Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome

Hasan Ali, O. and Yurchenko, A. A. and Pavlova, O. and Sartori, A. and Bomze, D. and Higgins, R. and Ring, S. S. and Hartmann, F. and Bühler, D. and Fritzsche, F. R. and Jochum, W. and Navarini, A. A. and Kim, A. and French, L. E. and Dermitzakis, E. and Christiano, A. M. and Hohl, D. and Bickers, D. R. and Nikolaev, S. I. and Flatz, L.. (2021) Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome. Journal of the European Academy of Dermatology and Venereology : JEADV, 35 (2). pp. 396-402.

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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.; 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.; 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.; 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
UniBasel Contributors:Navarini, Alexander
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Apr 2021 12:28
Deposited On:14 Apr 2021 12:28

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