title: Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression.
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.
authors.affiliation: Department of Dermatology, New York University School of Medicine, New York, New York, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Rose
authors.forename: Laura
authors.initials: L
authors.lastname: Poliseno
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Clark
authors.forename: Alexander
authors.initials: A
authors.lastname: Pearlman
authors.forename: Guimin
authors.initials: G
authors.lastname: Wang
authors.forename: Eleazar C
authors.initials: EC
authors.lastname: Vega Y Saenz de Miera
authors.forename: Ratna
authors.initials: R
authors.lastname: Medicherla
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christos
authors.forename: Richard
authors.initials: R
authors.lastname: Shapiro
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: David
authors.initials: D
authors.lastname: Polsky
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
authors.forename: Harry
authors.initials: H
authors.lastname: Ostrer
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D016014:Linear Models; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase