Genetic pathways to melanoma

Background: Cutaneous malignant melanoma (CMM) is a heterogeneous disease. Delineating the molecular pathogenesis underlying its varying clinical presentations will assist with the further understanding of the aetiology of this complex problem.
Methods: We have conducted genotype-phenotype studies on a cohort of 11 Australian CDKN2A (p16INK4a/p14ARF) mutation positive (-34G4T, Ala36Pro, Ile49Ser, Met53Ile, Gly67Ser, Asn71Ser) and 14 CDKN2A negative multiple-case CMM families (n ¼ 143 subjects, both affected and unaffected by CMM). First, we delineated associations between CMM and susceptibility alleles (CDKN2A, MC1R), naevus and sun-sensitive phenotypes by conditional logistic regression. Equations were modeled to adjust for CDKN2A and MC1R mutation status to
observe for variations in the strength of associations. We then explored, via factor analysis and receiver operating curves, hierarchical cluster analysis and the construction of dendrograms, the way in which these phenotypic and underlying genetic risk factors aggregated into distinct clusters. We aimed in this way to determine what clinical heterogeneity existed in the cohort, and how this might relate to degrees of CMM risk.
Results: Three clusters characterized by low, moderate and high risk of CMM were recognised. In the low risk category 6.5% of subjects had CMM, 20% in the moderate and 76% in the high riskcategory. The high-risk candidates’ clustered characteristics included positive CDKN2A mutation status and high counts of banal and clinically atypical naevi. The moderate risk group was typically CDKN2A mutation negative, had fewer moles, had darker features of pigmentation, but had greater evidence of sun-sensitivity indicating, perhaps, higher degrees of sun-exposure. Variants of MC1R were shown to be associated with this sun-sensitive phenotype.
Conclusions: These data provide further evidence of the clinical heterogeneity of individuals highly predisposed to CMM even in the presence of a strong family history. Further analysis is required to determine if the ‘‘lower risk’’ sun-sensitive cluster is truly due to intrinsic, potentially genetic, sun sensitivity or simply due to higher levels of sun exposure.