The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer
The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer
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DOI：
10.1002/ijc.21862
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发表时间：
2006-08-01
影响因子：
6.4
通讯作者：
Perucho, Manuel
中科院分区：
文献类型：
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作者：
Bilbao, Cristina;Rodriguez, German;Perucho, Manuel
微卫星不稳定性（MSI）和PTEN基因突变是参与子宫内膜癌发生的分子改变。关于它们在这类肿瘤中的作用，有相互矛盾的信息。出于这个原因，我们在205例散发性子宫内膜癌患者中研究了这两种分子病变。MSI 41例（20.0%），PTEN突变74例（36.1%）。存在与不存在MSI的肿瘤在基因型上存在差异。MSI肿瘤显示PTEN突变的频率更高（58.5%比30.4%）（p = 0.002， Fisher精确检验），PTEN基因单核苷酸束内单个核苷酸的插入或缺失（I/D）数量更高（45.8%比11.4%,p = 0.005）。相反，CpG二核苷酸的G:C到A:T的转变主要在微卫星稳定肿瘤中发现（57.7%比18.2%,p = 0.037）。总体而言，67.6%的PTEN突变肿瘤表现为多重突变或等位基因失衡（AI）。同一肿瘤中多个PTEN突变在MSI肿瘤中更为常见（60%比25.7%）；AI伴PTEN突变在微卫星稳定型肿瘤中较高（74.3% vs. 40%） （p = 0.028）。此外，两种基因改变的患者被诊断为更晚期的进展阶段（MSI为54.2%，MSS为20.0%）。p = 0.006)，预后差（风险比[95%可信区间]:3.0 [1.1-13.1],p = 0.034， log-rank检验）。我们的数据表明，DNA错配修复系统的状态影响：(i) PTEN的频率和突变谱；(h)使该肿瘤抑制基因失活的一种打击的性质；（三）患者的临床情况和行为。(c) 2006 Wiley-Liss, Inc。
Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p = 0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p = 0.005). Conversely G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p = 0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p = 0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS. p = 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p = 0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (h) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients. (c) 2006 Wiley-Liss, Inc.