title: Clonal analysis in recurrent astrocytic, oligoastrocytic and oligodendroglial tumors implicates IDH1- mutation as common tumor initiating event.
abstract: BACKGROUND
  To investigate the dynamics of inter- and intratumoral molecular alterations during tumor progression in recurrent gliomas.
  
  
  RESULTS
  To address intertumoral heterogeneity we investigated non-microdissected tumor tissue of 106 gliomas representing 51 recurrent tumors. To address intratumoral heterogeneity a set of 16 gliomas representing 7 tumor pairs with at least one recurrence, and 4 single mixed gliomas were investigated by microdissection of distinct oligodendroglial and astrocytic tumor components. All tumors and tumor components were analyzed for allelic loss of 1p/19q (LOH 1p/19q), for TP53- mutations and for R132 mutations in the IDH1 gene. The investigation of non-microdissected tumor tissue revealed clonality in 75% (38/51). Aberrant molecular alterations upon recurrence were detected in 25% (13/51). 64% (9/14) of these were novel and associated with tumor progression. Loss of previously detected alterations was observed in 36% (5/14). One tumor pair (1/14; 7%) was significant for both. Intratumoral clonality was detected in 57% (4/7) of the microdissected tumor pairs and in 75% (3/4) of single microdissected tumors. 43% (3/7) of tumor pairs and one single tumor (25%) revealed intratumoral heterogeneity. While intratumoral heterogeneity affected both the TP53- mutational status and the LOH1p/19q status, all tumors with intratumoral heterogeneity shared the R132 IDH1- mutation as a common feature in both their microdissected components.
  
  
  CONCLUSIONS
  The majority of recurrent gliomas are of monoclonal origin. However, the detection of divertive tumor cell clones in morphological distinct tumor components sharing IDH1- mutations as early event may provide insight into the tumorigenesis of true mixed gliomas.
authors: Clinical Cooperation Unit Neuropathology, German Cancer Center (DKFZ), Heidelberg, Germany.
authors: Ulrike
authors: U
authors: Lass
authors: Astrid
authors: A
authors: Nümann
authors: Kajetan
authors: K
authors: von Eckardstein
authors: Jürgen
authors: J
authors: Kiwit
authors: Florian
authors: F
authors: Stockhammer
authors: Jörn A
authors: JA
authors: Horaczek
authors: Julian
authors: J
authors: Veelken
authors: Christel
authors: C
authors: Herold-Mende
authors: Judith
authors: J
authors: Jeuken
authors: Andreas
authors: A
authors: von Deimling
authors: Wolf
authors: W
authors: Mueller
mesh_terms: D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D003062:Codon / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009837:Oligodendroglioma / Q000235:genetics* / Q000473:pathology*; D012008:Recurrence; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D003062:Codon; D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human