title: Amplification of the STOML3, FREM2, and LHFP genes is associated with mesenchymal differentiation in gliosarcoma.
abstract: Gliosarcoma is a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas that display either glial (glial fibrillary acidic protein-positive) or mesenchymal (reticulin-positive) differentiation. Previous analyses have shown identical genetic alterations in glial and mesenchymal tumor areas, suggesting that gliosarcomas are genetically monoclonal, and mesenchymal differentiation was considered to reflect the elevated genomic instability of glioblastomas. In the present study, we compared genome-wide chromosomal imbalances using array comparative genomic hybridization in glial and mesenchymal tumor areas of 13 gliosarcomas. The patterns of gain and loss were similar, except that the gain at 13q13.3-q14.1 (log(2) ratio >3.0), containing the STOML3, FREM2, and LHFP genes, which was restricted to the mesenchymal tumor area of a gliosarcoma. Further analyses of 64 cases of gliosarcoma using quantitative PCR showed amplification of the STOML3, FREM2, and LHFP genes in 14 (22%), 10 (16%), and 7 (11%) mesenchymal tumor areas, respectively, but not in glial tumor areas. Results of IHC analysis confirmed that overexpression of STOML3 and FREM2 was more extensive in mesenchymal than in glial tumor areas. These results suggest that the mesenchymal components in a small fraction of gliosarcomas may be derived from glial cells with additional genetic alterations.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nagaishi
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Felice
authors.initials: F
authors.lastname: Giangaspero
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brokinkel
authors.forename: Anne
authors.initials: A
authors.lastname: Vital
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Catherine
authors.initials: C
authors.lastname: Legras-Lachuer
authors.forename: Joel
authors.initials: J
authors.lastname: Lachuer
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance; D002454:Cell Differentiation / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018316:Gliosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D059470:Tetraspanins
chemical_list: D016326:Extracellular Matrix Proteins; C500786:FREM2 protein, human; C574052:LHFPL6 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; C486764:STOML3 protein, human; D059470:Tetraspanins