Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets.
Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets.
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发表时间：
2003-06
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通讯作者：
A. Hirasawa;F. Saito-Ohara;J. Inoue;D. Aoki;N. Susumu;T. Yokoyama;S. Nozawa;J. Inazawa;I. Imoto
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作者：
A. Hirasawa;F. Saito-Ohara;J. Inoue;D. Aoki;N. Susumu;T. Yokoyama;S. Nozawa;J. Inazawa;I. Imoto
尽管肿瘤分期被认为是卵巢透明细胞腺癌（OCCAs）的一个显著特征，但它不可能完全解释该疾病的临床和生物学特征。本研究的目的是研究OCCA肿瘤中DNA拷贝数的异常，并确定遗传标记，以增加我们对OCCA发病机制的了解，并有助于更准确地预测患有这种疾病的个体患者的结果。实验设计我们通过比较基因组杂交的方法测定了20例原发性OCCA肿瘤的拷贝数畸变，并研究了它们与临床病理资料的关系。我们还通过定量实时逆转录-PCR测量了关键区域内候选靶基因的表达水平，并将这些数据与拷贝数状态和患者结局进行了比较。结果：我们在20例原发性OCCA肿瘤中发现了几种非随机染色体畸变。其中，17 q21-q24的DNA增加与无病生存期和总生存期呈显著负相关（P = 0.0012和0.0039，log-rank检验）。这种相关性甚至适用于I期肿瘤患者。在17 q21-q24区域内的15个候选基因中，我们发现PPM 1D和APPBP 2的表达显著升高，并且它们的表达升高与无病生存率呈负相关（P = 0.0090，多重比较调整的对数秩检验）。结论：从我们相对较大的OCCA肿瘤组中获得的信息表明，17 q21-q24的获得和随后的两个潜在靶点PPM 1D和APPBP 2的过表达与该肿瘤的恶性表型相关，并可能是有用的预后预测因子。
PURPOSE Although tumor stage is considered a prognosticfeature for ovarian clear cell adenocarcinomas (OCCAs), it is not likely to fully account for the clinical and biological variability characteristic of the disease. The aim of this study was to investigate aberrations of DNA copy number in OCCA tumors and identify genetic markers that would increase our understanding of the pathogenesis of OCCA and assist in more accurately predicting the outcome for an individual patient with this disease. EXPERIMENTAL DESIGN We determined copy number aberrations among 20 primary OCCA tumors by means of comparative genomic hybridization and investigated their relationship to clinicopathological data. We also measured expression levels of candidate target genes within critical regions by quantitative real-time reverse transcription-PCRs and compared those data with copy number status and patient outcomes. RESULTS We identified several nonrandom chromosomal aberrations among the 20 primary OCCA tumors examined. Among them, gain of DNA at 17q21-q24 showed significantly negative correlation with disease-free and overall survival (P = 0.0012 and 0.0039, respectively, log-rank test). This correlation held even for patients with stage I tumors. Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons). CONCLUSIONS Information gained from our relatively large panel of OCCA tumors suggested that 17q21-q24 gain and consequent overexpression of two potential targets, PPM1D and APPBP2, are associated with malignant phenotypes of this tumor and may be useful predictors for prognosis.