![]() ![]() Conversely, evidence for a direct UV mutagenic effect in melanoma pathogenesis has been more equivocal. Several model systems have also linked UV-dependent tumorigenic effects to modulation of signaling pathways (e.g., enhanced gamma interferon secretion ( Zaidi et al., 2011) activation of JNK signaling pathway ( Derijard et al., 1994)), thus supporting a non-mutagenic role in melanoma. Epidemiological and experimental data have established a causal role for intense UV exposure during development (e.g., blistering sunburns early in life) in melanoma genesis (reviewed in ( Garibyan and Fisher, 2010)). Although methods to account for this mutation rate heterogeneity are an active area of research ( Chapman et al., 2011 Greenman et al., 2006 Lohr et al., 2012), rigorous approaches to address this challenge in melanoma have been lacking.Ī related question pertains to the tumorigenic effects of UV-induced DNA damage at the nucleotide level. Highly elevated somatic mutation rates that vary across genomic loci may limit the ability of statistical approaches that assume uniformity of the basal mutation rate to distinguish genes harboring ‘driver’ mutations (i.e., mutations that confer or at some point conferred a fitness advantage to the tumor cell) from those with ‘passenger’ mutations (i.e., mutations that never conferred a fitness advantage). ![]() ![]() In particular, cutaneous melanomas exhibit markedly elevated base mutation rates compared to nearly all other solid tumors ( Berger et al., 2012 Pleasance et al., 2010), which is almost entirely attributable to increased abundance of the cytidine to thymidine (C>T) transitions characteristic of an ultraviolet UV-light-induced mutational signature. While the potential of comprehensive genome sequencing for melanoma gene discovery is recognized, there is also increasing appreciation for the confounding impact of high mutational load due to UV mutagenesis. The continuing discovery of recurrently mutated melanoma genes ( Berger et al., 2012 Nikolaev et al., 2012 Stark et al., 2012 Wei et al., 2011), and the lack of identified driver mutations in the subtype without NRAS or BRAF mutation, suggests that genetic understanding of this malignancy remains incomplete. Other melanoma gene mutations that offer therapeutic insights include CDNK2A deletions, MITF amplification/alteration resulting in dysregulation of “druggable” anti-apoptotic proteins, and PTEN disruption leading to PI3 kinase/AKT activation (reviewed in ( Chin et al., 2006)). BRAF V600 mutations (present in 50% of melanomas) predict clinical efficacy of RAF inhibitors such as vemurafenib activating KIT aberrations may predict response to tyrosine kinase inhibitors such as imatinib, nilotinib, or dasatinib and some NRAS-mutant tumors may exhibit sensitivity to MEK inhibition (reviewed in ( Flaherty et al., 2012)). In recent years, much has been learned about the molecular basis of melanoma genesis, progression, and response to therapy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/ BRAF mutations. ![]() Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes ( PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. ![]()
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