Risk Factors

Risk factors for melanoma in general (often termed ''sporadic melanoma'') have either proven, or are most likely, to be also risk factors for familial melanoma. Apart from a family history of melanoma, the best known environmental risk factor for melanoma is sunlight exposure. This risk factor can, to a large part, explain the increase in melanoma incidence over recent decades and most probably also explains the geographical variance in penetrance figures for mutation-positive melanoma families (discussed later).

The phenotypic characteristics of fair skin (inability to tan), light hair (especially red) and eye color, extensive freckling, and high number of nevi (moles, particularly atypical) are all well-recognized risk factors for melanoma. Many have been shown to be independent risk factors, but their relative risks vary considerably among different studies. This variation is most probably due to differences in phenotypic definition. Elucidation of the genetic variants underlying these complex characteristics should lead to an even better defined phenotypic risk profile. Molecular analysis of one pigmentation gene, MC1R, a regulator of melanin production, has led to the identification of a genetic risk modifier for melanoma. Beyond the finding that certain MC1R variants are linked to the melanoma risk phenotypes of red hair, freckles, and fair skin, these variants also confer melanoma risk irrespective of the pigmentation phenotype.[8] Furthermore, MC1R variants have been found to increase melanoma penetrance in CDKN2A mutation-positive individuals.1-9'101

Of all the above-mentioned risk factors for melanoma, nevi (especially atypical) have by far the greatest clinical implication. Also apparent as precursor lesions both in sporadic and familial melanoma, many groups have reported the co-occurrence of a nevus phenotype with familial melanoma. Throughout the years familial melanoma has been referred to by many different names, which may reflect the difficulty to reach consensus on defining the associated nevus phenotype: B-K mole syndrome (initials of described families); dysplastic nevus syndrome (DNS), familial atypical multiple mole melanoma (FAMMM) syndrome, and atypical mole syndrome (AMS). Each of these definitions includes atypical nevi as the most predominant feature of the phenotype. Atypical nevi are defined as nevi that have a size of 5 mm or larger, have a flat component, and fulfill at least two of the following three criteria: 1) variegated pigmentation, 2) ill-defined border, and 3) irregular shape. The photographs in Fig. 1 illustrate melanoma and atypical nevi. Although both phenotypes are commonly coexpressed in familial melanoma, they are not always transmitted together.

DIFFERENTIAL DIAGNOSIS (OTHER RELATED SYNDROMES CONTAINING MELANOMA)

Melanoma/Pancreatic Cancer Syndrome

Melanoma susceptibility has also been reported in conjunction with gastrointestinal cancer and breast cancer, and an excess of pancreatic carcinoma is frequently being observed. Comparison of CDKN2A mutation-positive and -negative melanoma families showed an increased risk of pancreatic cancer in the mutation-positive group.[11] Interestingly, the increased risk for pancreatic cancer seems to be restricted to only some of the CDKN2A mutation-positive families, implying other genes and/or environmental factors are responsible for modifying the penetrance of this tumor type. Disentanglement of these issues is of utmost importance because of the high mor-

Fig. 1 Pigmented lesions on three different patients with familial melanoma or the atypical mole syndrome. The upper left picture shows several atypical nevi on the scalp, the lower picture shows the back of a patient with many common and atypical nevi, and the upper right picture shows a melanoma on the lower leg. (View this art in color at www.dekker.com.)

tality associated with this cancer and the lack of routine surveillance for it. Whether the correlation with other cancers is restricted to pancreatic cancer only or also involves different cancers remains to be answered by large-scale analysis of cancer history in melanoma families.

Cutaneous Melanoma/Uveal Melanoma Families

Another tumor sometimes described in familial melanoma kindred is uveal melanoma. Although the first CDKN2A mutation in such a family was recently published,[12] up to then no underlying gene defect has been found in uveal/cutaneous melanoma families. Genome-wide linkage scans are currently under way to localize additional predisposition genes in such families.

Melanoma/Nervous System Tumor Syndrome

Nervous system tumors are sporadically being described in melanoma families and multiple melanoma cases. In most of these the underlying genetic defect affects the p14ARF transcript of the CDKN2A locus (see below), either exclusively or concomitantly with the p16 tran-

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