Seidel Claudia, Bartel Frank, Rastetter Matthias, Bluemke Karen, Wurl Peter, Taubert Helge, Dammann Reinhard
Autonomous Work Group Tumor Genetics of the Medical Faculty, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
Int J Cancer. 2005 Apr 10;114(3):442-7. doi: 10.1002/ijc.20707.
Aberrant methylation is a main mechanism of tumor suppressor gene inactivation in carcinogenesis. In this study, the methylation status of RASSF1A, p16, MLH1, MSH2 and ERalpha was investigated in 84 primary soft tissue sarcomas (STSs), including 22 liposarcomas, 18 malignant fibrous histiocytomas (MFHs), 18 leiomyosarcomas, 6 rhabdomyosarcomas, 6 neurogenic sarcomas and several other sarcoma entities. RASSF1A hypermethylation was detected in 17 of 84 (20%) STSs; however, methylation was more frequent in leiomyosarcomas (39%) compared to MFHs (6%; p < 0.015) and liposarcomas (18%). The p16 CpG island was methylated in 22 out of 82 (27%) cases. In 7 out of 81 (9%) STS samples, the promoter of MLH1 was methylated and in liposarcoma the methylation frequency was higher (14%). For MSH2, no hypermethylation was detected. Methylation of ERalpha was detected in 48 of 63 (76%) STSs, but also in 4 of 8 (50%) normal tissue samples. Furthermore, we analyzed mutational activation of K-ras and BRAF. In 4 out of 84 (5%) of STSs, a substitution at codon 599 of BRAF was found; however, no alteration of K-ras was detected. In an univariate Cox proportional-hazards regression model, we found that the risk of a tumor-related death for STS patients with methylated RASSF1A was significantly increased (RR = 2.9; p = 0.037). In summary, our data indicate that inactivation of RASSF1A is a common event in STS, especially in leiomyosarcoma. Thus, the methylation status of cancer-related genes was distinct in different STS and methylation of RASSF1A promoter can serve as prognostic marker in STSs.
异常甲基化是肿瘤发生过程中肿瘤抑制基因失活的主要机制。在本研究中，对84例原发性软组织肉瘤（STS）进行了RASSF1A、p16、MLH1、MSH2和ERα的甲基化状态研究，其中包括22例脂肪肉瘤、18例恶性纤维组织细胞瘤（MFH）、18例平滑肌肉瘤、6例横纹肌肉瘤、6例神经源性肉瘤以及其他几种肉瘤类型。84例STS中有17例（20%）检测到RASSF1A高甲基化；然而，与MFH（6%；p < 0.015）和脂肪肉瘤（18%）相比，平滑肌肉瘤中甲基化更为常见（39%）。82例中有22例（27%）的p16 CpG岛发生甲基化。81例STS样本中有7例（9%）MLH1启动子发生甲基化，脂肪肉瘤中的甲基化频率更高（14%）。未检测到MSH2的高甲基化。63例STS中有48例（76%）检测到ERα甲基化，但8例正常组织样本中也有4例（50%）检测到。此外，我们分析了K-ras和BRAF的突变激活情况。84例STS中有4例（5%）发现BRAF第599密码子发生替换；然而，未检测到K-ras改变。在单因素Cox比例风险回归模型中，我们发现RASSF1A甲基化的STS患者肿瘤相关死亡风险显著增加（RR = 2.9；p = 0.037）。总之，我们的数据表明RASSF1A失活在STS中是常见事件，尤其是在平滑肌肉瘤中。因此，癌症相关基因的甲基化状态在不同的STS中有所不同，RASSF1A启动子甲基化可作为STS的预后标志物。
