A large de novo 9p21.3 deletion in a girl affected by astrocytoma and multiple melanoma
1 Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, Milan 20133, Italy
2 Department of Experimental Oncology and Molecular Medicine, Functional Genomics and Bioinformatics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, Milan 20133, Italy
3 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
4 Unit of Melanoma and Sarcoma, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
5 Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
6 Current address: Department of Medical Science, University of Turin, Turin, Italy
7 Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
BMC Medical Genetics 2014, 15:59 doi:10.1186/1471-2350-15-59Published: 17 May 2014
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.
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.
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.