Epigenetics in Melanoma Development and Drug Resistance

Melanomas, which originate from melanocytic cells, mainly develop in the skin but can also arise at other body sites. The disease accounts for approximately 90% of deaths related to cutaneous tumors with late stage metastatic melanoma having a very poor prognosis of 6–9 month median survival for untreated patients. Research in the last decades resulted in ground-breaking discoveries of melanoma genetics and biology. High frequency mutations in genes like BRAF, NRAS and KIT, which lead to hyper-activation of the MAPK signaling pathway, drive melanoma progression. Targeting the MAPK signaling pathway has successfully been translated into effective therapies that significantly improve patient survival. Despite the unquestionable importance of such genetic events, the involvement of epigenetic alterations for melanoma development, and resistance to aforementioned therapies is becoming increasingly apparent. In this chapter, epigenetic alterations commonly found in melanoma are introduced, with a focus on histone and DNA modifications and their relevance for melanoma development, progression and therapy response. Detailed knowledge about this emerging aspect of melanoma research will help to understand the plastic nature of melanoma and set the foundation for novel treatment strategies that target aberrant gene regulation on genetic and epigenetic levels

BRAF wild-type melanoma in situ arising in a BRAF V600E mutant dysplastic nevus

IMPORTANCE The BRAF V600E mutation accounts for the majority of BRAF mutations found in cutaneous melanoma and is also commonly found in nevi. We used dermoscopy-targeted sampling and a microbiopsy device coupled with DNA sequence analysis to highlight BRAF V600E heterogeneity within a multicomponent melanocytic proliferation. This sampling technique demonstrates the prospect of in vivo application in a clinical setting

BRAFV600E Mutation Status of Involuting and Stable Nevi in Dabrafenib Therapy with or without Trametinib

IMPORTANCE Recent advances in targeting BRAF(V600E) mutations, which occur in roughly 50% of melanomas and 70% of benign nevi, have improved response rates and survival in patients with melanoma. With increased survival, the importance of other comorbidities increases and requires consideration in long-term management. This case report discusses dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some conclusions regarding BRAF mutations and the changes

Whole-exome sequencing of acquired nevi identifies mechanisms for development and maintenance of benign neoplasms

The melanoma transformation rate of each nevus is rare despite the detection of oncogenic BRAF or NRAS mutations in 100% of nevi. Acquired melanocytic nevi (AMN) do however mimic melanoma and ∼30% of all melanomas arise within pre-existing nevi. Using whole-exome sequencing of 30 matched nevi, adjacent normal skin, and saliva we sought to identify the underlying genetic mechanisms for nevus development. All nevi were clinically, dermoscopically, and histopathologically documented. In addition to identifying somatic mutations, we found mutational signatures relating to ultra-violet radiation (UVR) mirroring those found in cutaneous melanoma. In nevi we frequently observed the presence of the UVR mutation signature compared to adjacent normal skin (97% vs 10% respectively). In copy number aberration (CNA) analysis, in nevi with copy number loss of tumor suppressor genes (TSG), these were balanced by loss of potent oncogenes. Moreover, reticular and non-specific patterned nevi revealed an increased (

Multiparameter analysis of naevi and primary melanomas identifies a subset of naevi with elevated markers of transformation

Here we have carried out a multiparameter analysis using a panel of 28 immunohistochemical markers to identify markers of transformation from benign and dysplastic naevus to primary melanoma in three separate cohorts totalling 279 lesions. We have identified a set of eight markers that distinguish naevi from melanoma. None of markers or parameters assessed differentiated benign from dysplastic naevi. Indeed, the naevi clustered tightly in terms of their immunostaining patterns whereas primary melanomas showed more diverse staining patterns. A small subset of histopathologically benign lesions had elevated levels of multiple markers associated with melanoma, suggesting that these represent naevi with an increased potential for transformation to melanoma