Response to the methylation inhibitor dihydro-5-azacytidine in mesothelioma is not associated with methylation of p16INK4a -: Results of cancer and leukemia group B 159904
Response to the methylation inhibitor dihydro-5-azacytidine in mesothelioma is not associated with methylation of p16INK4a -: Results of cancer and leukemia group B 159904
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DOI：
10.1097/jto.0b013e318168da0a
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发表时间：
2008-04-01
影响因子：
20.4
通讯作者：
Kern, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Kratzke, Robert A.;Wang, Xiaofei;Kern, Jeffrey A.
简介：间皮瘤中肿瘤发生的分子机制涉及细胞生长的负调节因子包括p16（INK 4a）的丢失。迄今为止，几乎所有间皮瘤肿瘤和细胞系都表现出p16（INK 4a）基因产物表达的缺失。在更常见的肿瘤如肺癌中也经常观察到p16（INK 4a）表达的缺失。在包括肺癌在内的多种恶性肿瘤中，已知p16（INK 4a）表达会因第一个外显子的超甲基化而失活。这个项目（CALGB 159904）旨在检验间皮瘤中通过甲基化导致的p16（INK 4a）丢失与对胞苷类似物和甲基化抑制剂二氢-5-氮杂胞苷（DHAC）的应答相关的假设。使用来自CALGB 8833和9031的组织样品，这两项临床研究在间皮瘤中使用基于DHAC的疗法，结果：20例标本中有4例p16甲基化（INK 4a）阳性，其中1例为阴性，另1例为阴性。尽管生存率有提高的趋势，但结果并不具有统计学意义。结论：p16（INK 4a）甲基化的存在与DHAC治疗的反应或总生存率之间没有显着相关性。
Introduction: The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16(INK4a) Absence of expression of the p16(INK4a) gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16(INK4a) expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16(INK4a) expression is known to be inactivated by hypermethylation of the first exon. This project (CALGB 159904) intended to test the hypothesis that in mesothelioma loss of p16(INK4a) via methylation would con-elate with response to the cytidine analog and methylation inhibitor dihydro-5-azacytidine (DHAC).Methods: Using tissue samples from CALGB 8833 and 9031, two clinical studies which used DHAC based therapy in mesothelioma, this study tested the hypothesis that tumors possessing methylation of p16(INK4a) would have a better response and survival following DHAC treatment than their nonmethylated counterparts.Results: Methylation of p16(INK4a) was identified in 4 of the 20 specimens. Although there was a trend towards improved survival the result was not statistically significant.Conclusions: There was no significant correlation between the presence of p16(INK4a) methylation and response to DHAC therapy or overall survival.