Using MC1R genotype to impact melanoma risk behavior.
Malignant melanoma, a potentially fatal form of cancer that arises in skin cells that produce pigment, has been increasing in the United States over the past few decades. While 5-year survival for localized early stage disease is 98%, survival for regional disease drops to 62%, and again to 15% for distant disease. Primary prevention and early detection behaviors such as sun protection and regular skin cancer screening can potentially reduce risk of developing melanoma or shift disease detection to an early and more treatable stage.
It is well established that individuals with ‘light’ phenotype characteristics such as red hair color, burning after exposure to the sun, and freckling are at increased risk for developing melanoma. However, our prior research on the genetics of melanoma has shown that inheriting certain changes in the melanonocortin-1 receptor (MC1R) gene increases risk of melanoma, and that the risk associated with these gene changes is as great or greater in individuals who have ‘dark’ phenotype characteristics, such as dark hair color, ability to tan well, and few freckles.
The focus of our research study is on this segment of the general population with darker complexions who may not know that they are at increased risk for melanoma. We seek to determine whether feedback of genetic information about inheritance of high risk MC1R genotypes to persons with darker phenotype characteristics can impact upon their melanoma prevention behaviors.
Inherited Genetic Variation, immune-related adverse events, and outcome in melanoma patients treated with immunotherapy.
Immunotherapies, including ipilimumab and nivolumab, have resulted in substantial improvements in the outcomes of patients with advanced melanoma . Similar to most treatments, not all patients respond, and some develop side effects. Ipilimumab and nivolumab given together as a combination therapy has the highest response rate, but also the greatest rate of side effects. In order to maximize the clinical utility of these immunotherapies, we need to be able to determine those patients most likely to respond to therapy and those at increased risk for developing side effects. However, no markers of response have been established, and none have been identified for side effects.
Multiple lines of evidence suggest that there may be inherited genetic variants associated with response and side effects. In order to identify informative inherited genetic markers, we have partnered with Bristol-Myers Squibb and identified patients treated on clinical trials with ipilimumab alone, nivolumab alone, or nivolumab/ipilumimab combination therapy. We propose to determine the association of inherited variation with side effects and overall survival. We will first examine the genetic pathways associated with immune function, and then take an unbiased approach to examine the whole genome to discover novel genetic markers associated with our outcomes of interest. We then will replicate our findings in an independent sample set of patients. Our long term goal is to identify inherited variation that can inform clinical decision making for patients treated with ipilimumab and nivolumab, either as mono- or combination therapy.