Journal article
Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome.
- Hasan Ali O Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
- Yurchenko AA Inserm U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France.
- Pavlova O Service of Dermatology and Venerology, CHUV, Lausanne, Switzerland.
- Sartori A Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
- Bomze D Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
- Higgins R Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
- Ring SS Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
- Hartmann F Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
- Bühler D Dermatologie Gossau, Gossau, Switzerland.
- Fritzsche FR PATHOdiagnostics AG, Herisau, Switzerland.
- Jochum W Institute of Pathology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
- Navarini AA Department of Dermatology, University Hospital Basel, Basel, Switzerland.
- Kim A Department of Dermatology, Columbia University Irving Medical Center, New York, USA.
- French LE Department of Dermatology and Allergology, Ludwig-Maximilian-University of Munich, Munich, Germany.
- Dermitzakis E Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
- Christiano AM Department of Dermatology, Columbia University Irving Medical Center, New York, USA.
- Hohl D Service of Dermatology and Venerology, CHUV, Lausanne, Switzerland.
- Bickers DR Department of Dermatology, Columbia University Irving Medical Center, New York, USA.
- Nikolaev SI Inserm U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France.
- Flatz L Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
- 2020-06-22
Published in:
- Journal of the European Academy of Dermatology and Venereology : JEADV. - 2020
English
BACKGROUND
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases, NBCCS presents with a late onset of BCC development.
OBJECTIVE
To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40 years. Two other siblings did not show signs of NBCCS.
RESULTS
We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763-6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss-of-function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations.
CONCLUSIONS
Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS.
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases, NBCCS presents with a late onset of BCC development.
OBJECTIVE
To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40 years. Two other siblings did not show signs of NBCCS.
RESULTS
We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763-6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss-of-function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations.
CONCLUSIONS
Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1111/jdv.16767
- PMID 32564428
- Persistent URL
- https://sonar.ch/global/documents/50694
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