Abnormalities of p16 gene and its expression in human brain tumors.

p16基因及其在人脑肿瘤中表达的异常。

• 批准号: 10670185
• 负责人: MOCHIZUKI Shigeki
• 金额: $ 1.02万
• 依托单位: Chiba Cancer Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670185/
• 关键词: human brain tumor; abnormalities in p16 gene; homozygous deletion; mutation; abnormal expression; p16遺伝子異常; E1β遺伝子変異

We have analyzed the status of candidate tumor suppressor p16 gene in 75 brain tumors (3 ependymomas, 9 oligodendrogliomas, 12 astrocytomas, 11 anaplastic astrosytomas, 1 medulloblastoma and 39 glioblastoma multiforms) from Japanese patients. With quantitative multiplex polymerase chain reaction (PCR) assay using the exon 2 primers of the p16 gene and control chromosome 9qSTS primers, we found homozygous deletion of the p16 gene in 7 cases; in 1 out of 11 anaplastic astrocytomas (HWO grade III), 6 out of 39 glioblastoma multiforms (gradeIV), but in none of the tumors of grade I or II. Using the single strand conformation polymorphism technique, mobility shift of PCR products were observed in 8 cases (1 astrocytoma, 1 anaplastic astrocytoma, 6 glioblastoma multiforms). DNA sequencing of the aberrantly migrated products revealed that 3 cases of glioblastoma multiform had mutations which caused amino acid substitutions in codon 66, 143 and 145.Immunohistochemical analysis using polyclonal anti-p16 antibody revealed frequent loss of p16 expression. Of 45 cases analyzed (1 ependymoma, 4 oligodendrogliomas, 5 astrocytomas, 6 anaplastic astrocytomas, 29 glioblastoma multiforms), 1 astrocytoma, 2 anaplastic astrocytomas, 6 glioblastoma multiforms did not express p16 in over 70% of tumor cells. In conclusion, homozygous deletion, mutation and abnormal expression of p16 gene was frequent in high grade malignancy. In addition, the low frequency of homozygous deletions shown in this study is quite different from previous reports that demonstrated frequently deleted p16 gene in malignant gliomas from Caucasian patients and suggesting a possible racial difference in the mechanism of the tumorigenesis of gliomas.

我们分析了75例日本脑肿瘤（3例室管膜瘤，9例少突胶质细胞瘤，12例星形细胞瘤，11例间变性星形细胞瘤，1例髓母细胞瘤和39例多形性胶质母细胞瘤）中候选肿瘤抑制基因p16的状态。采用p16基因外显子2引物和控制染色体9 qSTS引物进行定量多重聚合酶链反应（PCR）检测，我们发现7例p16基因纯合性缺失; 11例间变性星形细胞瘤（HWO III级）中有1例，39例多形性胶质母细胞瘤（IV级）中有6例，但I级或II级肿瘤中无一例。应用单链构象多态性技术，对8例星形细胞瘤（1例星形细胞瘤，1例间变性星形细胞瘤，6例多形性胶质母细胞瘤）的PCR产物进行了迁移率分析。DNA测序结果显示3例多形性胶质母细胞瘤中存在66、143和145位氨基酸的突变。免疫组化结果显示p16蛋白表达缺失。45例室管膜瘤1例，少突胶质细胞瘤4例，星形细胞瘤5例，间变性星形细胞瘤6例，多形性胶质母细胞瘤29例，其中1例星形细胞瘤，2例间变性星形细胞瘤，6例多形性胶质母细胞瘤70%以上肿瘤细胞不表达p16。结论：p16基因纯合性缺失、突变及异常表达在高度恶性肿瘤中较为常见。此外，本研究中所显示的低频率的纯合性缺失与以往报道的高加索人恶性胶质瘤中频繁缺失的p16基因有很大不同，提示胶质瘤发生机制可能存在种族差异。

项目成果

S.Mochizuki et al.: "Homozygous deletion of the p16/MTS-1/CDKN2 gene in malignant gliomas is infrequent among Japanese patients."Int. J. Oncol.. 15. 983-989 (1999)

S.Mochizuki 等人：“恶性胶质瘤中 p16/MTS-1/CDKN2 基因的纯合缺失在日本患者中并不常见。”Int.

S.Mochizuki et al.: "Abnormalities of p16 or PTEN gene in brain tumors"Proceedings of Annual Meeting of the Japanese Cancer Association. 57. 422 (1998)

S.Mochizuki 等：“脑肿瘤中 p16 或 PTEN 基因的异常”日本癌症协会年会论文集。

望月重信ら: "脳腫瘍におけるp16遺伝子およびPTEN遺伝子の異常"日本癌学会総会記事. 57. 422 (1998)

Shigenobu Mochizuki 等：“脑肿瘤中 p16 和 PTEN 基因的异常”日本癌症协会大会文章 57. 422 (1998)。

Y.Iwadate et al.: "Association of tumor suppressor genes alteration with chemosensitivity in astrocytic tumors"Annual Meeting of the Japan Neurosurgical Society. 57. 230 (1998)

Y.Iwadate 等人：“星形细胞肿瘤中肿瘤抑制基因改变与化疗敏感性的关联”日本神经外科学会年会。

岩立 康男ら: "Astrocytic tumorにおけるPTENおよびp16遺伝子異常と抗癌剤感受性との相関" 日本癌学会総会記事. 57. 139 (1998)

Yasuo Iwadate 等：“星形细胞肿瘤中 PTEN 和 p16 基因异常与抗癌药物敏感性之间的相关性”日本癌症协会大会文章 57. 139 (1998)。