title: Homozygous germline mutation of CDKN2A/p16 and glucose-6-phosphate dehydrogenase deficiency in a multiple melanoma case.
abstract: CDKN2A is regarded as a major melanoma susceptibility gene. A 19 bp deletion has been detected within Dutch families with familial atypical multiple mole-melanoma syndrome. Genetic analysis revealed two individuals with germline deletions in both copies of CDKN2A. One of them did not develop atypical naevi or melanoma, but died of adenocarcinoma at the age of 54 years. This report describes the results of the investigation of the second p16-null individual, who was also found to have glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and who has developed many atypical naevi and seven melanomas. Using electron microscopic techniques, striking alterations in melanosomal structures and deviations in their sulphur, iron and calcium composition indicating a strong preference for phaeomelanogenesis and increased oxidative stress were found in the naevus cells of the patient. Using an in vitro model, we demonstrated that leaking melanin precursors may strongly enhance oxidative DNA damage through iron release from ferritin. We conclude that the homozygous p16 deletion is not sufficient for the development of a dysplastic naevus phenotype and melanoma. However, when an additional modifying factor, such as G-6-PD deficiency, increases the level of oxidative DNA damage in melanin-producing cells, the risk of developing atypical naevi and their malignant transformation may increase significantly.
authors.affiliation: Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands. S. Pavel@lumc.nl
authors.forename: Stan
authors.initials: S
authors.lastname: Pavel
authors.forename: Nico P
authors.initials: NP
authors.lastname: Smit
authors.forename: Hans
authors.initials: H
authors.lastname: van der Meulen
authors.forename: Ria M
authors.initials: RM
authors.lastname: Kolb
authors.forename: Anton J
authors.initials: AJ
authors.lastname: de Groot
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.forename: Nelleke A
authors.initials: NA
authors.lastname: Gruis
authors.forename: Wilma
authors.initials: W
authors.lastname: Bergman
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D002118:Calcium / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D005293:Ferritins / Q000378:metabolism; D017353:Gene Deletion; D019942:Genes, p16; D018095:Germ-Line Mutation; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008854:Microscopy, Electron; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D012867:Skin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014965:X-Rays
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D005293:Ferritins; D007501:Iron; D005954:Glucosephosphate Dehydrogenase; D003849:Deoxyguanosine; D010100:Oxygen; D002118:Calcium