Moderate- to low-risk variant alleles of cutaneous malignancies and nevi: lessons from genome-wide association studies

Cutaneous malignancies, especially malignant melanoma, exhibit great genetic heterogeneity. As a result, some individuals and families have particularly increased risk due to genetic predisposition to the disease. The susceptibility alleles range from rarely occurring, heritable, high-risk variants to ubiquitously occurring low-risk variants. Although until now the focus has been mostly towards the familial high-risk genes, the development of genome-wide association studies has uncovered a number of moderate- to low-risk predisposition alleles. The ability to specifically identify genetic variation associated with visible pigmentation traits and disease risk has provided a much richer view of the genetics of cutaneous malignancies. In this review, we provide an update on the recently identified risk loci. Existing clinical data, combined with vast genome information, will provide a better understanding of the biology of disease, and increased accuracy in risk prediction

The RAS/Mitogen Activated Protein (MAP) Kinase Pathway in Melanoma Biology and Therapeutics

An effective treatment for metastatic melanoma remains one of the most elusive goals in all of oncology. Several generations of therapeutic trials have yet to yield any agents that can significantly prolong survival for widespread disease. Despite this disheartening history, our understanding of the biology and molecular genetics of melanoma hold the promise of a new era of molecular targets. One pathway that appears to be universally activated in and critically needed for melanoma growth is the Ras/mitogen activated protein (MAP) kinase signaling cascade. Since the enzymatic functions of the signaling partners are well characterized, this pathway offers many potential “druggable” candidates including Braf, Mek and Ras itself. In this review, we describe this pathway in the context of melanoma tumorigenesis and discuss some of the current relevant pharmacologic treatments and clinical trials

Cutaneous melanoma in women☆☆☆

Background: Gender disparity in melanoma outcome is consistently observed, suggesting that gender is as an important prognostic factor. However, the source of this gender disparity in melanoma remains unclear. Objective: This article reviews advances in our understanding of gender differences in melanoma and how such differences may contribute to outcomes. Methods: A broad literature search was conducted using the PubMed database, with search terms such as ‘gender differences in melanoma’ and ‘sex differences in melanoma.’ Additional articles were identified from cited references. Results: Herein, we address the gender-linked physiologic differences in skin and melanoma. We discuss the influence of estrogen on a woman’s risk for melanoma and melanoma outcomes with regard to pregnancy, oral contraceptives, hormone replacement therapy, and UV tanning. Conclusions: The published findings on gender disparities in melanoma have yielded many advances in our understanding of this disease. Biological, environmental, and behavioral factors may explain the observed gender difference in melanoma incidence and outcome. Further research will enable us to learn more about melanoma pathogenesis, with the goal of offering better treatments and preventative advice to our patients

Defining Clonal Color in Fluorescent Multi-Clonal Tracking

Clonal heterogeneity and selection underpin many biological processes including development and tumor progression. Combinatorial fluorescent protein expression in germline cells has proven its utility for tracking the formation and regeneration of different organ systems. Such cell populations encoded by combinatorial fluorescent proteins are also attractive tools for understanding clonal expansion and clonal competition in cancer. However, the assignment of clonal identity requires an analytical framework in which clonal markings can be parameterized and validated. Here we present a systematic and quantitative method for RGB analysis of fluorescent melanoma cancer clones. We then demonstrate refined clonal trackability of melanoma cells using this scheme

In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin

Melanoma is the most deadly form of skin cancer with a yearly global incidence over 232,000 patients. Individuals with fair skin and red hair exhibit the highest risk for developing melanoma, with evidence suggesting the red/blond pigment known as pheomelanin may elevate melanoma risk through both UV radiation-dependent and -independent mechanisms. Although the ability to identify, characterize, and monitor pheomelanin within skin is vital for improving our understanding of the underlying biology of these lesions, no tools exist for real-time, in vivo detection of the pigment. Here we show that the distribution of pheomelanin in cells and tissues can be visually characterized non-destructively and noninvasively in vivo with coherent anti-Stokes Raman scattering (CARS) microscopy, a label-free vibrational imaging technique. We validated our CARS imaging strategy in vitro to in vivo with synthetic pheomelanin, isolated melanocytes, and the Mc1re/e, red-haired mouse model. Nests of pheomelanotic melanocytes were observed in the red-haired animals, but not in the genetically matched Mc1re/e; Tyrc/c (“albino-red-haired”) mice. Importantly, samples from human amelanotic melanomas subjected to CARS imaging exhibited strong pheomelanotic signals. This is the first time, to our knowledge, that pheomelanin has been visualized and spatially localized in melanocytes, skin, and human amelanotic melanomas

Germline BAP1 Inactivation Is Preferentially Associated with Metastatic Ocular Melanoma and Cutaneous-Ocular Melanoma Families

Background: BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome. Design: To characterize BAP1’s contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds. Results: Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8 % vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29 % vs. 0.52%, p =.003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain i