High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors
High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors
复制标题
DOI：
10.1200/jco.2003.08.101
复制
发表时间：
2003-05-01
影响因子：
45.3
通讯作者：
G端nther, T
中科院分区：
文献类型：
--
作者：
Schneider-Stock, R;Boltze, C;G端nther, T
目的：胃肠道间质瘤（GIST）代表了一组独特的（但组织学异质性）肿瘤，其恶性潜力往往是不确定的。为了确定p16（INK 4）改变在GIST中的预后相关性，我们研究了一组较大的GIST，并将遗传学发现与临床病理因素和患者生存率相关联。我们通过甲基化特异性聚合酶链反应（PCR）评估启动子的甲基化状态，通过PCR-SSCP-测序评估突变的存在，p16（INK 4）基因座杂合性缺失采用免疫组化法检测39例患者43例GIST中p16（INK 4）蛋白的表达。43例GIST中25例（58.1%）发现p16（INK 4）改变，良性、交界性或恶性GIST在改变的类型和频率上无差异。p16（INK 4）的改变与p16（INK 4）蛋白表达的缺失相关（P <0.01）。肿瘤伴p16（INK 4）改变的患者预后比肿瘤不伴这种改变的患者差（P = 0.02）。p16（INK 4）改变仅在良性和交界性GIST组中对临床结果有较高的预测价值（P <0.01）。单变量考克斯比例风险回归分析显示p16（INK 4）改变、肿瘤大小、有丝分裂指数和总生存率之间存在强相关性（P <0.02），而多变量考克斯分析证实只有p16（INK 4）改变是独立的预后因素。我们认为p16（INK 4）改变状态的评估是一个有用的预测指标，特别是在良性和边缘性GIST组。
Purpose: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16(INK4) alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival.Material and Methods: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16(INK4) locus (using the c5.1 marker), and the immunohistochemical expression of p16(INK4) protein in 43 GISTs in 39 patients.Results: p16(INK4) alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16(INK4) alterations were correlated with a loss of p16(INK4) protein expression (P < .01). Patients who had tumors with p16(INK4) alterations had a poorer prognosis than patients with tumors without such alterations (P = .02). There was a high predictive value for p16(INK4) alterations only in the group of benign and borderline GISTs (P < .01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16(INK4) alterations, tumor size, mitotic index, and overall survival (P < .02), whereas multivariate Cox's analysis confirmed only p16(INK4) alterations as an independent prognostic factor.Conclusion: We believe that the evaluation of p16(INK4) alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.