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 #
5R01CA112243-08
Application #
8234210
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
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$511,659
Indirect Cost
$58,139
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
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
Orlow, Irene; Shi, Yang; Kanetsky, Peter A et al. (2018) The interaction between vitamin D receptor polymorphisms and sun exposure around time of diagnosis influences melanoma survival. Pigment Cell Melanoma Res 31:287-296
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 :
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
Mauguen, Audrey; Zabor, Emily C; Thomas, Nancy E et al. (2017) Defining Cancer Subtypes With Distinctive Etiologic Profiles: An Application to the Epidemiology of Melanoma. J Am Stat Assoc 112:54-63
Luo, Li; Orlow, Irene; Kanetsky, Peter A et al. (2017) No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival. PLoS One 12:e0174234
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
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:

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