Familial melanoma
Population-based studies have shown that 1% to 13% of patients with melanoma report the occurrence of the same disease in at least one first-degree relative. Cancer registry studies have shown that the relative risk to offspring of an affected parent is in the order of around 2, the risk to a sibling is around 3 and the relative risk where both a parent and a sibling are affected is around 9 [1]. The increased risk in relatives of melanoma patients probably reflects both shared genes and shared environmental exposures.
In some melanoma families, susceptibility is consistent with autosomal dominant inheritance of a single major gene (see next paragraph entitled "High risk/familial melanoma genes"). However, this does not appear to account for the bulk of familial clustering of melanoma, as demonstrated by the fact that segregation analysis in a large population-based sample of families failed to show a single gene being responsible for melanoma transmission [2]. Therefore, the majority of familial melanomas are likely due to a polygenic mode of inheritance.
The genetic variation, which is associated with melanoma risk is established to be related to the inheritance of variation in both high risk genes (such as CDKN2A [3]) and lower risk genes such as the gene coding for the melanocortin 1 receptor MC1R [4]. In understanding the impact of these genes, they are usually grouped therefore into genes associated with “high risk or familial melanoma” or those associated with lower risk clustering. Although this is a “false” distinction as risk associated with inherited genetic variation is likely to represent a continuum, the distinction does make the discussion easier to manage.
High risk/familial melanoma genes
The best understood melanoma susceptibility gene is CDKN2A on chromosome 9. Hereditary mutations in this gene underlie susceptibility to melanoma in 40% of families with 3 or more cases of melanoma [5]. The probability of identifying a mutation in a melanoma case from a family varies by continent but is generally increased if one of the cases has multiple primaries, or if there is onset at or under the age of 40 years [5]. In most populations there is also a strong relationship between gene mutation status and pancreatic cancer [6].
Specialist genetic risk and dermatological counselling is important for patients with 3 or more melanoma cases in the family, but there is debatable value in gene testing currently [7]. In countries with lower background population incidence rates, specialist counselling may be appropriate for 2 cases families. The relative lack of information to predict pancreatic cancer risk in particular families and a lack of proven screening for pancreatic cancer limit the value of testing for CDKN2A mutation positive families. For the majority of families (particularly in high incidence areas) there is no detectable mutation and there must be other hereditary mutations yet to be discovered. In these families therefore gene testing is unhelpful.
The CDKN2A locus is biologically of note as it codes for two alternatively spliced products: p16 and p14ARF. P16 binds to CDK4 and is a cell cycle inhibitor [3] having effects on cellular senescence. p16 is established specifically to play a role in the induction of senescence of melanocytes [8]. p14ARF is also a tumor suppressor gene, and mutations at the CDKN2A locus may lead to melanoma susceptibility if they impact on p16 alone, p14ARF alone [9,10], or both p16 and p14ARF.
Hereditary mutations are seen at this locus in less than 2% of apparently sporadic melanoma patients [11], which is in unselected melanoma patients.
Very rare families exist (2% of families with detectable mutations) who have hereditary mutations in the CDK4 gene which code for the p16 binding site [12,13].
The co-existence of melanoma and atypical nevi within families has been described and the syndrome has also been named B-K mole syndrome [14], the Dysplastic Nevus Syndrome or the Familial Atypical Multiple Mole and Melanoma (FAMMM) [15].
The lifetime risk (i.e. penetrance) of melanoma in CDKN2A mutation carriers is high, but variable, ranging from 58% in Europe to 91% in Australia by the age of 80 years [16], which underscores the importance of the environment (geographical location) even in familial melanoma.
Linkage studies suggest that approximately half of the melanoma families link to 9p21, although a CDKN2A mutation could not be found in all families that link to 9p21. The 9p21 locus is therefore supposed to harbour a second melanoma susceptibility gene, which is supported by several loss of heterozygosity (LOH) studies in melanoma patient material.
There is published evidence of familial melanoma genes at 1p36 [17] and 1p22 [18] but no causal genes have so far been identified.
Other familial cancer susceptibility genes
Cancer susceptibility syndromes are characterized by the genetic inheritance of a high likelihood of developing a variety of tumors. Some of these syndromes, such as Li-Fraumeni syndrome, Xeroderma pigmentosum, and Hereditary retinoblastoma confer a significant risk of melanoma development. For more details, see the "Risk factors" section (http://www.mmmp.org/MMMP/import.mmmp?page=riskfactors.mmmp).
Lower risk susceptibility genes
The most well understood common melanoma susceptibility gene to date is the MC1R gene which is established as a determinant of susceptible phenotypes such as red hair [19], sun sensitivity in the absence of red hair [20], and freckles [21]. The gene is also a melanoma susceptibility gene [22].
Other pigmentary genes (tyrosinase, TYR; TYR related protein 1, TYRP1; agouti signalling protein, ASIP) have also more recently been identified as melanoma susceptibility genes [23].
Additional candidate polymorphisms for melanoma susceptibility are listed in the MMMP Biocard #32 entitled: Gene Polymorphisms and Melanoma Risk.