%0 Journal Article
%T Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome.
%A Ye L
%A Wang L
%A Peng K
%A Fang O
%A Tian Z
%A Li C
%A Fu X
%A Chen Q
%A Chen J
%A Luan J
%A Zhang Z
%A Zhang Q
%A Ye L
%A Wang L
%A Peng K
%A Fang O
%A Tian Z
%A Li C
%A Fu X
%A Chen Q
%A Chen J
%A Luan J
%A Zhang Z
%A Zhang Q
%A Ye L
%A Wang L
%A Peng K
%A Fang O
%A Tian Z
%A Li C
%A Fu X
%A Chen Q
%A Chen J
%A Luan J
%A Zhang Z
%A Zhang Q
%J BMC Med Genomics
%V 15
%N 1
%D Aug 2022 5
%M 35932013
%F 3.622
%R 10.1186/s12920-022-01324-7
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.