Abstract PR6: Why redheads are at increased risk of melanoma: A novel BRAF mutant mouse model

Abstract

Abstract The goal of our studies was to develop a novel mouse model to investigate the long-standing epidemiological observation that redheads (who do not tan but rather burn in response to sun exposure) are at relatively high risk of developing melanoma. The most frequent genetic causes of the redhair/pale-skin phenotype are polymorphisms in the melanocortin 1 receptor (Mc1R) gene. Recent genome-wide association studies have found that polymorphisms in the Mc1R gene are the single greatest genetic risk factor for melanoma. The Mc1R protein is a receptor found on the cell surface of melanocytes, responsible for stimulating production of dark eumelanin pigment. In the presence of Mc1R red-hair/fair-skin polymorphisms, the receptor is dysfunctional; as a result, the red/yellow pheomelanin pigment is produced but the dark eumelanin pigment is lacking. Previously, it was hypothesized that individuals with Mc1R red-hair/fairskin polymorphisms are at increased risk of melanoma because they lacked eumelanin pigment, a known protective agent against genotoxic ultraviolet radiation from the sun. However, various observations have suggested that the Mc1R red-hair/fair-skin polymorphisms might promote melanoma via effects that are independent of UV. To investigate this possibility, three strains of C57B/6 mice were acquired that express 1) the wild-type Mc1R (black) phenotype, 2) an Mc1R polymorphic red-head phenotype, or 3) a tyrosinase mutant albino phenotype. Into each pigmentation variant a Cre-loxP system was introduced which allowed inducible, melanocyte-specific expression of the BRAF(V600E) oncogene. Murine models of melanocyte-specific BRAF(V600E) expression were recently shown to exhibit rapid onset, high-penetrance melanoma when combined with removal of either the p16 or PTEN tumor suppressor genes. We therefore utilized this murine BRAF(V600E) conditional knock-in model to ask whether the red-head (mc1re/e) background influences melanomagenesis. We observed a striking enhancement in melanoma incidence as well as shortened latency to tumor formation following BRAF(V600E) induction with topical tamoxifen in red-head mice vs. genetically matched black or albino animals. The tumors were diffusely positive for the marker S100, focally positive for the melanocytic marker HMB45, and displayed some evidence of microscopic pigmentation, though they were grossly amelanotic. There was also evidence of systemic metastases including malignant cells in the lymph node and liver. It is notable that genetically matched black BRAF(V600E) conditional knock-in mice develop benign melanocytic proliferations (presumably akin to nevi) and only develop invasive melanomas after much longer latency than red-head mc1re/e matched animals. Importantly, the elevated melanoma predisposition of the red-head allele is entirely independent of UV exposure in this study, since no animals were treated with ultraviolet radiation. We are currently utilizing a set of genetically defined gene disruption models to gain additional insights into the precise mechanism(s) by which Mc1R polymorphisms amplify UV-independent melanoma risk. This abstract is also presented as Poster B27. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR6.