Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas
Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas
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DOI：
10.1093/jnci/90.19.1473
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发表时间：
1998-10-07
期刊：
影响因子：
--
通讯作者：
Louis, DN
中科院分区：
文献类型：
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作者：
Cairncross, JG;Ueki, K;Louis, DN
背景/方法：胶质瘤是中枢神经系统常见的恶性肿瘤，在胶质瘤的主要亚型中，少突胶质瘤的特点是对化疗具有显着的敏感性，大约三分之二的间变性（恶性）少突胶质瘤对丙卡巴嗪、洛莫司汀和长春新碱（称为PCV）的联合治疗反应显着。不幸的是，这些肿瘤的临床或病理特征无法准确预测其对化疗的反应。间变性少突胶质细胞瘤也以独特的分子遗传学改变群为特征，包括50%-70%的肿瘤中染色体臂1 p和19 q的同时丢失。我们假设这些或其他特定的遗传改变可能预测间变性少突胶质细胞瘤患者对化疗的反应和预后，因此，我们分析了涉及染色体1 p、10 q和19 q以及TP 53的分子遗传改变。（在染色体17 p上）和CDKN 2A（染色体9 p）基因，以及39例间变性少突胶质细胞瘤患者的临床病理特征，可以评估其化疗反应和生存率。结果/结论：染色体1 p的等位基因丢失（或杂合性丢失）是化疗敏感性的统计学显著预测因子，染色体1 p和19 q的联合丢失与化疗敏感性和化疗后较长的无复发生存期统计学显著相关。此外，在单变量和多变量分析中，涉及染色体1 p和19 q的丢失与较长的总生存期密切相关，而CDKN 2A基因缺失和环增强（即，对比增强形成肿瘤周围的边缘）与预后显著较差相关。CDKN 2A基因缺失与染色体Ip和19 q丢失之间的反比关系进一步表明，这些差异性临床行为反映了间变性少突胶质细胞瘤的两个独立的遗传亚型。这些结果表明，分子遗传学分析可能有助于治疗决策和预测预后的患者间变性少突胶质细胞瘤。
Background/Methods: Gliomas are common malignant neoplasms of the central nervous system, Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas, Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed. Results/Conclusions: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes Ip and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas.