结直肠癌中p16和MGMT基因的共甲基化：与临床病理特征的相关性及预后价值
Comethylation of p16 and MGMT genes in colorectal carcinoma: correlation with clinicopathological features and prognostic value.
作者信息
Krtolica Koviljka, Krajnovic Milena, Usaj-Knezevic Slavica, Babic Dragan, Jovanovic Dusan, Dimitrijevic Bogomir
机构信息
Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, P. O. BOX 522, Belgrade, Serbia.
出版信息
World J Gastroenterol. 2007 Feb 28;13(8):1187-94. doi: 10.3748/wjg.v13.i8.1187.
AIM
To investigate the significance of p16 and O(6)-methylguanine-DNA methyltransferase (MGMT) genes promoter hypermethylation and K-ras mutations on colorectal tumorigenesis and progression.
METHODS
p16 and MGMT methylation status was examined on 47 tumor samples, and K-ras mutational status was examined on 85 tumor samples. For methylation analysis, a methylation specific PCR (MS-PCR) method was used.
RESULTS
p16 and MGMT promoter methylation was found in 51% (24/47) and 43% (20/47) of CRCs, respectively, and the K-ras mutation was found in 44% (37/85) of CRCs. Comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease within a two-year period of observation. Only 27% of patients with simultaneous p16 and MGMT methylation showed the detectable occurrence of metastasis and/or death, compared to 67% of patients without double methylation or with no methylation (3/11 vs 22/33, P < 0.05, chi(2)-test). In addition, p16 and MGMT comethylation showed a trend toward an association with longer survival in patients with CRCs (35.5 +/- 6.0 mo vs 23.1 +/- 3.2 mo, P = 0.072, Log-rank test). Progression of the disease within a two-year period was observed in 66% of patients carrying the K-ras mutation, compared to only 19% of patients with wild type K-ras (29/44 vs 7/37, P < 0.001, chi(2)-test). The presence of the K-ras mutation significantly correlated to shortened overall survival (20.0 +/- 1.9 mo vs 37.0 +/- 1.8 mo, P < 0.001, Log-rank test). The comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease even when K-ras mutations were included in the analysis as an independent variable.
CONCLUSION
Our data suggest that comethylation of promoters of p16 and MGMT genes could have a prognostic value in patients with CRC. Specifically, concurrent methylation of both genes correlates with better prognosis.
目的
探讨p16和O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因启动子高甲基化及K-ras突变在结直肠癌发生发展中的意义。
方法
检测47例肿瘤样本中的p16和MGMT甲基化状态，检测85例肿瘤样本中的K-ras突变状态。甲基化分析采用甲基化特异性PCR（MS-PCR）方法。
结果
在结直肠癌患者中，p16和MGMT启动子甲基化分别见于51%（24/47）和43%（20/47），K-ras突变见于44%（37/85）。在两年的观察期内，p16和MGMT基因的共同甲基化与疾病侵袭性较低显著相关。同时存在p16和MGMT甲基化的患者中，仅27%出现可检测到的转移和/或死亡，而无双重甲基化或无甲基化的患者中这一比例为67%（3/11 vs 22/33，P<0.05，卡方检验）。此外，p16和MGMT共同甲基化在结直肠癌患者中显示出与更长生存期相关的趋势（35.5±6.0个月 vs 23.1±3.2个月，P = 0.072，对数秩检验）。携带K-ras突变的患者中，66%在两年内疾病进展，而野生型K-ras患者中这一比例仅为19%（29/44 vs 7/37，P<0.001，卡方检验）。K-ras突变的存在与总生存期缩短显著相关（20.0±1.9个月 vs 37.0±1.8个月，P<0.001，对数秩检验）。即使将K-ras突变作为独立变量纳入分析，p16和MGMT基因的共同甲基化仍与疾病侵袭性较低显著相关。
结论
我们的数据表明，p16和MGMT基因启动子的共同甲基化可能对结直肠癌患者具有预后价值。具体而言，两个基因的同时甲基化与较好的预后相关。
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