Melanoma, which is rapidly increasing in incidence, remains a potentially fatal disease with poor medical treatment options and controversial methods of prevention. Because of the increasing burden of this disease and its lethality, improved methods of prevention, early diagnosis and treatment are expected to be of increasing importance. NRAS and BRAF, mediators in the RAS-RAF-MEK-ERK-MAP cell signaling pathway, are the most commonly mutated oncogenes thus far described for melanoma. However, despite the identification of these mutations in primary human melanomas, the frequency and mutational spectrum of NRAS and BRAF mutations in melanoma have not been fully characterized and there is a critical gap in the knowledge base regarding the association of these mutations with heterogeneity, precursor lesions, risk, and prognosis in melanoma.
The specific aims of this study are to: (1) determine the population-based frequency and mutational spectrum of NRAS and BRAF somatic alterations in primary cutaneous invasive melanoma and their associations with histologic subtype and potential precursor lesions, and (2) determine associations between NRAS and BRAF mutational phenotypes and known prognostic indicators and risk factors. For this study, a group of approximately 300 consecutive patients with malignant melanoma in North Carolina in the year 2000 has been assembled. Complete epidemiologic data, pathology, and tumor blocks have been obtained for these patients. NRAS and BRAF somatic mutations will be detected and characterized using the highly sensitive technique of single strand conformational polymorphism (SSCP) analysis combined with direct sequencing of PCR products. The population-based frequency of these mutations will be determined and compared between pathologically distinct subtypes of melanoma (superficial spreading, lentigo maligna, nodular, and acral lentiginous). In melanoma samples associated with a nevus, this component will be analyzed separately for mutations using laser capture microdissection. Mutational phenotype will be associated with subtype, potential precursor lesions, risk factors, and prognostic indicators. The data derived from this study is expected to clarify the role of NRAS and BRAF in the development, progression and heterogeneity of melanoma, ultimately leading to better prevention, classification and treatment. Elucidation of how these mutations might arise in relationship to environmental and hereditary factors should result in more evidence-based recommendations for risk factor avoidance. In addition, understanding how mutations arise in relationship to precursors should provide information regarding which potential precursors should be removed. This study is also expected to lead to identification of new hemotherapeutic targets and more efficient testing of inhibitors for NRAS and BRAF signaling, which have recently been developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07CA102096-04
Application #
7092158
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2003-08-05
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$130,058
Indirect Cost
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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Thomas, Nancy E; Busam, Klaus J; From, Lynn et al. (2013) Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol 31:4252-9
Lindsay, Colin R; Lawn, Samuel; Campbell, Andrew D et al. (2011) P-Rex1 is required for efficient melanoblast migration and melanoma metastasis. Nat Commun 2:555
Thomas, Nancy E; Kanetsky, Peter A; Begg, Colin B et al. (2010) Melanoma molecular subtypes: unifying and paradoxical results. J Invest Dermatol 130:12-4
Thomas, Nancy E; Kanetsky, Peter A; Edmiston, Sharon N et al. (2010) Relationship between germline MC1R variants and BRAF-mutant melanoma in a North Carolina population-based study. J Invest Dermatol 130:1463-5
Thomas, Nancy E; Kricker, Anne; From, Lynn et al. (2010) Associations of cumulative sun exposure and phenotypic characteristics with histologic solar elastosis. Cancer Epidemiol Biomarkers Prev 19:2932-41
Lachiewicz, Anne M; Berwick, Marianne; Wiggins, Charles L et al. (2008) Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the Surveillance, Epidemiology, and End Results (SEER) program. Arch Dermatol 144:515-21
Kricker, Anne; Armstrong, Bruce K; Goumas, Chris et al. (2007) Ambient UV, personal sun exposure and risk of multiple primary melanomas. Cancer Causes Control 18:295-304
Walters, Ruth Fulghum; Groben, Pamela A; Busam, Klaus et al. (2007) Consumption of the epidermis: a criterion in the differential diagnosis of melanoma and dysplastic nevi that is associated with increasing breslow depth and ulceration. Am J Dermatopathol 29:527-33
Hao, Honglin; Muniz-Medina, Vanessa M; Mehta, Heena et al. (2007) Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth. Mol Cancer Ther 6:2220-9

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