Review on Familial melanoma, with data on clinics, and the genes involved

Gruis, NA

Snoo, de FA

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Cancer Prone Disease Section 
Mini Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(3)  
 
266 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
OPEN ACCESS JOURNAL AT INIST-CNRS 
Familial melanoma 
Femke de Snoo, Nelleke Gruis 
Dept Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands (FAS, 
NAG) 
 
Published in Atlas Database: April 2005 
Online updated version: http://AtlasGeneticsOncology.org/Kprones/FamilialMelanomID10088.html 
DOI: 10.4267/2042/38231 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Alias 
Familial atypical multiple mole melanoma syndrome 
(FAMMM). 
Dysplastic Nevus Syndrome (DNS). 
Note 
Used to also be known by B-K mole syndrome. 
Inheritance 
Autosomal dominant with high penetrance and variable 
expression. 
Clinics 
Note 
Familial melanoma is a heterogenous entity including 
several clinical variants. 
Phenotype and clinics 
Melanoma is hereditary in approximately 10% of the 
cases. The definition of hereditary melanoma is now 
described as a family in which either 2 first-degree 
relatives are diagnosed with melanoma or families with
3 melanoma patients (irrespective of degree of 
relationship). The co-existence of melanoma and 
atypical nevi within families has been described anthe 
syndrome has therefore been named Familial Atypical 
Multiple Mole-Melanoma (FAMMM). 
Initially it was assumed that a simple dominant factor 
would be responsible for both melanoma and atypical 
nevi. However, after the cloning of the first melanoma 
susceptibility gene, genotype/phenotype correlation 
studies in mutation positive families soon revealed the 
complexities of the FAMMM syndrome. It appeared  
that atypical nevi do not neatly segregate with the
mutation; this means that also non-carriers could have a 
florid nevus phenotype. 
Neoplastic risk 
The penetrance of melanoma in CDKN2A mutation 
carriers has recently been investigated by the 
International Melanoma Genetics Consortium, in which 
research groups from all over the world participate and 
is estimated to be 67% by the age of 80 years. This
same study also showed the penetrance figures in 
hereditary melanoma to be different depending on 
geographic location. These differences between 
geographic locations were proportionate to the 
differences seen in sporadic melanoma, with the 
penetrance in Australia, USA and Sweden being 3.74 
times higher than in Western Europe. 
Risk of several other tumors has been reported but 
remains to be confirmed. However, the evidence for an 
increased risk of pancreatic carcinoma in CDKN2A 
mutation positive families is very strong. 
Treatment 
Yearly surveillance of melanoma patients and their 
first- and second-degree relatives from age 12 onwards. 
Prognosis 
If melanoma is identified at an early stage the disease 
has a good clinical outcome. On the other hand, life 
expectancy figures drop quickly with an increasing 
thickness of the tumour (approximately 55% 5 year 
survival with thickness over 1.5 mm). Early recognition 
of melanoma, or even better so, early recognition of 
precursor lesions of melanoma by skin screening for 
those at risk is therefore of utmost importance. 
Familial melanoma Snoo de FA, Gruis NA 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(3)  
 
267 
 
Pigmented lesions on the back of a patient from a melanoma family, displaying many common and atypical nevi. 
 
Genes involved and proteins 
Note 
Linkage studies suggest that approximately half of the 
melanoma families link to 9p21. Not in all families that 
link to 9p21, a CDKN2A mutation could be found. The 
9p21 locus is therefore thought to harbour a second 
melanoma susceptibility gene, which is supported by 
several LOH studies in melanoma patient material. 
Recently however, 2 mutations have been described in 
the non-coding region of CDKN2A. Both the mutation 
in the 5' untranslated region of Canadian melanoma 
families as well as the deep intronic mutation in UK
families turn out to be the most common CDKN2A 
mutations in those populations. Intronic mutations 
might explain a large part of the 9p21 linked families, 
in which no exonic CDKN2A mutation has been found. 
The joint effort of the International Melanoma Genetics 
Consortium to search for more melanoma susceptibility 
genes has recently led to convincing evidence for an 
additional melanoma susceptibility locus on 
chromosome 1p22. 
CDKN2A 
Location 
9p21 
Note 
Is the first identified melanoma susceptibility gene. By 
using different first exons, exon 1a and 1ß respectiv ly, 
CDKN2A encodes for 2 proteins: p16 and p14ARF. 
 
 
DNA/RNA 
By using different first exons, exon 1a and 1b  
respectively, CDKN2A encodes for 2 proteins: p16 and
p14ARF, usually affected together. However, families 
displaying mutation affecting merely one gene indicate 
both p16 and p14ARF to be melanoma susceptibility 
genes by themselves. 
Description: p16: 3 exons (1a, 2 and 3) encoding 156 
aminoacids. p14ARF: 3 exons (1b, 2 and 3) encoding 
132 aminoacids. 
Protein 
Note: By using different first exons, exon 1a and 1ß 
respectively, CDKN2A encodes for 2 proteins: p16 and
p14ARF. 
Description: p16: 156 aminoacids, encoding a protein 
of 15.8 kDa. p14ARF: 132 aminoacids, encoding a 
protein of approximately 14 kDa. 
Expression: The normal levels of p16 and p14ARF 
expression are low in tissues and primary cells and are 
upregulated with in vitro senescence, ageing, and 
illegitimate oncogene activation. Loss of p16 
expression is observed during tumor progression. 
Localisation: Interpretation of p16 stains by 
immunohistochemistry is controversial. Some consider 
both nuclear and cytoplasmic staining to be specific, 
whereas others consider cytoplasmic staining to be a 
confounding background and see only nuclear staining 
as relevant for p16 function. p16 is a small protein hat 
might freely diffuse in and out of the nucleus and 
should be available to interact with its partners in both 
cellular compartments.  
Familial melanoma Snoo de FA, Gruis NA 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2005; 9(3)  
 
268 
 
The CDKN2A locus and its transcripts, p16 and p14ARF, generated by alternative splicing. Boxes indicate exons, and coloured sections 
the protein coding regions within them. 
 
Some immunofluorescence studies on inactivating 
mutations within CDKN2A have shown that they lead 
to accumulation or mislocalization of the mutant forms 
of p16 preferentially in one or other compartment. 
P14ARF is localized predominantly in the nucleolus 
but is also present in the nucleoplasm. 
Function: Cell cycle regulation. 
Mutations 
CDKN2A mutations in FAMMM families are scattered 
throughout exons 1a and exon 2. The mutation 
detection rate is assumed to be somewhere between 
1.5-50%. This figure varies greatly among different 
studies, depending on family and population selection. 
The CDKN2A mutation detection rate rises with 
increasing number of affected cases in the family. Most 
mutations are missense mutations. Among the 
CDKN2A mutations that have been published, several 
are founder mutations. 
Somatic: In 17 to 20% of sporadic melanomas a 
somatic mutation is found. 
CDK4 
Location 
12q13 
Note 
Candidate gene searches have led to the finding of a 
second melanoma susceptibility gene. 
DNA/RNA 
All CDK4 mutations found so far are located in exon 2 
and affect codon 24, which is directly involved in the 
binding of p16INK4A. However, since CDK4 has only 
been found to be affected in 3 families worldwide, its 
role in familial melanoma does not seem to be of great 
impact. 
Description: CDK4 gene contains 8 exons (1441 bp) 
and spans 5 kb. 
Protein 
Description: CDK4 consists of 8 exons, of which the
first is noncoding, within a 5 kb segment, encoding a 
protein of 34 kDa. 
Function: Cell cycle regulation. 
Mutations 
All CDK4 mutations found so far are located in exon 2 
and affect codon 24. 
References 
Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop 
JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, 
Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, 
Mantelli M, Nancarrow D, Platz A, Tucker MA. Geographical 
variation in the penetrance of CDKN2A mutations for 
melanoma. J Natl Cancer Inst. 2002 Jun 19;94(12):894-903 
de Snoo FA, Bergman W, Gruis NA. Familial melanoma: a 
complex disorder leading to controversy on DNA testing. Fam 
Cancer. 2003;2(2):109-16 
Ghiorzo P, Villaggio B, Sementa AR, Hansson J, Platz A, 
Nicoló G, Spina B, Canepa M, Palmer JM, Hayward NK, 
Bianchi-Scarrà G. Expression and localization of mutant p16 
proteins in melanocytic lesions from familial melanoma 
patients. Hum Pathol. 2004 Jan;35(1):25-33 
de Snoo FA, Hayward NK. Cutaneous melanoma susceptibility 
and progression genes. Cancer Lett. 2005 Dec 18;230(2):153-
86 
This article should be referenced as such: 
Snoo de FA, Gruis NA. Familial melanoma. Atlas Genet 
Cytogenet Oncol Haematol. 2005; 9(3):266-268. 


Familial melanoma

http://documents.irevues.inist.fr/bitstream/2042/38231/3/04-2005-FamilialMelanomID10088.pdf

Familial melanoma

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