PPM1D is a potential target for 17q gain in neuroblastoma.

Neuroblastomas (NBs) show complex patterns of genetic abnormalities, which may include amplification of the MYCN gene, deletion of 1p, or a gain of DNA at 17q, the last being the most frequent observation in NB tumors. However, the specific genes and the molecular mechanisms responsible for development and progression of NB remain poorly understood. We investigated aberrations of DNA copy number in 25 NB cell lines using comparative genomic hybridization and identified a minimal common region of gain at 17q23. Although gain of distal 17q is the most powerful genetic predictor of adverse outcome currently available for patients with NB, thus far, no potential target genes have been reported for that region. Therefore, we defined the 17q23 amplicon in detail and determined expression levels of 15 genes located within the smallest region of overlap observed among our NB cell lines to identify the most likely target gene(s). Among them, seven (CLTC, VMP1, delta-tubulin, RPS6KB1, FLJ22087, APPBP2, and PPM1D) were consistently overexpressed through increases in regional copy number. Analysis of expression levels of those seven genes in 32 primary NB tumors revealed a significant correlation between higher expression and poorer clinical outcome only with respect to PPM1D. Moreover, down-regulation of PPM1D by transfection of an antisense oligonucleotide suppressed the growth of NB cell lines to a remarkable degree, at least partly by participating in a process leading to apoptotic cell death. Taken together, our results indicate that PPM1D is the most likely target of the 17q23 gain/amplification in NB tumors and may have an important role in the pathogenesis of this disease.

[1]  N. Bown.  Neuroblastoma tumour genetics: clinical and biological aspects. , 2001, Journal of clinical pathology.

[2]  A. Cantor,et al.  Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. , 1993, The New England journal of medicine.

[3]  J. Carroll,et al.  Mechanisms of growth arrest by c-myc antisense oligonucleotides in MCF-7 breast cancer cells: implications for the antiproliferative effects of antiestrogens. , 2002, Cancer research.

[4]  J. Strahler,et al.  High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification. , 1991, The Journal of clinical investigation.

[5]  O. Delattre,et al.  Molecular analysis of chromosome arm 17q gain in neuroblastoma , 2000, Genes, chromosomes & cancer.

[6]  Rogier Versteeg,et al.  Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. , 1996, The New England journal of medicine.

[7]  J. Silber,et al.  Successful management of low-stage neuroblastoma without adjuvant therapies: a comparison of two decades, 1972 through 1981 and 1982 through 1992, in a single institution. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  I. Lewis,et al.  Gain of chromosome arm 17q predicts unfavourable outcome in neuroblastoma patients. U.K. Children's Cancer Study Group and the U.K. Cancer Cytogenetics Group. , 1997, European journal of cancer.

[9]  M. Wolter,et al.  Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Fiscella,et al.  Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F. Couch,et al.  Structural analysis of the 17q22-23 amplicon identifies several independent targets of amplification in breast cancer cell lines and tumors. , 2001, Cancer research.

[12]  F. Couch,et al.  17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes. , 2000, Cancer research.

[13]  J Pritchard,et al.  Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992. , 2000, European journal of cancer.

[14]  Lawrence A. Donehower,et al.  Mice Deficient for the Wild-Type p53-Induced Phosphatase Gene (Wip1) Exhibit Defects in Reproductive Organs, Immune Function, and Cell Cycle Control , 2002, Molecular and Cellular Biology.

[15]  H. Sather,et al.  Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. , 1985, The New England journal of medicine.

[16]  Marc J. van de Vijver,et al.  Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers , 2000, Nature Genetics.

[17]  D. Pinkel,et al.  Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors , 2022 .

[18]  A. Look,et al.  Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. , 1984, The New England journal of medicine.

[19]  F. Speleman,et al.  Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. , 1999, The New England journal of medicine.

[20]  D. Le Paslier,et al.  Additional copies of a 25 Mb chromosomal region originating from 17q23.1‐17qter are present in 90% of high‐grade neuroblastomas , 1996, Genes, chromosomes & cancer.

[21]  U. Galderisi,et al.  Differentiation and apoptosis of neuroblastoma cells: Role of N‐myc gene product , 1999, Journal of cellular biochemistry.

[22]  J. Inazawa,et al.  Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas. , 2001, Cancer research.

[23]  C. Wittwer,et al.  Continuous fluorescence monitoring of rapid cycle DNA amplification. , 1997, BioTechniques.

[24]  F. Speleman,et al.  Genetic heterogeneity of neuroblastoma studied by comparative genomic hybridization , 1998, Genes, chromosomes & cancer.

[25]  F. Speleman,et al.  Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumors lacking MYCN amplification , 2001, International journal of cancer.

[26]  K. Matthay,et al.  Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization. , 1997, The American journal of pathology.

[27]  Jeffrey R. Marks,et al.  Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23 , 2002, Nature Genetics.

[28]  Anne Kallioniemi,et al.  Targets of gene amplification and overexpression at 17q in gastric cancer. , 2002, Cancer research.

[29]  J. Inazawa,et al.  CD44 is a potential target of amplification within the 11p13 amplicon detected in gastric cancer cell lines , 2000, Genes, chromosomes & cancer.

[30]  J. Kononen,et al.  Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. , 2000, Cancer research.

[31]  H. Drexler,et al.  Detection of p53 gene mutations by single strand conformational polymorphism (SSCP) in human acute myeloid leukemia-derived cell lines. , 2002, Leukemia research.

[32]  G. Tonini,et al.  Numerical and structural aberrations in advanced neuroblastoma tumours by CGH analysis; survival correlates with chromosome 17 status , 2000, British Journal of Cancer.

[33]  K. Kawa,et al.  Stratification of treatment of stage 4 neuroblastoma patients based on N-myc amplification status. Study Group of Japan for Treatment of Advanced Neuroblastoma, Tokyo, Japan. , 1998, Medical and pediatric oncology.

[34]  S. Knuutila,et al.  Comparative genomic hybridization reveals changes in DNA-copy number in poor-risk neuroblastoma. , 2001, Cancer genetics and cytogenetics.

[35]  Masakazu Ueda,et al.  TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas , 2002, Hepatology.

[36]  M. Ohira,et al.  High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma , 2000, Oncogene.

[37]  Albert J. Fornace,et al.  Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity , 2002, Nature Genetics.

[38]  R. Simon,et al.  Comparative genomic hybridization and telomerase activity analysis identify two biologically different groups of 4s neuroblastomas. , 1998, British Journal of Cancer.

[39]  H. Taubert,et al.  Genomic imbalances of 7p and 17q in malignant peripheral nerve sheath tumors are clinically relevant , 1999, Genes, chromosomes & cancer.

[40]  T. Strachan,et al.  Breakpoint position on 17q identifies the most aggressive neuroblastoma tumors , 2002, Genes, chromosomes & cancer.

[41]  F. Berthold,et al.  Revisions of the international criteria for neuroblastoma diagnosis, staging and response to treatment. , 1993, Progress in clinical and biological research.

[42]  Michael L. Bittner,et al.  Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[43]  C. James,et al.  PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. , 2001, Journal of the National Cancer Institute.