Genetic, Epigenetic and Molecular Changes in Melanoma: A New Paradigm for Biological Classification

Abstract

The last two decades have registered a progressive decline of both the incidence and mortality rates for some human cancers, worldwide (Jemal et al., 2010). However, in the same time interval, the incidence of cutaneous melanoma (CM), has progressively increased (Gallagher et al., 2005; Jemal et al., 2010), up to an epidemic level in Western countries and Australia (Beddingfield et al., 2003; Cancer facts & Figures, 2009). To date, the average lifetime risk for developing melanoma ranges from 1/50 in the United States (men and women) (Meyle & Guldberg, 2009; Horner et al. 2011) up to 1/25 for Australian men (Hocker et al., 2008). CM is an extremely aggressive skin cancer, and constitutes one of the most lethal human malignancies, notwithstanding the progressive increase of early diagnosis and surgical excision registered from 1990s. This poor prognosis may be due, at least in part, to the possible occurrence of metastasis even in early phases of melanoma progression, as well as to the very low response to current systemic therapy. The 5 yearsurvival rate for patients with disseminated disease is about 10%, with death for disease ultimately occurring within 2 years from metastases (Balch et al., 2000; Chin et al., 2006; Zbytek et al., 2008; Ugurel et al., 2009; Cancer facts & Figures, 2009). This underscores the need to uncover the mechanisms underlying melanoma biology, with the aim to identify reliable early markers of response and to select patients eligible for new rational avenues for therapy (Siena et al., 2009). The formidable aggressive potential of CM is thought to represent the result of multiple intersecting molecular alterations of the control pathways governing cell proliferation, cell death, DNA-repair, and tumor-stromal interaction. These molecular alterations are thought to be involved also in the peculiar histomorphological features and different biological behavior of the four “classical” types of CM. Three of them (superficial spreading melanoma, SSM; malignant lentigo melanoma, LM; acral melanoma, AM) are characterized by the sequential progression from junctional (radial) and pagetoid (intraepithelial) growth phase, to invasive (vertical) growth. The radial growth phase (RGP) is characterized by lateral melanocyte growth at the dermo-epidermal interface (junctional area), whereas the vertical growth phase (VGP) shows the spreading of melanoma cells into the dermis and subcutis, this being correlated with the occurrence of metastasis. The fourth