Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression

Amy E. Rose, Laura Poliseno, Jinhua Wang, Michael Clark, Alexander Pearlman, Guimin Wang, Eleazar C. Vega Y Saenz De Miera, Ratna Medicherla, Paul J. Christos, Richard Shapiro, Anna Pavlick, Farbod Darvishian, Jiri Zavadil, David Polsky, Eva Hernando, Harry Ostrer, Iman Osman

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N = 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM.

Original languageEnglish (US)
Pages (from-to)2561-2571
Number of pages11
JournalCancer research
Volume71
Issue number7
DOIs
StatePublished - Apr 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Rose, A. E., Poliseno, L., Wang, J., Clark, M., Pearlman, A., Wang, G., Vega Y Saenz De Miera, E. C., Medicherla, R., Christos, P. J., Shapiro, R., Pavlick, A., Darvishian, F., Zavadil, J., Polsky, D., Hernando, E., Ostrer, H., & Osman, I. (2011). Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression. Cancer research, 71(7), 2561-2571. https://doi.org/10.1158/0008-5472.CAN-10-2958