title: Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma.
abstract: BACKGROUND
  Mediastinal gray zone lymphoma is a newly recognized entity with transitional morphological and immunophenotypic features between the nodular sclerosis subtype of Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma. Diagnostic criteria for mediastinal gray zone lymphoma are still challenging, and the optimal therapy is as yet undetermined. Epigenetic changes have been implicated in the loss of the B-cell program in classical Hodgkin's lymphoma, and might provide a basis for the immunophenotypic alterations seen in mediastinal gray zone lymphoma.
  
  
  METHODS
  We performed a large-scale DNA methylation analysis of microdissected tumor cells to investigate the biological underpinnings of mediastinal gray zone lymphoma and its association with the related entities classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, making comparisons with the presumptively less related diffuse large B-cell lymphoma.
  
  
  RESULTS
  Principal component analysis demonstrated that mediastinal gray zone lymphoma has a distinct epigenetic profile intermediate between classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma but remarkably different from that of diffuse large B-cell lymphoma. Analysis of common hypo- and hypermethylated CpG targets in mediastinal gray zone lymphoma, classical Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma was performed and confirmed the findings of the principal component analysis. Based on the epigenetic profiles we were able to establish class prediction models utilizing genes such as HOXA5, MMP9, EPHA7 and DAPK1 which could distinguish between mediastinal gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma with a final combined prediction of 100%.
  
  
  CONCLUSIONS
  Our data confirm a close relationship between mediastinal gray zone lymphoma and both classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma. However, important differences were observed as well, allowing a clear distinction from both parent entities. Thus, mediastinal gray zone lymphoma cannot be assigned to either classical Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma, validating the decision to create an intermediate category in the World Health Organization classification.
authors: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Franziska C
authors: FC
authors: Eberle
authors: Jaime
authors: J
authors: Rodriguez-Canales
authors: Lai
authors: L
authors: Wei
authors: Jeffrey C
authors: JC
authors: Hanson
authors: J Keith
authors: JK
authors: Killian
authors: Hong-Wei
authors: HW
authors: Sun
authors: Lisa G
authors: LG
authors: Adams
authors: Stephen M
authors: SM
authors: Hewitt
authors: Wyndham H
authors: WH
authors: Wilson
authors: Stefania
authors: S
authors: Pittaluga
authors: Paul S
authors: PS
authors: Meltzer
authors: Louis M
authors: LM
authors: Staudt
authors: Michael R
authors: MR
authors: Emmert-Buck
authors: Elaine S
authors: ES
authors: Jaffe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D008875:Middle Aged; D008957:Models, Genetic; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D063146:Polycomb-Group Proteins; D012097:Repressor Proteins