently detected in both syndromic and nonsyndromic cases, hypermethylation of the PTCH1 promoter was not identified in the present series. Of all the 44 cases examined, 13 were identified to fit the two-hit model, 14 to conform to a one-hit model, and the remaining 17 cases showing no alteration in PTCH1. The distribution of two-hit, one-hit, and non-hit cases was significantly different between syndrome and nonsyndrome patients (P < 0.02).
This study indicates that PTCH1 gene alternation may play a significant role in the pathogenesis of NBCCS and the related sporadic tumors. Not only the standard two-hit model, but also haploinsufficiency or dominant-negative isoforms may be implicated in the inactivation of the PTCH1 gene.
PTCH1 已被确定为神经嵴发育不良基底细胞癌综合征（NBCCS）的致病基因。牙源性角化囊性瘤（KCOT）是一种侵袭性颌骨病变，可单独发生或与 NBCCS 相关。本研究旨在探讨 NBCCS 相关和散发性 KCOT 中 PTCH1 基因失活的遗传和/或表观遗传机制。
分析了 44 例患者（15 例 NBCCS 相关，29 例散发性 KCOT）的杂合性缺失，所有患者均先前进行了 PTCH1 突变分析。在携带两个同时突变的肿瘤中确定等位基因位置。分析了一组 KCOT 中 PTCH1 mRNA 表达和启动子甲基化状态，以确定表观遗传效应对 PTCH1 失活的可能作用。
虽然在综合征和非综合征病例中经常检测到 PTCH1 突变和杂合性缺失，但在本研究系列中未发现 PTCH1 启动子的高甲基化。在所有 44 例检查的病例中，13 例符合双打击模型，14 例符合单打击模型，其余 17 例病例 PTCH1 无改变。双打击、单打击和非打击病例的分布在综合征和非综合征患者之间存在显著差异（P < 0.02）。
本研究表明，PTCH1 基因改变可能在 NBCCS 和相关散发性肿瘤的发病机制中起重要作用。不仅标准的双打击模型，而且单倍不足或显性负性异构体也可能参与 PTCH1 基因的失活。
