Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome

BMC Med Genomics. 2022 Aug 5;15(1):172. doi: 10.1186/s12920-022-01324-7.


Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Gorlin-Goltz syndrome; Mutational signatures; PTCH1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basal Cell Nevus Syndrome* / genetics
  • Basal Cell Nevus Syndrome* / metabolism
  • Basal Cell Nevus Syndrome* / pathology
  • Carcinoma, Basal Cell* / genetics
  • Carcinoma, Basal Cell* / pathology
  • Hedgehog Proteins / genetics
  • Humans
  • Mutation
  • Skin Neoplasms* / genetics
  • Skin Neoplasms* / pathology


  • Hedgehog Proteins