Germline Variants in Childhood Cutaneous Melanoma.

Exposure to UVR and genetic variation associated with fair skin and the development of melanocytic nevi are the major risk factors for cutaneous melanoma (CM) ( Landi et al., 2020 Landi M.T. Bishop D.T. MacGregor S. Machiela M.J. Stratigos A.J. Ghiorzo P. et al. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility. Nat Genet. 2020; 52: 494-504 Crossref PubMed Scopus (89) Google Scholar ; Whiteman and Green, 1994 Whiteman D. Green A. Melanoma and sunburn. Cancer Causes Control. 1994; 5: 564-572 Crossref PubMed Scopus (102) Google Scholar ). High-penetrance pathogenic variants associated with CM have been identified in several genes ( Abdel-Rahman et al., 2011 Abdel-Rahman M.H. Pilarski R. Cebulla C.M. Massengill J.B. Christopher B.N. Boru G. et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011; 48: 856-859 Crossref PubMed Scopus (375) Google Scholar ; Aoude et al., 2015b Aoude L.G. Pritchard A.L. Robles-Espinoza C.D. Wadt K. Harland M. Choi J. et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst. 2015; 107: dju408 Crossref PubMed Scopus (122) Google Scholar ; Horn et al., 2013 Horn S. Figl A. Rachakonda P.S. Fischer C. Sucker A. Gast A. et al. Tert promoter mutations in familial and sporadic melanoma. Science. 2013; 339: 959-961 Crossref PubMed Scopus (1329) Google Scholar ; Hussussian et al., 1994 Hussussian C.J. Struewing J.P. Goldstein A.M. Higgins P.A. Ally D.S. Sheahan M.D. et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994; 8: 15-21 Crossref PubMed Scopus (1143) Google Scholar ; Njauw et al., 2012 Njauw C.N. Kim I. Piris A. Gabree M. Taylor M. Lane A.M. et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One. 2012; 7e35295 Crossref PubMed Scopus (199) Google Scholar ; Robles-Espinoza et al., 2014 Robles-Espinoza C.D. Harland M. Ramsay A.J. Aoude L.G. Quesada V. Ding Z. et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014; 46: 478-481 Crossref PubMed Scopus (270) Google Scholar ; Zuo et al., 1996 Zuo L. Weger J. Yang Q. Goldstein A.M. Tucker M.A. Walker G.J. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996; 12: 97-99 Crossref PubMed Scopus (679) Google Scholar ). Screening studies have estimated that 2–5% of patients with CM have a predisposing variant in one of the major high-penetrance genes: CDKN2A, CDK4, BAP1, and POT1 ( Aitken et al., 1999 Aitken J. Welch J. Duffy D. Milligan A. Green A. Martin N. et al. CDKN2A variants in a population-based sample of Queensland families with melanoma. J Natl Cancer Inst. 1999; 91: 446-452 Crossref PubMed Scopus (173) Google Scholar ; Aoude et al., 2015a Aoude L.G. Gartside M. Johansson P. Palmer J.M. Symmons J. Martin N.G. et al. Prevalence of germline BAP1, CDKN2A, and CDK4 mutations in an Australian population-based sample of cutaneous melanoma cases. Twin Res Hum Genet. 2015; 18: 126-133 Crossref PubMed Scopus (24) Google Scholar ; Begg et al., 2005 Begg C.B. Orlow I. Hummer A.J. Armstrong B.K. Kricker A. Marrett L.D. et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005; 97: 1507-1515 Crossref PubMed Scopus (178) Google Scholar ; Simonin-Wilmer et al., 2022 Simonin-Wilmer I. Ossio R. Leddin E. Harland M. Pooley K.A. Martil de la Garza M.G. et al. Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort. J Med Genet. 2022; ([e-pub ahead of print]) (accessed 2 September, 2022)https://doi.org/10.1136/jmg-2022-108776 Crossref PubMed Scopus (1) Google Scholar ), leading to clusters of cases in families.