Melanoma can metastasize at an early stage, and these metastases are typically resistant to medical treatment. In addition, melanoma is rising in incidence and mortality, greatly increasing the need for methods of prevention and treatment. Evidence suggests that chemokines and their receptors are important regulators of tumor immunity, progression, metastasis, and, angiogenesis in many cancers, including melanoma. The activities of chemokines and their receptors have been shown to be altered by polymorphisms but the impact of these changes on melanoma remains to be elucidated. Preliminary work has identified a polymorphism of a single chemokine receptor that influences the risk of melanoma, but as yet no comprehensive investigations of links between melanoma and chemokine or chemokine receptor polymorphisms have been performed. We propose to detail inherited variations in chemokines and their receptors and determine their associations with melanoma risk, survival, and NRAS and BRAF mutational subtypes in the large international population-based Genes, Environment, and Melanoma (GEM) study. We will also determine whether these relationships are modified by age, ultraviolet exposure, phenotypic traits, and polymorphisms in other genes. Few previous studies have simultaneously addressed the 'immunogenicity'of melanoma along with the oncogenic pathways. The results are likely to improve risk prediction and evidence-based recommendations for environmental protection and enable better outcomes prediction and customization of treatment paradigms for affected patients.

Public Health Relevance

The objective of this competitive renewal is to determine whether inherited variants of chemokines and their receptors, which are key modulators of tumor immunity, are associated with melanoma risk, survival, and tumor mutations in melanoma, with a particular focus on covariates of risk: age and ultraviolet radiation. The work will be done in the context of a large international population-based study of over 3,000 melanoma patients. The results should lead to better risk prediction and more evidence-based recommendations for environmental protection and enable better survival prediction and the identification of patient groups most likely to benefit from targeted therapies for melanoma treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112243-10
Application #
8607510
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Elena, Joanne W
Project Start
2005-05-13
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2014
Total Cost
$444,762
Indirect Cost
$50,683
Name
University of North Carolina Chapel Hill
Department
Dermatology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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White, Kirsten A M; Luo, Li; Thompson, Todd A et al. (2016) Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study. Cancer Med 5:3336-3345
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Gibbs, David C; Orlow, Irene; Kanetsky, Peter A et al. (2015) Inherited genetic variants associated with occurrence of multiple primary melanoma. Cancer Epidemiol Biomarkers Prev 24:992-7
Vicory, Jared; Couture, Heather D; Thomas, Nancy E et al. (2015) Appearance normalization of histology slides. Comput Med Imaging Graph 43:89-98
Taylor, Nicholas J; Busam, Klaus J; From, Lynn et al. (2015) Inherited variation at MC1R and histological characteristics of primary melanoma. PLoS One 10:e0119920
Carson, Craig C; Moschos, Stergios J; Edmiston, Sharon N et al. (2015) IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma. Clin Cancer Res 21:2167-76
Thomas, Nancy E; Edmiston, Sharon N; Alexander, Audrey et al. (2015) Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma. JAMA Oncol 1:359-68
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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