Data for this review were identified using Medline and the Public Library of Medicine using the following keywords and phrases: “familial melanoma”, “melanoma genetics”, “polymorphism”, “epidemiology of melanoma”, “melanocytic naevi”, and “CDKN2A”. Only papers published in English up until June 2006, were reviewed. Papers reporting data from larger scale collaborative studies of familial melanoma and population-based studies on risk were preferentially reported.
ReviewManagement of familial melanoma
Introduction
Clustering of melanoma in families has implications of increased risk for the melanoma patient and for their family. We review the evidence for the genetic and environmental causes of that increased risk. We also review the data on the phenotypic markers of increased risk and the evidence for advice given to families at high risk of melanoma designed to moderate that risk.
Section snippets
Genetic determinants of melanoma
In family studies, melanoma is reported as a relatively infrequent component of family cancer syndromes such as familial retinoblastoma,1 in male carriers of BRCA2 mutations,2 and in Li-Fraumeni syndrome.3 Some families have a predominance of melanoma compared with 1 in 30 Australians who will develop melanoma in their lifetime. These rare families have been described in Europe, Australia, and in the Americas. In many of these families there are multiple cases of melanoma,4 and patients may
Genetic predisposition to melanoma within populations
The evidence for the extent to which melanoma is familial in populations comes from genetic epidemiology studies. Increased risk within families does not define to what degree melanoma is caused by genetics or environment, because families commonly share both factors. Moreover, the likelihood is that clustering of the malignancy in families indicates a combined effect of genetic and environmental factors. A North American study of a clinic-based series of patients with melanoma reported an
Low-penetrance susceptibility genes
The susceptibility genes identified in families with melanoma explain a very small proportion of melanoma in the population. A recent report from the multicentre GEM study showed that inherited mutations in the CDKN2A gene were only found in 1–2% of cases, even in those who had developed multiple primary tumours.26 The data on risk to relatives of patients provides evidence for increased risk to relatives in populations, which cannot therefore be explained by the CDKN2A mutation alone. Some of
Environmental effects on susceptibility
Melanoma is mainly a tumour of fair-skinned people. Incidence varies with latitude, so that the highest incidence occurs where white-skinned people live at low latitudes, such as in Australia.40 This strong evidence supports the view that sun exposure is causal for melanoma. The type of sun exposure that is important remains controversial, but the most significant pattern of sun exposure is intermittent intense sun exposure, recently published in a meta-analysis of the largest reported studies.
Naevi and melanoma
The presence of increased numbers of melanocytic naevi (Figure 3, Figure 4) is the most potent phenotypic risk factor for melanoma, which has recently been explored in a meta-analysis.27 The presence of increased numbers of naevi of normal appearance is an important risk factor, as is the presence of so-called atypical naevi. Although difficulties remain in unequivocally defining such naevi, atypical naevi are generally agreed to be 5 mm or larger in diameter, with an irregular or blurred edge
Taking a family history of cancer
The first priority is to identify families at increased risk of melanoma, and taking a family history is therefore of great importance in all oncology services. To construct a pedigree, the site of origin of the cancer, age of onset, and the presence of multiple primary tumours must be recorded. In families with melanoma, the family history could indicate Li-Fraumeni syndrome (eg, sarcomas and breast cancer), BRCA2, or familial retinoblastoma, but most of these families will be at increased
Conclusions
In families with melanoma predominantly, predictors of germline mutations in the melanoma susceptibility gene CDKNA include early age of onset, and the presence of multiple cases of melanoma, multiple primary melanomas in family members, and pancreatic cancer. CDKN2A penetrance (the risk of melanoma in mutation carriers) varies between continents. Some published studies5, 19 of sufficient power give useful estimates in clinical situations, but improved data adjusted for factors such as place of
Search strategy and selection criteria
References (81)
- et al.
Localization of a novel melanoma susceptibility locus to 1p22
Am J Hum Genet
(2003) - et al.
Population-based prevalence of CDKN2A mutations in Utah melanoma families
J Invest Dermatol
(2006) - et al.
Familial and attributable risks in cutaneous melanoma: effects of proband and age
J Invest Dermatol
(2003) - et al.
Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi
Eur J Cancer
(2005) - et al.
Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors
Eur J Cancer
(2005) - et al.
MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations
Am J Hum Genet
(2001) - et al.
Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma
Am J Hum Genet
(2001) - et al.
A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs
Am J Hum Genet
(1999) - et al.
The effect of sun exposure in determining nevus density in UK adolescent twins
J Invest Dermatol
(2005) - et al.
Cutaneous melanoma susceptibility and progression genes
Cancer Lett
(2005)
Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure
Eur J Cancer
High prevalence of vitamin D inadequacy and implications for health
Mayo Clin Proc
Vitamin D: its role in cancer prevention and treatment
Prog Biophys Mol Biol
Vitamin D and prostate cancer prevention and treatment
Trends Endocrinol Metab
Does sunlight have a beneficial influence on certain cancers?
Prog Biophys Mol Biol
How common is the atypical mole syndrome phenotype in apparently sporadic melanoma?
J Am Acad Dermatol
The epidemiology of nevi and signs of skin aging in the adult general population: results of the KORA-survey 2000
J Invest Dermatol
The p16INK4a/CDKN2A tumor suppressor and its relatives
Biochim Biophys Acta
Longitudinal assessment of the nevus phenotype in a melanoma kindred
J Invest Dermatol
Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations
J Invest Dermatol
Genetic testing for melanoma
Lancet Oncol
Cost-effectiveness of pancreatic cancer screening in familial pancreatic cancer kindreds
Gastrointest Endosc
For whom the bell tolls: susceptibility to common adult cancers in retinoblastoma survivors
J Natl Cancer Inst
Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature
J Clin Oncol
p53 germline mutation in a patient with Li-Fraumeni syndrome and three metachronous malignancies
J Cancer Res Clin Oncol
Hereditary cutaneous malignant melanoma: a 20-year family update
Anticancer Res
Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents
J Med Genet
CDKN2A mutations in multiple primary melanomas
N Engl J Med
The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma
Hum Mol Genet
The melanocortin-1-receptor gene is the major freckle gene
Hum Mol Genet
Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus
Nat Genet
A cell cycle regulator potentially involved in genesis of many tumor types
Science
Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma
Nat Genet
The genetics of melanoma
Br J Hosp Med
Role of the CDKN2A locus in patients with multiple primary melanomas
J Clin Oncol
Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome
Pancreas
Systemic cancer and the FAMMM syndrome
Br J Cancer
Familial melanoma and pancreatic cancer
N Engl J Med
High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL
Cancer Res
Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study
Cancer
Cited by (51)
European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics: Update 2022
2022, European Journal of CancerCitation Excerpt :Individuals with high numbers of common naevi and those with large congenital naevi, multiple and/or atypical naevi (dysplastic naevi) are at greater risk, and this phenotype is also genetically determined [11–14]. The inheritance of melanoma is in most cases caused by variants in common lower risk susceptibility genes, but 5%–10% of melanomas appear in melanoma-prone families who are likely to carry mutations in high penetrance susceptibility genes [15,16]. The most important exogenous factor is exposure to UV irradiation, particularly intermittent high sun exposure [17–19].
European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics – Update 2019
2020, European Journal of CancerCitation Excerpt :Individuals with high numbers of common naevi and those with large congenital naevi, multiple and/or atypical naevi (dysplastic naevi) are at greater risk, and this phenotype is also genetically determined [16–19]. The inheritance of melanoma is, in most cases, seen in people with common lower risk susceptibility genes, but 5–10% of melanomas appear in melanoma-prone families that carry high penetrance susceptibility genes [20,21]. The most important exogenous factor is exposure to UV irradiation, particularly intermittent high sun exposure [22–24].
Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016
2016, European Journal of CancerCitation Excerpt :Individuals with high numbers of common naevi and those with large congenital naevi, multiple and/or atypical naevi (dysplastic naevi) are at a greater risk and this phenotype is also genetically determined [13–16]. The inheritance of melanoma is in most cases seen in people with common lower risk susceptibility genes but; 5–10% of melanomas appear in melanoma-prone families who carry high penetrance susceptibility genes [17,18]. The most important exogenous factor is exposure to UV irradiation, particularly intermittent sun exposure [19–21].
Update on melanocytic nevi in children
2015, Clinics in DermatologyMultiple primary (even in situ) melanomas in a patient pose significant risk to family members
2014, European Journal of CancerCitation Excerpt :However, when we considered a detailed family history of MPM, more than 10-fold elevated familial risk was noted for ⩾4 melanomas in one FDR or for ⩾2 melanomas in ⩾2 FDRs. Given that the frequency of a CDKN2A mutation is strongly elevated if the number of affected family relatives or the occurrence of multiple melanomas in an individual increases [6,17], our findings suggest that for families having one FDR with at least four melanomas, or having at least two FDRs with minimum two melanomas, the probability of carrying melanoma-related germline mutations such as mutation in CDKN2A gene may be substantially high, implying the necessity of genetic testing for such mutations, in line with other studies [18]. Additionally, this is the first study reporting that familial risks were rather similar for two (or three) melanomas in one FDR or for a single melanoma in at least two FDRs.
Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2012
2012, European Journal of CancerCitation Excerpt :Individuals with high numbers of common naevi and those with large congenital naevi, multiple and/or atypical naevi (dysplastic naevi) are at greater risk.10–13 The inheritance of melanoma is in most cases polygenic; 5–10% of melanomas appear in melanoma-prone families.14,15 In addition to these genetic and constitutional factors, the most important exogenous factor is exposure to UV irradiation, particularly intermittent sun exposure.16–18