Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer
Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer
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DOI：
10.1038/sj.onc.1208906
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发表时间：
2005-11-17
期刊：
影响因子：
8
通讯作者：
Schwartz, S
中科院分区：
文献类型：
--
作者：
Oliveira, C;Velho, R;Schwartz, S
RASSF 1A的甲基化相关失活经常在几种人类恶性肿瘤中观察到，包括散发性结直肠癌和胃癌。然而，在MMR缺陷的胃肠道肿瘤中，RASSF 1A甲基化状态还不清楚。在这项研究中，我们系统地分析了KRAS，BRAF和RASSF 1A的改变，以确定。在MSI胃肠道肿瘤的三个不同亚群中，这些遗传/表观遗传改变的频率和模式。此外，RASSF 1A甲基化和临床病理参数之间的相关性研究，以确定前。隐藏着这种表观遗传事件的肿瘤。通过MSP和DNA测序分析了56例MSI散发性胃肠道肿瘤（31例结直肠肿瘤和25例胃肿瘤）和20例MSI HNPCC的RASSF 1A启动子超甲基化。散发性MSI结直肠癌和胃癌与HNPCC癌RASSF 1A甲基化频率无显著差异（P = 0.31）。31例散发性MSI结直肠癌中有16例（52%）、25例MSI胃癌中有11例（44%）以及20例HNPCC癌中有6例（30%）存在RASSF 1A甲基化。近36%的MSI散发性结直肠癌（CRC）在KRAS和/或BRAF处存在RASSF 1A甲基化和激活突变。相比之下，只有10%和8%的HNPCC和散发性胃癌，分别伴随KRAS突变和RASSF 1A甲基化。RASSF 1A甲基化的MSI散发性胃癌和CRC优先低分化（P = 0.03，0.05，分别）。我们证明了亲。尽管RASSF 1A、KRAS/BRAF的改变在三组MSI胃肠道肿瘤中存在差异。此外，我们证明MSI散发性CRC在RASSF 1A、KRAS/BRAF中积累了比MSI散发性胃癌或HNPCC显著更多的表观遗传/遗传改变（P = 0.016）。这些结果可能在不久的将来具有治疗意义，因为在携带KRAS或BRAF突变和RASSF 1A甲基化的MSI肿瘤类型中单独使用特异性激酶抑制剂或与去甲基化剂联合使用的可能性。
Methylation-associated inactivation of RASSF1A has frequently been observed in several human malignancies including sporadic colorectal and gastric cancer. However, nothing is known about the RASSF1A methylation status in the setting of MMR-deficient gastrointestinal tumours. In this study, we analysed systematically alterations in KRAS, BRAF and RASSF1A, in order to de. ne the frequency and the pattern of these genetic/epigenetic alterations in three distinct subsets of MSI gastrointestinal tumours. Further, an association study was performed between RASSF1A methylation and the clinicopathological parameters in order to determine the pro. le of tumours harbouring this epigenetic event. A total of 56 MSI sporadic gastrointestinal tumours (31 colorectal and 25 gastric) and 20 MSI HNPCC analysed for KRAS/BRAF were analysed for RASSF1A promoter hypermethylation by MSP and DNA sequencing. No significant differences were found between the frequency of RASSF1A methylation in sporadic MSI colorectal and gastric carcinomas and HNPCC carcinomas (P = 0.31). Methylation of RASSF1A was present in 16 of 31 (52%) sporadic MSI colorectal and 11 of 25 (44%) MSI gastric carcinomas, and in six of 20 (30%) HNPCC carcinomas. Nearly 36% of MSI sporadic colorectal carcinomas (CRCs) had RASSF1A methylation and activating mutations at KRAS and/or BRAF. In contrast, only 10 and 8% of HNPCC and sporadic gastric carcinomas, respectively, had concomitant KRAS mutations and RASSF1A methylation. The MSI sporadic gastric and CRCs with RASSF1A methylation were preferentially poorly differentiated (P = 0.03, 0.05, respectively). We show that the pro. le of alterations RASSF1A, KRAS/BRAF is different among the three groups of MSI gastrointestinal tumours. Further, we demonstrate that MSI sporadic CRCs accumulated significantly more epigenetic/genetic alterations in RASSF1A, KRAS/BRAF than MSI sporadic gastric or HNPCC carcinomas (P = 0.016). These results are likely to have therapeutic implications in the near future, due to the possibilities of using specific kinase inhibitors alone or in association with demethylating agents in MSI tumour types harbouring KRAS or BRAF mutations and RASSF1A methylation.