Sancy Leachman's laboratory focuses on the genetics of human melanoma. The lab has three primary research efforts:
Molecular Determinants of Melanoma Susceptibility and Progression
Melanoma is a disease with unpredictable behavior and can in fact be difficult to diagnose using purely histological attributes in a subset of cases. Prediction of the different phases of melanoma progression has proved elusive with the use of clinical and histological factors alone. To date, no biomarkers are used in the routine diagnostic or prognostic assessment of melanoma patients. Initial studies analyzing the expression of thousands of genes have identified a number of possible melanoma progression genes. More recent studies have begun to identify a finite number of potentially useful diagnostic and prognostic markers for melanoma. However, important further studies are required to validate the role of these markers in independent cohorts in order to develop clinically useful assays. We propose to identify and validate reliable genetic markers of melanoma vulnerability and progression. These data can be used to identify individuals who require intensified screening for the disease, increase the effectiveness of treatment for melanoma, reduce morbidity, and ultimately, save lives.
Melanocortin 1 Receptor Gene
The melanocortin 1 receptor (MC1R) gene is a main determinant of human pigmentation, and a melanoma susceptibility gene. The activated MC1R stimulates eumelanin synthesis, and enhances nucleotide excision repair and antioxidant responses in UV-irradiated human melanocytes, thus reducing the risk for melanoma. Functional variants of MC1R disrupt receptor function and alter the pigmentary phenotype by varying extents. Using human melanocytes that naturally express this gene and are a physiological target for melanocortins, we found that expression of two red hair variants abolished the response to α-melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. Expression data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.
In addition to the MC1R gene, the p16 INK4A (p16) is also a melanoma predisposition gene, with mutations in p16 having the highest impact on risk, and MC1R loss of function (LOF) variants being the most common in melanoma patients and melanoma-prone individuals. The increased risk of co-inheritance of p16 and MC1R mutations is supported by compelling epidemiological evidence, but the molecular mechanisms by which the interaction of these two genes impacts melanoma risk is not well understood. Earlier work has attributed their combined effects to cell cycle deregulation and DNA repair deficiencies. Our team has discovered that these two risk factors share molecular mechanisms that also involve the antioxidant capacity of melanocytes. Using unique primary cultures of skin cells including melanocytes derived from patients with mutations in both p16 and MC1R provides us with the unprecedented opportunity to identify novel common pathways that can be targeted for melanoma prevention and treatment. We are testing the hypothesis that co-inheritance of germline mutations in p16 and MC1R causes synergistic disruption of the antioxidant and DNA repair responses of melanocytes to UV, and that deficiencies in these protective mechanisms underlie the extremely high risk for melanoma observed in individuals who carry mutations in both genes. We are evaluating the effect mutations have on the cell cycle, DNA repair, and oxidative stress, using cultured melanocytes and 3-D skin constructs, and we will examine the effect UV irradiation has on mutant melanocytes. These studies will improve risk assessment of melanoma susceptible individuals and development of effective strategies for melanoma prevention, early detection, and treatment.
Impact of Melanoma Genetic Testing on Health Cognitions and Prevention Behaviors
Cancer genetic testing alerts mutation carrier members to their elevated risk before disease onset, when early detection and even prevention may be possible. Little is known about the effect of genetic test reporting on prevention behaviors, as prior studies have focused on screening. Familial melanoma presents an ideal context in which to examine the impact of genetic test reporting on prevention behaviors because avoidance of UVR, a well-established risk factor in this population, represents a quantifiable prevention measure. We hypothesize that melanoma genetic test reporting will improve patient compliance with prevention and screening recommendations above that observed with counseling alone, and that specific cognitive and individual difference characteristics will be associated with compliance and non-compliance in the familial melanoma population. More broadly, our research strategy permits elucidation of cognitive processes that determine a patient's response to genetic test reporting. This ongoing work examines how a positive genetic test result influences high-risk participants' understanding and management of their melanoma risk over a two-year period, compared to participants who receive standard counseling based on family history alone, and whether genetic test reporting improves prevention behavior and screening (skin examination) adherence. Ultimately, it may be possible to tailor genetic test results to maximize compliance with prevention recommendations.