title: A large de novo 9p21.3 deletion in a girl affected by astrocytoma and multiple melanoma.
abstract: BACKGROUND
  Association of melanoma, neural system tumors and germ line mutations at the 9p21 region in the CDKN2A, CDKN2B and CDKN2BAS genes has been reported in a small number of families worldwide and described as a discrete syndrome in melanoma families registered as a rare disease, the melanoma-astrocytoma syndrome.
  
  
  METHODS
  We here studied two young patients developing melanoma after radiotherapy for astrocytoma, both reporting lack of family history for melanoma or neural system tumors at genetic counselling. Patient A is a girl treated for anaplastic astrocytoma at 10 years and for multiple melanomas on the scalp associated to dysplastic nevi two years later. Her monozygotic twin sister carried dysplastic nevi and a slow growing, untreated cerebral lesion. Direct sequencing analysis showed no alterations in melanoma susceptibility genes including CDKN2A, CDK4, MC1R and MITF or in TP53. By microsatellite analysis, multiplex ligation-dependent probe amplification, and array comparative genomic hybridization a deletion including the CDKN2A, CDKN2B and CDKN2BAS gene cluster was detected in both twin sisters, encompassing a large region at 9p21.3 and occurring de novo after the loss of one paternal allele.Patient B is a boy of 7 years when treated for astrocytoma then developing melanoma associated to congenital nevi on the head 10 years later: sequencing and multiplex ligation-dependent probe amplification revealed a normal profile of the CDKN2A/CDKN2B/CDKN2BAS region. Array comparative genomic hybridization confirmed the absence of deletions at 9p21.3 and failed to reveal known pathogenic copy number variations.
  
  
  CONCLUSIONS
  By comparison with the other germ line deletions at the CDKN2A, CDKN2B and CDKN2BAS gene cluster reported in melanoma susceptible families, the deletion detected in the two sisters is peculiar for its de novo origin and for its extension, as it represents the largest constitutive deletion at 9p21.3 region identified so far.In addition, the two studied cases add to other evidence indicating association of melanoma with exposure to ionizing radiation and with second neoplasm after childhood cancer. Melanoma should be considered in the monitoring of pigmented lesions in young cancer patients.
authors.forename: Simona
authors.initials: S
authors.lastname: Frigerio
authors.forename: Vittoria
authors.initials: V
authors.lastname: Disciglio
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.forename: Gabriella
authors.initials: G
authors.lastname: Della Torre
authors.forename: Andrea
authors.initials: A
authors.lastname: Maurichi
authors.forename: Paola
authors.initials: P
authors.lastname: Collini
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
authors.forename: Giacomo
authors.initials: G
authors.lastname: Gotti
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferrari
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Maura
authors.initials: M
authors.lastname: Massimino
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, Milan 20133, Italy. monica.rodolfo@istitutotumori.mi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Rodolfo
mesh_terms: D000293:Adolescent; D000483:Alleles; D001254:Astrocytoma / Q000175:diagnosis* / Q000235:genetics*; D001706:Biopsy; D002648:Child; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D055028:Comparative Genomic Hybridization; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D009423:Nervous System Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D017384:Sequence Deletion; D000096142:Cutaneous Malignant Melanoma