Multiple neurofibromas as the presenting feature of familial atypical multiple malignant melanoma (FAMMM) syndrome

Abstract

Mutations in the cyclin-dependent kinase inhibitor-2A (CDKN2A) gene have been associated with a number of malignancies, most notably cutaneous malignant melanoma (CMM). Mutations in this gene have also been associated with pancreatic cancer and breast cancer, as well as astrocytomas and other nervous system tumors (NST). Among NST, rare solitary internal neurofibromas have been reported, but multiple cutaneous neurofibromas have only been described in two families. In the first family, the affected individuals all carried a heterozygous G>C mutation at the splice acceptor site of intron 1 resulting in skipping of CDKN2A exon 2, while the affected individuals in the second family had a deletion that encompassed the whole CDKN2A/CDKN2B/ANRIL locus. We now report on a proposita presenting with multiple biopsy-proven cutaneous neurofibromas and a solitary spinal neurofibroma found to have a deletion of 14 nucleotides in exon 2 of CDKN2A, providing further evidence that p14, p16, and/or ANRIL are specifically involved in the pathogenesis of neurofibromas as a feature of the familial atypical multiple malignant melanoma spectrum.

An interstitial deletion within 9p21.3 and extending beyondCDKN2Apredisposes to melanoma, neural system tumours and possible haematological malignancies

“…However, in their study, they also identified a new long non-coding RNA, within the germline deletion, which they called ANRIL (Antisense Noncoding RNA in the INK4A Locus). More recently, Vanneste et al 34 reported a patient with multiple neurofibromas and a solitary spinal neurofibroma who was found to have a deletion of 14 nucleotides in exon 2 of CDKN2A, providing further evidence that p14 ARF , p16 INK4A and/or ANRIL , now designated CDKN2B-AS1, may be specifically involved in the aetiology of neurofibromas as a feature of FAMMM. However, numerous FCMM families with large deletions impacting p14 ARF do not have neural system tumours3 35 [Goldstein et al unpublished data 2015].…”

Masked hypodiploidy in anaplastic meningiomas by duplication of the original clone found in atypical meningiomas: Illustration of the evolution of genetic alterations

“…These findings raised the question whether the genes involved in these biallelic losses are tumor suppressor genes and therefore crucial for tumor progression. The deleted region at 9p21 of a size 4 Mb is already known to have the tumor recessive gene CDKN2A , which codes for two tumor suppressor genes, p14 and p16, and has been associated with development of malignant melanoma, pancreatic cancer, breast cancer, astrocytomas and nervous system tumors . Deletion of 9p21 has been seen in 17% of benign, 52% of atypical, and 74% of anaplastic meningiomas and has been considered to be associated with malignant progression and poor prognosis.…”

“…The deleted region at 9p21 of a size 4 Mb is already known to have the tumor recessive gene CDKN2A, which codes for two tumor suppressor genes, p14 and p16, and has been associated with development of malignant melanoma, pancreatic cancer, breast cancer, astrocytomas and nervous system tumors. 32 Deletion of 9p21 has been seen in 17% of benign, 52% of atypical, and 74% of anaplastic meningiomas and has been considered to be associated with malignant progression and poor prognosis. The overall survival rates at 1, 2 and 3 years for patients with anaplastic meningiomas with no.…”

Function and Clinical Implications of Long Non-Coding RNAs in Melanoma

“…Due to alternative splicing, several long, short and circular isoforms of ANRIL exist [91]. ANRIL expression has been linked to several conditions, including the risk of melanoma [92,93]. …”