Department of Dermatology, Haikou People's Hospital, Xiangya Medical College, Central South University, Hainan, China.
Department of Dermatology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
BMC Med Genomics. 2022 Aug 5;15(1):172. doi: 10.1186/s12920-022-01324-7.
Gorlin-Goltz syndrome (GS) is an inherited disease characterized by predisposition to basal cell carcinomas (BCCs) and various developmental defects, whose numerous disease-causing PTCH1 mutations have been identified in the hedgehog (Hh) signaling pathway.
In this study, whole exome sequencing was used to screen for both somatic and germline deleterious mutations in three sisters with a lethal GS. The mutations we found were confirmed by subcloning and Sanger sequencing of the genomic DNA. RNA-seq was performed to profile gene expression in paired BCCs samples and the expression levels for selected genes were validated by quantitative PCR.
The clinical and histopathologic features were analyzed for the proband in the three-generation GS family. We identified the insertion mutation PTCH1 c.1341dupA (p. L448Tfs*49), which segregated with BCC phenotype and contributed to the death of two in four patients from a Chinese family with GS. Compared with adjacent non-cancerous tissues (ANCT), four second-hit mutations were found in four of the six pairs of BCC from three patients. Of note, somatic genomic alterations in all six BCC samples were mainly clustered into non-clock-like Signature 7 (ultraviolet mutagenesis) and 11 (related to certain alkylating agents). Both RNA-seq and quantitative RT-PCR confirmed that the mRNA levels of PTCH1 and its effector GLI1 were markedly upregulated in six pairs of BCC samples versus ANCT.
The distinct non-clock-like signatures of BCCs indicated that GS was not a life-threatening illness. The main reasons for untimely death of GS patients were PTCH1 mutation, exposure to intense ultraviolet radiationand the poor economic conditions.
Gorlin-Goltz 综合征（GS）是一种遗传性疾病，其特征为基底细胞癌（BCC）易感性和多种发育缺陷，其 Hedgehog（Hh）信号通路中的许多致病 PTCH1 突变已被确定。
本研究采用外显子组测序技术筛选了三姐妹中致死性 GS 的体细胞和种系有害突变。我们发现的突变通过基因组 DNA 的亚克隆和 Sanger 测序进行了验证。RNA-seq 用于对配对的 BCC 样本进行基因表达谱分析，并通过定量 PCR 验证了选定基因的表达水平。
对三代 GS 家系中的先证者进行了临床和组织病理学特征分析。我们发现了 PTCH1 c.1341dupA（p.L448Tfs*49）的插入突变，该突变与 BCC 表型分离，并导致来自中国 GS 家系的 4 例患者中的 2 例死亡。与相邻非癌组织（ANCT）相比，在来自 3 例患者的 6 对 BCC 中的 4 对中发现了 4 个二次打击突变。值得注意的是，所有 6 例 BCC 样本中的体细胞基因组改变主要聚类为非时钟样特征 7（紫外线诱变）和 11（与某些烷化剂有关）。RNA-seq 和定量 RT-PCR 均证实，与 ANCT 相比，在 6 对 BCC 样本中 PTCH1 和其效应物 GLI1 的 mRNA 水平明显上调。
BCC 的独特非时钟样特征表明 GS 不是危及生命的疾病。GS 患者死亡的主要原因是 PTCH1 突变、暴露于强烈的紫外线辐射和较差的经济条件。
