Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway
Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway
复制标题
DOI：
10.1038/onc.2009.474
复制
发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Aburatani, H.
中科院分区：
文献类型：
--
作者：
Murayama-Hosokawa, S.;Oda, K.;Aburatani, H.
子宫内膜癌是其中可能发生染色体不稳定性（CIN）或微卫星不稳定性（MSI）的肿瘤类型之一。已知其在Ras-PI 3 K（磷脂酰肌醇30-激酶）途径中频繁地具有突变。我们对31例具有染色体失衡配对DNA的子宫内膜癌进行了全面的基因组调查（25例通过50 K单核苷酸多态性（SNP）阵列，6例通过250 K单核苷酸多态性（SNP）阵列）），并对31个样本中的25个样本进行了MSI状态和突变状态筛查Ras-PI 3 K途径基因。我们在9例（29%）肿瘤中检测到5个或更多拷贝数变化（分类为CIN广泛），17例（55%）肿瘤中检测到1至4个变化（CIN中间），5例（16%）肿瘤中无变化（CIN阴性）。MSI阳性率在CIN-广泛性肿瘤（14%）中较CIN-中等/阴性肿瘤（50%）低，多因素分析显示CIN-广泛性肿瘤是一个独立的预后不良因素。SNP芯片分析显示13例（42%）肿瘤在54个位点存在拷贝数中性洛丢失，其中4个位于PTEN位点。除了8例（26%）PTEN缺失的肿瘤外，我们还分别在4例（13%）、4例（13%）和6例（19%）肿瘤中检测到NF 1、K-Ras和PIK 3CA的染色体不平衡。总的来说，9个CIN广泛性肿瘤中的7个在PTEN和/或NF 1的基因座中具有缺失，而所有10个MSI阳性肿瘤具有PTEN、PIK 3CA和/或K-Ras突变。我们的研究结果表明，Ras-PI 3 K通路的基因组改变在子宫内膜癌中非常普遍，无论基因组不稳定的类型如何，并表明CIN的程度是子宫内膜癌预后的有用生物标志物。Oncogene（2010）29，1897-1908; doi：10.1038/onc.2009.474; 2010年1月11日在线发表
Endometrial cancer is one of the tumor types in which either chromosomal instability (CIN) or microsatellite instability (MSI) may occur. It is known to possess mutations frequently in the Ras-PI3K (phosphatidylinositol 30-kinase) pathway. We performed a comprehensive genomic survey in 31 endometrial carcinomas with paired DNA for chromosomal imbalances (25 by the 50K and 6 by the 250K single-nucleotide polymorphism (SNP) array), and screened 25 of the 31 samples for MSI status and mutational status in the Ras-PI3K pathway genes. We detected five or more copy number changes (classified as CIN-extensive) in 9 (29%), 1 to 4 changes (CIN-intermediate) in 17 (55%) and no changes (CIN-negative) in 5 (16%) tumors. Positive MSI was less common in CIN-extensive tumors (14%), compared with CIN-intermediate/negative tumors (50%), and multivariate analysis showed that CIN-extensive is an independent poor prognostic factor. SNP array analysis unveiled copy number neutral LOH at 54 loci in 13 tumors (42%), including four at the locus of PTEN. In addition to eight (26%) tumors with PTEN deletions, we detected chromosomal imbalances of NF1, K-Ras and PIK3CA in four (13%), four (13%) and six (19%) tumors, respectively. In all, 7 of the 9 CIN-extensive tumors harbor deletions in the loci of PTEN and/or NF1, whereas all the 10 MSI-positive tumors possess PTEN, PIK3CA and/or K-Ras mutations. Our results showed that genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability, and suggest that the degree of CIN is a useful biomarker for prognosis in endometrial carcinomas. Oncogene (2010) 29, 1897-1908; doi:10.1038/onc.2009.474; published online 11 January 2010