Elsevier

The Lancet Oncology

Volume 8, Issue 1, January 2007, Pages 46-54
The Lancet Oncology

Review
Management of familial melanoma

https://doi.org/10.1016/S1470-2045(06)71010-5Get rights and content

Summary

Relatives of patients with melanoma are at increased risk of melanoma. We review the evidence that this risk may be attributed both to shared susceptibility genes (both high-penetrance and lower-penetrance genes) and shared environment. The most frequent high-penetrance susceptibility gene is CDKN2A, and environmental effects on the risk to gene carriers are evident in that CDKN2A penetrance is higher in CDKN2A-mutation-positive families living in Australia than those in Europe. We review the approaches to managing melanoma families, in which the likelihood of there being detectable CDKN2A mutations is positively correlated with the number of cases of melanoma in the family. Within families, risk that an individual carries a germline mutation can be estimated by pedigree analysis for autosomal dominant genes with incomplete penetrance. Prevention advice to families relates to moderation of sun exposure and self-examination of naevi, although there are few supportive data.

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

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.

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