FaCD Online Syndrome Fact Sheet
Last updated: 05 Apr 2008
Name: Familial Malignant Melanoma and Tumors of the Nervous System
Synonym: Familial Melanoma and Astrocytoma
Mode of Inheritance: AD
Genes
CDKN2A/p14(ARF), mapped to 9p21
CDKN2A/p16(INK4), mapped to 9p21
cgd(9p21), mapped to 9p21
p15(INK4)/CDKN2B, mapped to 9p21
p19(INK4D)/CDKN2D, mapped to 9p13
Tumor featuresastrocytoma
melanoma, cutaneous
meningioma
neurofibroma of the skin
pancreatic adenocarcinoma
primitive neuroectodermal tumor (PNET)
schwannoma (neurilemmoma), peripheral nerve
vestibular schwannoma
Tumor features (possible)endometrial cancer
ependymoma
medulloblastoma
pituitary adenoma
thyroid adenoma
Non-tumor featurescafé au lait spots
dysplastic/atypical nevi
hairy pigmented nevi
Comment
A three generation family with malignant melanoma and astrocytoma was reported by Kaufman et al.[1]. Dysplastic nevi were absent. In general a wide range of central nervous system tumors may be found in melanoma patients and their relatives. Bahuau et al.[2] also reported melanoma and astrocytoma in successive generations. However in that particular family other nervous system tumors developed as well: schwannoma, neurofibroma and meningioma. Also, dysplastic nevi, hairy nevi and cafe au lait spots were observed. This family resembled a combination of NF1 and FAMMM. Azizi et al.[3] studied the occurrence of nervous system tumors in a series of 904 melanoma patients and their families and observed an association of melanoma and nervous system tumor clustering (in addition to the above mentioned tumors including medulloblastoma and ependymoma) in a subset of 15 families.
Bahuau et al.[4] detected a large germline mutation, a contiguous gene defect in 9p21, encompassing the p16 (CDKN2A), p19 and p15(INK4) genes in the family previously reported by them[2] and a smaller defect encompassing p16 and p19, but not p15 in the family reported by Kaufman et al.[1]. The larger defect was associated with a wider tumor spectrum. CDKN2A encodes two proteins through alternative splicing: p16 and p14.
Petronzelli et al detected a CDKN2A deletion affecting both p16(ink4) and p14(arf) proteins in a a family with melanomas, neurofibromas, and multiple dysplastic nevi[5].
Randerson-Moore at reported a germline deletion of only the p14(ARF) encoding exon 1beta of CDKN2A in a proband with melanomas, dysplastic naevi, thyroid adenomata (age of 52 years), a uterine adenocarcinoma (age of 53 years), chest wall neurilemmoma (age of 54) years) and pituitary macroadenoma (age of 70 years) and melanomas in her relatives[6]. They therefore suggested that loss of p14 alone is sufficient to cause this type of syndrome.
In the GenoMEL series , neural tumor risk was only marginally associated with p14 affecting CDKN2A mutations, however, power to detect these associations was low[7].
References
[1] Kaufman DK, Kimmel DW, Parisi JE, Michels VV. A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma. Neurology 1993; 43:1728-1731.
[2] Bahuau M, Vidaud D, Kujas M, Palangie A, Assouline B, Chaignaud-Lebreton M, Prieur M, Vidaud M, Harpey JP, Lafourcade J, Caille B. Familial aggregation of malignant melanoma/dysplastic naevi and tumours of the nervous system: An original syndrome of tumour proneness. Ann Genet Paris 40[2], 78-91. 1997.
[3] Azizi E, Friedman J, Pavlotsky F, Iscovich J, Bornstein A, Shafir R, Trau H, Brenner H, Nass D. Familial cutaneous malignant melanoma and tumors of the nervous system: A herediatry cancer syndrome. Cancer 1995; 76:1571-1578.
[4] Bahuau M, Vidaud D, Jenkins RB, Bieche I, Kimmel DW, Assouline B, Smith JS, Alderete B, Cayuela JM, Harpey JP, Caille B, Vidaud M. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res 58[11], 2298-2303. 1998.
[5] Petronzelli F, Sollima D, Coppola G, Martini-Neri ME, Neri G, Genuardi M. CDKN2A germline splicing mutation affecting both p16(ink4) and p14(arf) RNA processing in a melanoma/neurofibroma kindred. Genes, chromosomes & cancer 2001; 31(4):398-401.
[6] Randerson-Moor JA, Harland M, Williams S, Cuthbert-Heavens D, Sheridan E, Aveyard J, Sibley K, Whitaker L, Knowles M, Bishop JN, Bishop DT. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Human molecular genetics 2001; 10(1):55-62.
[7] Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, Azizi E, Bianchi-Scarra G, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon Albright LA, Demenais F, Elder DE, Ghiorzo P, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, Mackie RM, Magnusson V, Mann GJ, Niendorf K, Newton Bishop J, Palmer JM, Puig S, Puig-Butille JA, de Snoo FA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E, . High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer research 2006; 66(20):9818-28.
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