title: Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers.
abstract: BACKGROUND
  Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia.
  
  
  RESULTS
  We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2gamma) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13-40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH.
  
  
  CONCLUSIONS
  This study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females.
authors.affiliation: University Dept. of Growth & Reproduction, Rigshospitalet, Copenhagen, Denmark. chh@dadlnet.dk
authors.forename: Christina E
authors.initials: CE
authors.lastname: Hoei-Hansen
authors.forename: Sigrid M
authors.initials: SM
authors.lastname: Kraggerud
authors.forename: Vera M
authors.initials: VM
authors.lastname: Abeler
authors.forename: Janne
authors.initials: J
authors.lastname: Kaern
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D018236:Carcinoma, Embryonal / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000032:analysis; D002454:Cell Differentiation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000032:analysis; D004407:Dysgerminoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D054278:Embryonal Carcinoma Stem Cells; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D005865:Gestational Age; D018238:Gonadoblastoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis; D009154:Mutation; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000032:analysis; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000032:analysis; D009867:Oogonia / Q000737:chemistry / Q000473:pathology; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D010053:Ovary / Q000737:chemistry / Q000196:embryology; D039904:Pluripotent Stem Cells / Q000737:chemistry / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics*; D050656:Transcription Factor AP-2 / Q000032:analysis
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C104948:CTAG1B protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C095204:MAGEA4 protein, human; D008565:Membrane Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C493679:TFAP2C protein, human; C497749:TSPY1 protein, human; D050656:Transcription Factor AP-2; D019009:Proto-Oncogene Proteins c-kit