Melanoma-Astrocytoma Syndrome

A number sign (#) is used with this entry because of evidence that the melanoma-astrocytoma syndrome is caused by mutation in the CDKN2A gene (600160) on chromosome 9p21.

Clinical Features

Kaufman et al. (1993) described a family in which cutaneous malignant melanoma (CMM) or cerebral astrocytoma, or both, developed in 8 members over 3 generations. In 2 patients with both malignant melanoma and astrocytoma, the brain tumor followed the diagnosis of melanoma by a period of 2 and 10 years, respectively, and was the primary cause of morbidity and mortality. Kaufman et al. (1993) suggested that this may be a newly described genetic disorder. There were instances of male-to-male transmission.

Azizi et al. (1995) specifically examined the question whether tumors of the nervous system have an increased likelihood in families of patients with cutaneous melanoma. They examined the occurrence of nervous system tumors as second cancers in a series of 904 patients with cutaneous melanoma and/or their family members. In 15 families with 17 members with cutaneous melanoma, one or more additional relatives had tumors of the nervous system, including astrocytoma, medulloblastoma, glioblastoma multiforme, ependymoma, glioma, meningioma, and acoustic neurilemmoma. Another subgroup of 10 patients with cutaneous melanoma had either a meningioma (n = 9) or acoustic neurilemmoma (n = 1) as a second tumor. In 20 of 25 of the cutaneous melanoma patients in this series and in additional first-degree relatives of 9 of 11 of the affected families, atypical melanocytic nevi had occurred as are found in the familial atypical multiple mole-melanoma syndrome (155600).

Bahuau et al. (1997) also described a family with a cancer syndrome of CMM and nervous system tumors. Pathologic findings of CMM, dysplastic nevi, astrocytoma, neurofibroma, schwannoma, and meningioma indicate a strong overlap with the NF1 (162200) tumor spectrum. However, mutation screening of the NF1 gene (613113) and segregation analyses excluded allelism of this familial syndrome with NF1.

Cytogenetics

The families reported by Bahuau et al. (1997) and Kaufman et al. (1993) were the basis of a study by Bahuau et al. (1998) which showed that both families were linked to deletions of 9p. In the family of Bahuau et al. (1997), a large germline deletion ablated the entire p16, p19, and p15 gene cluster, whereas a more circumscribed molecular lesion disrupting p16 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome family.

Baker et al. (2016) and Vengoechea and Tallo (2017) each reported families with deletions encompassing the CDKN2A and CDKN2B (600431) genes as well as the MTAP gene (156540). Both families had nerve sheath tumors, gliomas, and melanomas. These phenotypic features extended beyond the melanoma-astrocytoma syndrome seen with isolated deletion of CDKN2A. Vengoechea and Tallo (2017) suggested that comprehensive chromosome microarray analysis is needed in patients where full deletion of CDKN2A is identified, to determine the extent of the deletion and so whether the patient and family members are at risk of additional cancers. The family described by Vengoechea and Tallo (2017) had a significant burden of breast cancer, the relationship of which to the 9p21.3 deletion was unclear.

Molecular Genetics

In a family with melanoma-astrocytoma syndrome, Tachibana et al. (2000) identified a heterozygous germline deletion of the p16/CDKN2A gene.

Randerson-Moor et al. (2001) described a family characterized by multiple melanoma and neural cell tumors segregating with a germline deletion of the p14(ARF)-specific exon 1-beta of the CDKN2A gene (600160.0012). The deletion did not affect the coding or minimal promoter sequences of either the CDKN2A or CDKN2B genes. The authors hypothesized that the phenotype was due either to loss of p14(ARF) function, rather than contiguous loss of both CDKN2A and CDKN2B; or to disruption of expression of p16.

Using long-range PCR and nucleotide sequencing, Pasmant et al. (2007) characterized the exact endpoints of the deletion in the French family with melanoma-NST syndrome, originally described by Bahuau et al. (1997), and found that the deletion was exactly 403,231 bp long and encompassed the p15/CDKN2B, p16/CDKN2A, and p14/ARF genes. Pasmant et al. (2007) identified a large antisense noncoding RNA, which they designated ANRIL (CDKN2BAS; 613149), within the 403-kb germline deletion. Reanalysis of the large 9p21 germline deletions previously reported in families with hereditary melanoma with or without NST revealed that ANRIL exon 1 was deleted in 2 U.K. families, 1 without NSTs ('family A', previously reported by Mistry et al., 2005) and 1 with NSTs ('family B,' originally described by Randerson-Moor et al., 2001), whereas the ANRIL promoter was clearly deleted in 1 U.S. family without NSTs ('family E,' originally reported by Laud et al., 2006) and probably deleted in another U.S. family with NSTs ('family D,' originally studied by Kaufman et al., 1993). Pasmant et al. (2007) suggested that ANRIL might be involved in melanoma-NST syndrome families and in melanoma-prone families with no identified p16/CDKN2A mutations as well as in somatic tumors.

Exclusion Studies

Liu et al. (1995) analyzed the family reported by Kaufman et al. (1993) for germline mutations in the p15 gene (CDKN2B; 600431), the p16 gene (CDKN2A; 600160), including exon 1-beta, and the CDK4 gene (123829); no mutations were found.