Melanoma has the fastest growing incidence among all cancers in the United States;researchers estimate there were over 62,000 new melanoma cases in 2008. Most patients with melanoma present with early stage disease and are cured with surgery alone. However, despite their overall good outcome, more than 15% of melanoma patients will suffer a recurrence. Standard clinical features (tumor thickness, ulceration, sentinel lymph node status) cannot completely predict which patients will recur. For those who do recur, current therapies are effective in only a minority. Thus, identifying more effective biologic markers to select high-risk patients for adjuvant therapies, identify those who will respond to treatment, elucidate mechanisms of recurrence, and suggest novel therapies is a necessity. One important way to identify relevant biologic markers is to examine the relationship of human genetic variation (genetic polymorphisms) to disease recurrence and progression, and an important potential mechanism regulating melanoma recurrence and progression is variation in the immune and inflammatory response to melanoma. Our recent investigations have identified specific polymorphisms in human leukocyte antigen (HLA) class II and transforming growth factor-iSl (TGF-i81) genes as markers of prognosis in early-stage melanoma patients. HLA class II polymorphisms can regulate melanoma immune responses by differential binding of peptide antigens, whereas TGF-|31 polymorphisms can regulate tumor growth and metastasis by differential expression of TGF-jSI and immunomodulation. We hypothesize that genetic polymorphisms in these and other immune and inflammatory genes influence host response to melanoma and thereby melanoma progression. We propose a coordinated investigation of our most promising and mechanistically related polymorphisms in a large cohort of patients with melanoma (Aim 1) together with a genome-wide analysis to identify candidate loci most strongly linked with melanoma progression (Aim 2). We will use this information to develop an integrated and iterative risk model of melanoma progression incorporating clinical, histopathologic, serologic, and genetic information from more than 2000 patients with melanoma (Aim 3).
Determination of the most important genetic polymorphisms influencing melanoma progression will lead to more accurate identification of high-risk patients for adjuvant therapies, more accurate selection of systemic therapies for patients who have recurrences, and suggest novel treatment strategies.
|Ling, Hui; Pickard, Karen; Ivan, Cristina et al. (2016) The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis. Gut 65:977-89|
|Kim, Sun-Hee; Hashimoto, Yuuri; Cho, Sung-Nam et al. (2016) Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression. Pigment Cell Melanoma Res 29:297-308|
|Oba, Junna; Wei, Wei; Gershenwald, Jeffrey E et al. (2016) Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma. Medicine (Baltimore) 95:e3073|
|Van Roosbroeck, Katrien; Fanini, Francesca; Setoyama, Tetsuro et al. (2016) Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clin Cancer Res :|
|Roszik, Jason; Haydu, Lauren E; Hess, Kenneth R et al. (2016) Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. BMC Med 14:168|
|Paladini, Laura; Fabris, Linda; Bottai, Giulia et al. (2016) Targeting microRNAs as key modulators of tumor immune response. J Exp Clin Cancer Res 35:103|
|Siiskonen, Satu J; Zhang, Mingfeng; Li, Wen-Qing et al. (2016) A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants. Cancer Epidemiol Biomarkers Prev 25:714-20|
|Roszik, Jason; Wu, Chang-Jiun; Siroy, Alan E et al. (2016) Somatic Copy Number Alterations at Oncogenic Loci Show Diverse Correlations with Gene Expression. Sci Rep 6:19649|
|Han, Jun; Walters, James T R; Kirov, George et al. (2016) Gender differences in CNV burden do not confound schizophrenia CNV associations. Sci Rep 6:25986|
|Vaysse, Amaury; Fang, Shenying; Brossard, Myriam et al. (2016) A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants. Int J Cancer 139:2012-20|
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