Glioblastoma multiforme (GBM), a malignant astrocytic tumour, represents the most frequent tumour of the human brain. Nevertheless, its molecular pathology is not well understood. We utilized the immune system, which contributes to cancer protection, to help identify new GBM-related genes. By screening a human GBM cDNA library with autologous patient serum (SEREX-approach), we isolated a gene termed PHF3 (PHD finger protein 3). The gene product of PHF3 is immunogenic in GBM as tested in an allogenic patient serum screening demonstrating antibodies in 24 of 39 (61.53%) sera, whereas none of the 14 healthy persons had antibodies against PHF3. While previous SEREX studies revealed allogenic antibody responses up to 40%, our results for PHF3 represent the highest reported rate for a speci®c antibody response. We show that GBM patients with an antibody response against PHF3 show signi®cant better survival than patients without PHF3-speci®c antibodies. Because the amino acid sequence of PHF3 contains a PHD ®nger (also termed LAP motif), a TFIIS homology, a proline rich region and nuclear localization signals, it supposedly functions as a transcription factor. A polyclonal antibody generated against PHF3 shows nuclear expression in most investigated formalin-®xed, paran embedded tissues. In GBM, PHF3 expression is concentrated in cells surrounding necroses. Oncogene (2001) 20, 4107 ± 4114.
Using serological identification of recombinantly expressed tumor antigens (SEREX), we identified several autoantibodies against glioma‐expressed antigens including GLEA1, GLEA2 and PHD‐finger protein3 (PHF3). Analysing sera of 62 glioblastoma patients, we found an antibody response against GLEA1 in 15 sera (24.2%), against GLEA2 in 30 sera (48.4%) and against PHF3 in 35 sera (56.5%). Relating patient survival to the occurrence of autoantibodies against either GLEA1, GLEA2 or PHF3, we found a significant prolonged survival for glioblastoma patients positive for autoantibodies against GLEA2 (p = 0.0115) and PHF3 (p = 0.0031), respectively. The median survival of patients with GLEA2 antibodies was increased to 17.4 months and for patients with PHF3 antibodies to 14.7 months, as compared to 7.2 months for patients without GLEA2 or PHF3 antibodies. There was no significant correlation between patient survival and GLEA1‐autoantibodies (p = 0.1611). Herein we present autoantibodies that are: (i) most frequent in glioblastoma patients; (ii) specific for glioblastoma‐associated antigens; and (iii) significantly correlated with prolonged survival in patients with glioblastoma. © 2005 Wiley‐Liss, Inc.
SUMMARYGlioma constitutes the most frequent brain tumour in man with glioblastoma as the most prevalent and malignant type. The average survival time of less than 16 months underlines the need for improvements in diagnosis and therapy. Here, we report the identification of a novel antigen termed glioma-expressed antigen 2 (GLEA2) causing a frequent immune response in glioma patients. Screening of 450 000 clones from a glioblastoma lambda zap expression library with autologous patient serum revealed a group of five serum-positive clones sharing a high sequence homology. Further sequence analysis showed a sequence homology to a hepatocellular carcinoma associated antigen 58 (HCA58).
Glioblastoma is the most frequent brain tumor and accounts for approximately 50–60% of all astrocytic tumors. Many chromosome alterations have been described in glioblastoma, but only for a few alterations were the genes identified and linked to genetic pathways in glioblastoma development. To contribute to the identification of novel genes involved in glioblastoma development we used a combined immunological and molecular screening approach. Here we report the identification and expression analysis of a novel gene from human chromosome 6q12 that is considered to be the third member of a family of PHD finger containing genes and is termed PHF3. PHF3 is ubiquitously expressed in normal tissues including brain, but its expression is significantly reduced or lost in glioblastoma, glioblastoma cell lines, anaplastic astrocytomas and astrocytomas. The PHF3 protein sequence contains several protein motifs frequently found in transcription factors. One of those motifs is a PHD finger, also termed LAP motif and known to bind large portions of DNA. Another region of the protein revealed a high homology to the transcription factor TFIIS, especially to a region that is necessary for the Polymerase II binding properties of TFIIS. Combining these results, PHF3 is a novel member of a large class of regulatory proteins containing a LAP motif, and loss of its expression in glioblastoma may contribute to glioma development.
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