Melanoma risk and progression has been studied extensively for many years. However, the incidence rate continues to rise, indicating either that risk is not well understood, or that communication efforts with the public have not been fruitful. The biology of melanoma has been interrogated extensively with new technology and at this point common mutations in the BRAF and NRAS genes has been studied in depth, but as the new TCGA melanoma analyses demonstrate, additional mutations found commonly in primary melanomas further complicate the molecular landscape of melanoma and require large studies with even more rigorous tumor collection and analysis to determine the significance of tumor characteristics. This project seeks to develop the infrastructure of the Genes, Environment, and Melanoma Study (GEM), an international population-based study of melanoma that has the potential to provide unique insights into the pathogenesis of this important disease. The GEM Study was originally designed as a case-control study of multiple primary melanoma. It accrued 2,373 individuals with incident primary cutaneous melanoma in the year 2000 and 1206 individuals with an incident second or higher order primary between 1998 and 2003. Rigorous pathologic review was conducted centrally by expert dermatopathologists. Extensive data on risk factors were collected from participants, including pigmentary traits, mole counts, thorough lifetime history of UV exposure patterns, and family history of melanoma. We collected germline DNA from all participants to examine genetic risk. In subsequent follow-up studies the GEM participants have been followed for survival through 2007. In addition primary melanoma tissue was sought from a subset of the contributing sites and was successfully obtained from 1,636 patients; of these we currently have 192 pairs of melanomas from the same person. To the 3,579 melanoma patients in GEM, we now wish to add 1,253 patients from Western Australia, 172 of whom are multiple primary melanomas. The Western Australia Melanoma Health Study was conducted In the same way as GEM, collecting both single and multiple primary melanoma, with a similar survey to collect all known environmental and host risk factors, collecting germline DNA with the ability to collect primary tumor tissues. A major innovation in this application is our development of the largest population-based study in the world of 4,834 individuals newly diagnosed with melanoma, containing associated germline DNA and a large proportion of tumors, lymph nodes and, in some cases, metastases. The two groups, GEM and WAHMS, will have an impressive number of melanomas with tissue and annotation of double primaries. This new grant will lead to new hypotheses and will be widely available to new researchers interested in melanoma. PUBLIC HEALTH RELEVANCE: We propose to consolidate two cohorts of melanoma patients, one from the Genes, Environment and Melanoma study (GEM) with 3,589 melanoma patients and one from the Western Australian Melanoma Health Study (WAHMS) with 1,253 melanoma patients. We will conduct follow up through 2015 and collect approximately 1,700 new tumors from those previously not contacted to enlarge our tumor bank of 1,636 melanoma tumors in order to have an appropriate number of tumors to conduct robust studies. This project thus will be able to identify new factors to identify risk and progression in this rapidly increasing and fatal disease.