Abstract #2604: HMGA2 is a novel prognostic factor in melanoma

Abstract

BACKGROUND: The molecular genetic alterations contributing to the pathogenesis of melanoma are incompletely defined and few independent prognostic features have been identified beyond the pathologic characteristics of the primary tumor. Early stage melanoma is frequently curable, in contrast to the inferior prognosis of melanomas with regional lymph nodes involvement and the incurability of distant metastatic disease. The identification of novel tumor-specific markers may improve our understanding of melanoma progression and prognostic accuracy. METHODS: To find differentially expressed genes that can distinguish melanoma from normal tissue, we performed a whole genome expression profiling of 46 primary melanoma samples, 12 regional or distant metastases, and 16 normal skin samples using Affymetrix U133 2.0 Plus array. RESULTS: HMGA2, previously unrecognized in the pathogenesis of melanoma, is an oncogene and transcription factor that is significantly upregulated both in primary melanoma and metastatic melanoma (p-values=1.2x10-7 and 9x10-5) compared to normal skin. Overexpression of HMGA2 is associated with BRAF/NRAS mutations (Odds ratio = 22.7, 95% confidence interval (CI) = 4.7-109.0, p= <0.0001). Survival analysis using Cox multivariable model and stratified log-rank test showed that expression levels of HMGA2 are significantly associated with disease-free survival (hazard ratio (HR) = 3.5, 95% CI = 1.2-10.1, p=0.0195), overall survival (log-rank p=0.0093), and distant metastases-free survival (HR=4.8, 95% CI = 1.2-18.6, p=0.0239). The median follow-up was 4 years in the primary melanoma group. In addition, the multivariate survival analysis, which included AJCC stage, demonstrated that overexpression of HMGA2 in primary melanoma is an independent predictor of regional lymph node metastases and local recurrence, even after adjustment for BRAF/NRAS mutations. CONCLUSIONS: HMGA2 is a transcription factor that is expressed during embryogenesis, is absent or undetectable in normal tissue, and is highly overexpressed in melanoma. HMGA2 expression is also strongly associated with the presence of regional and distant metastases and warrants further investigation as a biomarker predictive of lymph node metastases in prospective clinical trials. HMGA2 expression is an independent predictor of disease-free survival and overall survival in melanoma.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2604.