title: Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations.
abstract: BACKGROUND
  Pheochromocytoma and paraganglioma are rare neural-crest-derived tumors. They are metastatic in 15% of cases, and the identification of a germline mutation in the SDHB gene is a predictive risk factor for malignancy and poor prognosis. To date, the link between SDHB mutations and malignancy is still missing.
  
  
  OBJECTIVE
  Epithelial to mesenchymal transition (EMT) is a developmental event, reactivated in cancer cells to promote cell mobility and invasiveness. The aim of this study was to address the participation of EMT in the metastatic evolution of pheochromocytoma/paraganglioma.
  
  
  METHODS
  Transcriptomic profiling of EMT was performed on 188 tumor samples, using a set of 94 genes implicated in this pathway. Activation of EMT was further confirmed at protein level by immunohistochemistry in a second set of 93 tumors.
  
  
  RESULTS
  Hierarchical unsupervised classification showed that most SDHB-metastatic samples clustered together, indicating that EMT is differently regulated in these tumors. Major actors of EMT, metalloproteases and components of cellular junctions, were either up-regulated (LOXL2, TWIST, TCF3, MMP2, and MMP1) or down-regulated (KRT19 and CDH2) in SDHB-metastatic tumors compared with nonmetastatic ones. Interestingly, within metastatic tumors, most of these genes (LOXL2, TWIST, TCF3, MMP2, and KRT19) also allowed us to discriminate SDHB-mutated from non-SDHB-related tumors. In the second set of tumors, we studied Snail1/2 expression by immunohistochemistry and observed its specific nuclear translocation in all SDHB-metastatic tumors.
  
  
  CONCLUSIONS
  We have identified the first pathway that distinguishes SDHB-metastatic from all other types of pheochromocytomas/paragangliomas and suggest that activation of the EMT process might play a critical role in the particularly invasive phenotype of this group of tumors.
authors.affiliation: Centre de recherche cardiovasculaire de l'Hôpital Européen Georges Pompidou, 56 rue Leblanc 75015 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Loriot
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Noémie
authors.initials: N
authors.lastname: Gadessaud
authors.forename: Laure
authors.initials: L
authors.lastname: Vescovo
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D007365:Intercellular Junctions / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010235:Paraganglioma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics* / Q000556:secondary; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000594:Amino Acid Oxidoreductases; D051792:Basic Helix-Loop-Helix Proteins; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; D013385:Succinate Dehydrogenase; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C000604407:SNAI1 protein, human; C407909:TCF3 protein, human; C103173:TWIST1 protein, human; C108095:SDHB protein, human; C119091:LOXL2 protein, human