Melanoma provides a unique model for studies of gene-gene and gene-environmental interaction in the development of cancer. It has several key features. First, there is a major environmental cause of melanoma, exposure to solar UV radiation, which may account for as much as 90 percent of cases in populations of European origin. Second, variants of or mutations in at least three classes of genes with very different functions may determine variation in melanoma risk-cell cycle genes, nucleotide excision repair genes and genes relating to cutaneous pigmentation. Third, the latter two classes of genes are involved in protection against the effects of UV radiation. These features permit the study of gene-gene and gene-environment interactions under circumstances largely free from confounding environmental factors and with genes whose functions and relationships to the environmental factor are reasonably well understood. We hypothesize that there are wide variations among individuals in terms of susceptibility to melanoma. This variation is probably influenced in a heterogeneous manner by multiple susceptibility genes, and sun exposure, the major known exogenous factor, may exert its influence interacting with these genes. Our proposed study will permit evaluation of the public health impact of genetic mutations and polymorphisms and their interaction with sun exposure, via estimation of relevant population parameters in a novel study design. In a large, international population-based case control study covering a wide range of latitudes, we will 1. Determine the relative risk for developing melanoma due to germline mutations and polymorphisms in the cell cycle genes, CDKN2A and CDK4. 2. Determine the relative risk for developing melanoma due to polymorphisms in the melanocortin receptor gene MC1R, a major pigmentary gene. 3. Determine the relative risk for developing melanoma due to allelic variation in the DNA repair genes that specialize in removing DNA damage due to UV radiation, the nucleotide excision repair genes (NER). 4. Analyze the interactions among genetic variants that are associated with the development of melanoma and their association with solar UV radiation. We will do this by way of a novel epidemiological design, a population-based case-control study in which the controls are subjects with incident primary melanoma and the cases are subjects diagnosed with a second or higher order primary melanoma. This design offers substantially greater statistical power to test our hypotheses than a classical case-control study with general population non-diseased control (Begg and Berwick 1997) and, in principle, higher participation rates by both cases and controls. It has substantial potential for application to other areas of cancer susceptibility.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1-SRRB-K (M1))
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Seminara, Daniela
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University of New Mexico
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Gibbs, D C; Ward, S V; Orlow, I et al. (2017) Functional melanoma-risk variant IRF4 rs12203592 associated with Breslow thickness: a pooled international study of primary melanomas. Br J Dermatol 177:e180-e182
Vernali, Steven; Waxweiler, Weston T; Dillon, Patrick M et al. (2017) Association of Incident Amelanotic Melanoma With Phenotypic Characteristics, MC1R Status, and Prior Amelanotic Melanoma. JAMA Dermatol 153:1026-1031
Schwitzer, Emily; Orlow, Irene; Zabor, Emily C et al. (2017) No association between prediagnosis exercise and survival in patients with high-risk primary melanoma: A population-based study. Pigment Cell Melanoma Res 30:424-427
Thomas, Nancy E; Edmiston, Sharon N; Kanetsky, Peter A et al. (2017) Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma. J Invest Dermatol 137:2588-2598
RodrĂ­guez, Vivian M; Berwick, Marianne; Hay, Jennifer L (2017) Communication about melanoma and risk reduction after melanoma diagnosis. Psychooncology 26:2142-2148
Orlow, Irene; Reiner, Anne S; Thomas, Nancy E et al. (2016) Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study. Carcinogenesis 37:30-8
Gibbs, David C; Orlow, Irene; Bramson, Jennifer I et al. (2016) Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways. J Natl Cancer Inst 108:
Taylor, Nicholas J; Thomas, Nancy E; Anton-Culver, Hoda et al. (2016) Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma. Int J Cancer 139:1217-22
Taylor, Nicholas J; Reiner, Anne S; Begg, Colin B et al. (2015) Inherited variation at MC1R and ASIP and association with melanoma-specific survival. Int J Cancer 136:2659-67

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