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Frequent alterations of cell-cycle regulators in astrocytic tumors as detected by molecular genetic and immunohistochemical analyses

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Abstract

Alterations ofCDKN2A, RB, andcyclin D1 genes and expression of their products in astrocytic tumors were studied using a combination of molecular genetic and immunohistochemical assays. In addition, the association of gene status with clinical outcome was evaluated. Alterations ofCDKN2A andRB gene in 30 lesions were analyzed by single-strand conformation polymorphism of polymerase chain reaction (PCR-SSCP), direct sequencing, and Western blotting. Methylation of theCDKN2A promoter was detected by methylation-specific PCR. Immunohistochemistry was applied to determine the expression of gene products in tumors from 94 patients for whom clinical outcome was also evaluated. Analyses of theCDKN2A gene revealed 12 homozygous or hemizygous deletions, one mutation in exon 1, and three methylations in the promoter. Expression of p16 protein was not detected in 18 of 30 cases.RB mutations leading to loss of expression of the pRb were found in four (13%) cases, and six were immunohistochemically negative for this protein. Overexpression of cyclin D1 was obtained in 51 (54%) of 94 cases. Patients with pRb-negative tumors had a significantly greater risk of earlier death than those with p16 and cyclin D1 alterations. Both p16 and pRb immunohistochemistry provides useful complementary information and may provide valuable predictive information in screening. The biological consequences of deregulating individual components along cell control pathways are unequal, perhaps reflecting their hierarchical roles in the G1 checkpoint.

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Authors and Affiliations

  1. Department of Neurosurgery, Nara Medical University, 840 Shijocho, Kashihara, 634-8522, Nara, Japan

    Mitsutoshi Nakamura, Shigeru Tsunoda, Hiroyuki Nakase, Toshihide Tsuzuki, Hideo Aoki, Hiroyuki Sakitani & Toshisuke Sakaki

  2. Second Department of Pathology, Nara Medical University, Nara, Japan

    Noboru Konishi, Yoshio Hiasa & Takuo Inui

Authors
  1. Mitsutoshi Nakamura
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  2. Noboru Konishi
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  3. Yoshio Hiasa
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  4. Shigeru Tsunoda
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  5. Hiroyuki Nakase
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  6. Toshihide Tsuzuki
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  7. Hideo Aoki
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  8. Hiroyuki Sakitani
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  9. Takuo Inui
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  10. Toshisuke Sakaki
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Correspondence to Mitsutoshi Nakamura.

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Nakamura, M., Konishi, N., Hiasa, Y. et al. Frequent alterations of cell-cycle regulators in astrocytic tumors as detected by molecular genetic and immunohistochemical analyses. Brain Tumor Pathol 15, 83–88 (1998). https://doi.org/10.1007/BF02478888

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  • DOI: https://doi.org/10.1007/BF02478888

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