Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome
Abstract 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,...
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| Format: | Article |
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BMC
2022-08-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-022-01324-7 |
| _version_ | 1818505440904871936 |
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| author | Lihua Ye Li Wang Kexin Peng Ou Fang Zhen Tian Caihua Li Xiaopeng Fu Qingdong Chen Jia Chen Jing Luan Zhenghua Zhang Qiaoan Zhang |
| author_facet | Lihua Ye Li Wang Kexin Peng Ou Fang Zhen Tian Caihua Li Xiaopeng Fu Qingdong Chen Jia Chen Jing Luan Zhenghua Zhang Qiaoan Zhang |
| author_sort | Lihua Ye |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T21:50:49Z |
| format | Article |
| id | doaj.art-63cc10a5a6284b20923be292ca252378 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-10T21:50:49Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-63cc10a5a6284b20923be292ca2523782022-12-22T01:32:11ZengBMCBMC Medical Genomics1755-87942022-08-011511910.1186/s12920-022-01324-7Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndromeLihua Ye0Li Wang1Kexin Peng2Ou Fang3Zhen Tian4Caihua Li5Xiaopeng Fu6Qingdong Chen7Jia Chen8Jing Luan9Zhenghua Zhang10Qiaoan Zhang11Department of Dermatology, Haikou People’s Hospital, Xiangya Medical College, Central South UniversityDepartment of Dermatology, Haikou People’s Hospital, Xiangya Medical College, Central South UniversityDepartment of Dermatology, Huashan Hospital, Shanghai Medical College, Fudan UniversityGenesky Biotechnologies IncDepartment of Dermatology, Huashan Hospital, Shanghai Medical College, Fudan UniversityGenesky Biotechnologies IncDepartment of Dermatology, Haikou People’s Hospital, Xiangya Medical College, Central South UniversityDepartment of Dermatology, Dongfang People’s HospitalDepartment of Dermatopathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji UniversityDepartment of Dermatology, Huashan Hospital, Shanghai Medical College, Fudan UniversityDepartment of Dermatology, Huashan Hospital, Shanghai Medical College, Fudan UniversityDepartment of Dermatology, Huashan Hospital, Shanghai Medical College, Fudan UniversityAbstract 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.https://doi.org/10.1186/s12920-022-01324-7Gorlin-Goltz syndromePTCH1Mutational signatures |
| spellingShingle | Lihua Ye Li Wang Kexin Peng Ou Fang Zhen Tian Caihua Li Xiaopeng Fu Qingdong Chen Jia Chen Jing Luan Zhenghua Zhang Qiaoan Zhang Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome BMC Medical Genomics Gorlin-Goltz syndrome PTCH1 Mutational signatures |
| title | Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome |
| title_full | Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome |
| title_fullStr | Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome |
| title_full_unstemmed | Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome |
| title_short | Distinct non-clock-like signatures of the basal cell carcinomas from three sisters with a lethal Gorlin-Goltz syndrome |
| title_sort | distinct non clock like signatures of the basal cell carcinomas from three sisters with a lethal gorlin goltz syndrome |
| topic | Gorlin-Goltz syndrome PTCH1 Mutational signatures |
| url | https://doi.org/10.1186/s12920-022-01324-7 |
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