We have brought together 12 institutions in order to promote a better understanding of the biology of melanoma and how that affects an individual?s survival. Our hypothesis is that primary melanomas will have molecular and clinical features that will allow the stratification of melanoma tumors at AJCC TNM Stages IIA/IIB/IIC/IIIA/IIIB, where there is little effective adjuvant therapy, into those with a good prognosis and those with poor prognosis. The current mortality rate for individuals diagnosed at these stages ranges between 18- 47% for Stages IIA/IIB/IIC and 32-78% for Stage IIIA/IIIB patients. The ability to improve clinical care and patient outcomes for these patients might be achieved by focusing on the identification and prioritization of biomarkers ? both molecular and clinical ? that might triage high risk patients for new adjuvant therapies. In this study, we will identify somatic tumor mutations, CNVs, an immune profile, methylation profiles, and microRNA/mRNA signatures in primary melanoma that are associated with prognosis, with the ultimate intent of translating this information into the clinic to personalize care. Currently, there is a dearth of studies in the melanoma field looking at epidemiologic/genomic factors and melanoma survival. In order to identify, confirm and develop such biomarkers, we have brought together 9 cohorts of melanoma patients at AJCC TNM stages IIA/IIB/IIC/IIIA/IIIB, comprising 1000 individuals, 500 of whom have died from their disease as of 2012 and 500 whom have lived at least 5 years. Patients will be frequency matched for stage. As we integrate data from multiple platforms, we will randomly divide the dataset into a training set (660 tumors, half aggressive and half non-aggressive) and a validation set (340 tumors, half aggressive and half non-aggressive). Significant findings in the training set will be replicated in the validation set. These patients have all been treated using standard-of-care surgery. All patients in this study will have adequate tumor tissue, germline DNA and clinical, pathologic and demographic information recorded. Our objective is to identify prognostic biomarkers associated with survival. The goal is to identify patients for whom more aggressive therapy prior to developing metastases would be relevant, that is would make a difference to their survival. Our central hypothesis is that melanoma prognosis is largely determined early in tumor development and that DNA and RNA markers, combined with clinicopathologic and protein characteristics in primary melanoma will add information to outcome prediction beyond the pathologic features used in AJCC tumor staging. We are taking an integrative approach to take advantage of and organize the large amount of information generated from each project. Such information will be available to clinicians and other investigators as soon as possible.
Biomarkers for melanoma prognosis have held great promise, but unfortunately few have made it into clinical use likely due to the small cohorts of patients used for their development as well as the platforms used. In this program we are integrating multiple platforms (mutation, methylation, and expression) in a 1,000 melanoma patients who are diagnosed at AJCC TNM stages IIA/IIB/IIC/IIIA/IIIB. This project is expected to improve the understanding of the underlying biology of melanoma progression and allow us to identify at diagnosis those patients who will have poor survival and might benefit from adjuvant therapies.
|Thomas, Nancy E; Edmiston, Sharon N; Orlow, Irene et al. (2018) Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes. J Invest Dermatol 138:2398-2404|
|Gorlov, Ivan; Orlow, Irene; Ringelberg, Carol et al. (2018) Identification of gene expression levels in primary melanoma associated with clinically meaningful characteristics. Melanoma Res 28:380-389|
|Miles, Jonathan A; Orlow, Irene; Kanetsky, Peter A et al. (2018) Relationship of Chromosome Arm 10q Variants to Occurrence of Multiple Primary Melanoma in the Population-Based GEM Study. J Invest Dermatol :|
|Gorlov, Ivan P; Pikielny, Claudio W; Frost, Hildreth R et al. (2018) Gene characteristics predicting missense, nonsense and frameshift mutations in tumor samples. BMC Bioinformatics 19:430|
|Thomas, Nancy E; Edmiston, Sharon N; Tsai, Yihsuan S et al. (2018) Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis. Am J Dermatopathol :|