Melanoma-Astrocytoma syndrome

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Melanoma-Astrocytoma syndrome

Written	2006-04	Juliette Randerson-Moor, Kairen Kukalizch, D Timothy Bishop
		Section of Epidemiology, Biostatistics, Leeds Institute of Molecular Medicine, Cancer Genetics Building, St James's Hospital, Beckett Street, LEEDS LS9 7TF, UK

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Identity

Other names Melanoma and neural system tumour syndrome
Atlas_Id 10115

Genes implicated in CDKN2A
Inheritance Autosomal dominant inheritance with high penetrance and variable expression

Clinics

Note Listed as a rare disease by the Office of Rare Disease (ORD) of the NIH. The disease affects less than 200,000 people in the USA.

Phenotype and clinics Characterised by families with cutaneous malignant melanoma (CMM) and nervous system tumours. Initially described in a family with malignant melanoma and/or cerebral astrocytoma in eight members over three generations. Astroctytomas and cutaneous malignant melanoma have been identified in a number of well defined syndromes such as neurofibromatosis, Turcot's, Lynch type II cancer, Li-Fraumeni and tuberous sclerosis. However, astrocytomas and CMM have been reported in families where the disease pattern does not fit the defined syndromes due to the absence of additional cancer types normally associated with these syndromes and mutations in genes known to predispose to these conditions (NF1, TP53, APC, MSH2 MLH1, TSC1, TSC2). In addition to astrocytoma, melanoma-astrocytoma syndrome families show other tumours such as medullablastomas, glioblastoma multiforme, ependymoma, glioma, meningioma, neuroblastomas, schwannoma and acoustic neurilemmoma. All these tumours are of neural crest, mesenchymal and/or neuroepithelium origin. These families may/may not show evidence of the dysplastic naevus syndrome (DNS) common in familial melanoma.

Neoplastic risk The neoplastic risk of melanoma-astocytoma syndrome has not been determined due to the small number of families identified. However penetrance appears consistent with that of melanoma in CDKN2A carriers. This was investigated in 2002 by the International Melanoma Genetics Consortium (GenoMEL) and is estimated to be 67% by 80 years of age.

Treatment Treatment consistent with that of familial melanoma patients Yearly surveillance of patients and first and second degree relatives.

Prognosis Melanoma has a good clinical outcome if identified at an early stage. Increasing thickness of tumour is associated with a rapid decline in life expectancy, highlighting the need for careful surveillance for precursor lesions. Prognosis of nervous system tumours is dependent on type, location and stage, however it is generally poor. Cancer Research UK reports a 5yr survival of between 10 and 15% for brain and central nervous system tumours since the mid-eighties.

Genes involved and Proteins

Note To date all published families documented with melanoma-astrocytoma syndrome are linked to the CDKN2 locus on 9p21.

Gene Name CDKN2A

Alias MTS1 (Multiple Tumour Suppressor 1) INK4A (INhibitor of Cyclin-dependent Kinase 4)

Location 9p21

Note First identified gene associated with susceptibility to cutaneous malignant melanoma (CMM) .Unique gene structure leads to encoding of two functionally distinct cell cycle proteins: p16 and p14ARF.

DNA/RNA
Note CDKN2A has a gene structure unique in the human genome. Two common exons, 2 and 3, are spliced to one of two alternative first exons, 1a or 1b, in two different reading frames. This results in two functionally unrelated protein products, p16 and p14ARF.

Description Four exons. 1a, 1b, 2 and 3.

Transcription Two splice products in alternate reading frames.
P16 consisting exons 1a, 2 and 3 with a stop codon in exon 3
p14ARF consisting exons 1b, 2 and 3 with the stop codon occurring in exon 2

Protein
Note CDKN2A encodes two functionally distinct cell cycle proteins, p16 and p14ARF, through use of an alternative first exon coupled with alternate reading frames

Description p16. Exons 1a, 2 and 3. Encodes 156 amino acids. ~15.8kD proteinp14ARF. Exons 1b, 2 and 3 in alternate reading frame. Encodes 152 amino acids. ~14kD

Expression Both p16 and p14ARF expression levels are low in normal tissue. Both proteins are upregulated in cells during in vitro senescence consistent with a role in ageing. Expression of p16 is often lost during progression of a tumour.

Localisation Following controversy concerning the cellular localisation of p16 it has recently been shown that p16 can be expressed in both the nuclear and cytoplasmic compartments and that both nuclear and cytoplasmic p16 forms complexes with CDK4 and CDK6. Cytoplasmic p16 occurs in two forms whilst nuclear p16 appears predominantly in just one.
The p14ARF protein is predominantly localised to the nucleolus but can also be detected in the nucleoplasm.

Function Cell cycle regulation. P16 inhibits the binding of CDK4 and 6 to Cyclin D preventing phosphorylation of Rb and leading to G1 arrest. P14ARF sequesters HDM2 in the nucleolus preventing the targeting of p53 for ubiquitination and thus p53 stabilisation and G2 arrest

Homology The p16 protein has functional homology with p15 the product of the CDKN2B gene (exon 2 of both genes share 90% sequence homology), also located at 9p21. In contrast p14ARF appears to be unique with no obvious homology with any known proteins.

Mutations
Note The majority of mutations identified in CDKN2A are located in exons 1a and 2. These mutations affect either p16 alone or both p16 and p14ARF and appear to be associated solely with susceptibility to melanoma. A small number of mutations have been identified in exon 1b which appear to affect p14ARF alone.

Germinal Germline mutations affecting the CDKN2A locus have been described for a number of melanoma-astrocytoma syndrome families. To date no mis-sense or nonsense mutations of the coding region have been identified. To date three families have been identified with deletions of part or all of the CDKN2 locus and a further two families have been identified with a splice acceptor mutation intron 1 of the CDKN2A gene leading to abnormal p16 and p14ARF mRNA transcripts. Concurrent loss of both p14ARF and p16 may therefore be responsible for the development of NSTs in this syndrome. In one family a deletion affecting the p14ARF-specific exon 1b was observed which was not predicted to affect p16 function suggesting abnormal p14ARF function alone may be the key factor in this family.

Somatic According to COSMIC somatic mutations of CDKN2A are found in approximately 24% of sporadic melanoma and around 22% of tumours of the central nervous system dependent on tumour type.

Bibliography

Familial cutaneous malignant melanoma and tumors of the nervous system. A hereditary cancer syndrome.

Azizi E, Friedman J, Pavlotsky F, Iscovich J, Bornstein A, Shafir R, Trau H, Brenner H, Nass D

Cancer. 1995 ; 76 (9) : 1571-1578.

PMID 8635060

Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.

Bahuau M, Vidaud D, Jenkins RB, Bièche I, Kimmel DW, Assouline B, Smith JS, Alderete B, Cayuela JM, Harpey JP, Caille B, Vidaud M

Cancer research. 1998 ; 58 (11) : 2298-2303.

PMID 9622062

Trends and socioeconomic inequalities in cancer survival in England and Wales up to 2001.

Coleman MP, Rachet B, Woods LM, Mitry E, Riga M, Cooper N, Quinn MJ, Brenner H, Estève J

British journal of cancer. 2004 ; 90 (7) : 1367-1373.

PMID 15054456

A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma.

Kaufman DK, Kimmel DW, Parisi JE, Michels VV

Neurology. 1993 ; 43 (9) : 1728-1731.

PMID 8414022

Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumor cells.

Nilsson K, Landberg G

International journal of cancer. Journal international du cancer. 2006 ; 118 (5) : 1120-1125.

PMID 16161044

CDKN2A germline splicing mutation affecting both p16(ink4) and p14(arf) RNA processing in a melanoma/neurofibroma kindred.

Petronzelli F, Sollima D, Coppola G, Martini-Neri ME, Neri G, Genuardi M

Genes, chromosomes & cancer. 2001 ; 31 (4) : 398-401.

PMID 11433531

Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred.

Prowse AH, Schultz DC, Guo S, Vanderveer L, Dangel J, Bove B, Cairns P, Daly M, Godwin AK

Journal of medical genetics. 2003 ; 40 (8) : page e102.

PMID 12920094

A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family.

Randerson-Moor JA, Harland M, Williams S, Cuthbert-Heavens D, Sheridan E, Aveyard J, Sibley K, Whitaker L, Knowles M, Bishop JN, Bishop DT

Human molecular genetics. 2001 ; 10 (1) : 55-62.

PMID 11136714

Citation

This paper should be referenced as such :

Randerson-Moor, J ; Kukalizch, K ; Bishop, DT

Melanoma-Astrocytoma syndrome

Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):288-291.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/MelanomAstrocytomID10115.html

External links

OMIM 155755

Orphanet Astrocytoma

MeSH D001254

MedGen D001254

UMLS C0004114

Other database International Melanoma Genetics Consortium

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

Other names	Melanoma and neural system tumour syndrome
Atlas_Id	10115
Genes implicated in	CDKN2A
Inheritance	Autosomal dominant inheritance with high penetrance and variable expression

Note	Listed as a rare disease by the Office of Rare Disease (ORD) of the NIH. The disease affects less than 200,000 people in the USA.
Phenotype and clinics	Characterised by families with cutaneous malignant melanoma (CMM) and nervous system tumours. Initially described in a family with malignant melanoma and/or cerebral astrocytoma in eight members over three generations. Astroctytomas and cutaneous malignant melanoma have been identified in a number of well defined syndromes such as neurofibromatosis, Turcot's, Lynch type II cancer, Li-Fraumeni and tuberous sclerosis. However, astrocytomas and CMM have been reported in families where the disease pattern does not fit the defined syndromes due to the absence of additional cancer types normally associated with these syndromes and mutations in genes known to predispose to these conditions (NF1, TP53, APC, MSH2 MLH1, TSC1, TSC2). In addition to astrocytoma, melanoma-astrocytoma syndrome families show other tumours such as medullablastomas, glioblastoma multiforme, ependymoma, glioma, meningioma, neuroblastomas, schwannoma and acoustic neurilemmoma. All these tumours are of neural crest, mesenchymal and/or neuroepithelium origin. These families may/may not show evidence of the dysplastic naevus syndrome (DNS) common in familial melanoma.
Neoplastic risk	The neoplastic risk of melanoma-astocytoma syndrome has not been determined due to the small number of families identified. However penetrance appears consistent with that of melanoma in CDKN2A carriers. This was investigated in 2002 by the International Melanoma Genetics Consortium (GenoMEL) and is estimated to be 67% by 80 years of age.
Treatment	Treatment consistent with that of familial melanoma patients Yearly surveillance of patients and first and second degree relatives.
Prognosis	Melanoma has a good clinical outcome if identified at an early stage. Increasing thickness of tumour is associated with a rapid decline in life expectancy, highlighting the need for careful surveillance for precursor lesions. Prognosis of nervous system tumours is dependent on type, location and stage, however it is generally poor. Cancer Research UK reports a 5yr survival of between 10 and 15% for brain and central nervous system tumours since the mid-eighties.

Gene Name	CDKN2A
Alias	MTS1 (Multiple Tumour Suppressor 1) INK4A (INhibitor of Cyclin-dependent Kinase 4)
Location	9p21
Note	First identified gene associated with susceptibility to cutaneous malignant melanoma (CMM) .Unique gene structure leads to encoding of two functionally distinct cell cycle proteins: p16 and p14ARF.

DNA/RNA
Note	CDKN2A has a gene structure unique in the human genome. Two common exons, 2 and 3, are spliced to one of two alternative first exons, 1a or 1b, in two different reading frames. This results in two functionally unrelated protein products, p16 and p14ARF.


Description	Four exons. 1a, 1b, 2 and 3.
Transcription	Two splice products in alternate reading frames. P16 consisting exons 1a, 2 and 3 with a stop codon in exon 3 p14ARF consisting exons 1b, 2 and 3 with the stop codon occurring in exon 2

Protein
Note	CDKN2A encodes two functionally distinct cell cycle proteins, p16 and p14ARF, through use of an alternative first exon coupled with alternate reading frames


Description	p16. Exons 1a, 2 and 3. Encodes 156 amino acids. ~15.8kD proteinp14ARF. Exons 1b, 2 and 3 in alternate reading frame. Encodes 152 amino acids. ~14kD
Expression	Both p16 and p14ARF expression levels are low in normal tissue. Both proteins are upregulated in cells during in vitro senescence consistent with a role in ageing. Expression of p16 is often lost during progression of a tumour.
Localisation	Following controversy concerning the cellular localisation of p16 it has recently been shown that p16 can be expressed in both the nuclear and cytoplasmic compartments and that both nuclear and cytoplasmic p16 forms complexes with CDK4 and CDK6. Cytoplasmic p16 occurs in two forms whilst nuclear p16 appears predominantly in just one. The p14ARF protein is predominantly localised to the nucleolus but can also be detected in the nucleoplasm.
Function	Cell cycle regulation. P16 inhibits the binding of CDK4 and 6 to Cyclin D preventing phosphorylation of Rb and leading to G1 arrest. P14ARF sequesters HDM2 in the nucleolus preventing the targeting of p53 for ubiquitination and thus p53 stabilisation and G2 arrest
Homology	The p16 protein has functional homology with p15 the product of the CDKN2B gene (exon 2 of both genes share 90% sequence homology), also located at 9p21. In contrast p14ARF appears to be unique with no obvious homology with any known proteins.

Mutations
Note	The majority of mutations identified in CDKN2A are located in exons 1a and 2. These mutations affect either p16 alone or both p16 and p14ARF and appear to be associated solely with susceptibility to melanoma. A small number of mutations have been identified in exon 1b which appear to affect p14ARF alone.


Germinal	Germline mutations affecting the CDKN2A locus have been described for a number of melanoma-astrocytoma syndrome families. To date no mis-sense or nonsense mutations of the coding region have been identified. To date three families have been identified with deletions of part or all of the CDKN2 locus and a further two families have been identified with a splice acceptor mutation intron 1 of the CDKN2A gene leading to abnormal p16 and p14ARF mRNA transcripts. Concurrent loss of both p14ARF and p16 may therefore be responsible for the development of NSTs in this syndrome. In one family a deletion affecting the p14ARF-specific exon 1b was observed which was not predicted to affect p16 function suggesting abnormal p14ARF function alone may be the key factor in this family.
Somatic	According to COSMIC somatic mutations of CDKN2A are found in approximately 24% of sporadic melanoma and around 22% of tumours of the central nervous system dependent on tumour type.

OMIM	155755
Orphanet	Astrocytoma
MeSH	D001254
MedGen	D001254
UMLS	C0004114
Other database	International Melanoma Genetics Consortium

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed