Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome.
Journal
Journal of the European Academy of Dermatology and Venereology : JEADV
ISSN: 1468-3083
Titre abrégé: J Eur Acad Dermatol Venereol
Pays: England
ID NLM: 9216037
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
23
11
2019
accepted:
29
05
2020
pubmed:
22
6
2020
medline:
15
5
2021
entrez:
22
6
2020
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 32564428
doi: 10.1111/jdv.16767
pmc: PMC7750252
mid: NIHMS1617995
doi:
Substances chimiques
Patched Receptors
0
Patched-1 Receptor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
396-402Subventions
Organisme : NIAMS NIH HHS
ID : P30 AR069632
Pays : United States
Organisme : NCI NIH HHS
ID : UH3 CA213384
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES020344
Pays : United States
Organisme : National Institute of Health
ID : P30AR069632-01
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : PP00P3_157448
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : Krebsforschung Schweiz
ID : KFC-3985-08-2016
Organisme : Gustave Roussy
Organisme : ARC 2017
Organisme : National Institute of Health
ID : R01ES020344-04
Organisme : NIEHS NIH HHS
ID : R01 ES030481
Pays : United States
Informations de copyright
© 2020 European Academy of Dermatology and Venereology.
Références
J Skin Cancer. 2011;2011:217378
pubmed: 21152126
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Cancer Res. 2005 Oct 1;65(19):8597-603
pubmed: 16204023
BMC Med Genomics. 2015 Mar 01;8:9
pubmed: 25889339
Am J Med Genet A. 2012 Feb;158A(2):351-7
pubmed: 22246785
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
JAMA Dermatol. 2016 Mar;152(3):323-7
pubmed: 26677003
Hum Mutat. 2015 Apr;36(4):E2423-9
pubmed: 25703262
Curr Protoc Hum Genet. 2010 Apr;Chapter 4:Unit 4.14.1-28
pubmed: 20373515
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Br J Dermatol. 2018 Jan;178(1):198-206
pubmed: 28733979
Cell. 1996 Jun 14;85(6):841-51
pubmed: 8681379
Eur J Hum Genet. 2013 Oct;21(10):
pubmed: 23361221
J Comput Biol. 2004;11(2-3):377-94
pubmed: 15285897
Nat Biotechnol. 2013 Mar;31(3):213-9
pubmed: 23396013
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
J Am Acad Dermatol. 2018 Apr;78(4):673-681.e9
pubmed: 29217346
Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3
pubmed: 5279523
Fam Cancer. 2014 Sep;13(3):477-80
pubmed: 24659465
J Am Acad Dermatol. 2014 Aug;71(2):359-65
pubmed: 24725477
J Invest Dermatol. 2018 Jul;138(7):1636-1644
pubmed: 29476775
Science. 2015 Jan 9;347(6218):1254806
pubmed: 25525159
J Am Acad Dermatol. 2018 Mar;78(3):540-559
pubmed: 29331385
Hum Mol Genet. 1994 Mar;3(3):447-8
pubmed: 8012356
J Clin Invest. 2012 Feb;122(2):455-63
pubmed: 22293184
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Genome Med. 2018 Apr 25;10(1):33
pubmed: 29695279
Br J Dermatol. 2015 Jan;172(1):94-100
pubmed: 24947307
Genome Res. 2014 Feb;24(2):349-55
pubmed: 24389049
Science. 2019 Jun 07;364(6444):
pubmed: 31171663
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Int J Mol Sci. 2017 Nov 22;18(11):
pubmed: 29165358
Hum Mutat. 2006 Mar;27(3):215-9
pubmed: 16419085
Nat Genet. 2016 Apr;48(4):398-406
pubmed: 26950094
Nature. 2017 May 11;545(7653):175-180
pubmed: 28467829
Am J Clin Dermatol. 2014 Jul;15(3):197-216
pubmed: 24733429
Dermatology. 2016;232(3):285-92
pubmed: 27054559
Am J Med Genet. 1997 Mar 31;69(3):299-308
pubmed: 9096761