Genetic analysis identifies putative tumor suppressor sites at 2q35-q36.1 and 2q36.3-q37.1 involved in cervical cancer progression
Genetic analysis identifies putative tumor suppressor sites at 2q35-q36.1 and 2q36.3-q37.1 involved in cervical cancer progression
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DOI：
10.1038/sj.onc.1206432
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发表时间：
2003-05-29
期刊：
影响因子：
8
通讯作者：
Murty, VVVS
中科院分区：
文献类型：
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作者：
Narayan, G;Pulido, HA;Murty, VVVS
我们进行了比较基因组杂交（CGH）和高分辨率缺失定位的长臂2号染色体（2 q）的浸润性宫颈癌（CC）。对52个CC进行CGH分析，发现2 q33-q36的遗传丢失，3q 26-q29的遗传获得，以及频繁的染色体扩增。通过杂合性缺失（洛）对60例原发性肿瘤的2 q缺失进行表征，确定了2 q35-q36.1和2q36.3-q37.1的两个最小缺失区域位点。为了描述这些基因改变在CC进展中发生的阶段，我们分析了33例宫颈上皮内瘤变（CIN）的洛缺失。我们发现89%的高级别（CINII和CINIII）和40%的低级别（CINI）CINs在2 q处表现出洛缺失。为了确定靶肿瘤抑制基因（TSG），我们对定位于缺失区域的许多候选基因进行了广泛的遗传和表观遗传分析。我们没有发现CASP 10，BARD 1，XRCC 5或PPP 1 R7基因定位到缺失区域的失活突变。然而，我们确实发现了CC细胞系中CFLAR、CASP 10和PPPIR 7基因表达下调的证据。我们还发现，在CC细胞系在体外暴露于去甲基化和组蛋白去乙酰化酶（HDAC）抑制剂后，基因表达重新激活。因此，这些数据确定了CC中频繁的染色体扩增，以及在CC发展中至关重要的2 q35-q36.1和2q36.3-q37.1处的TSG位点。
We performed comparative genomic hybridization (CGH) and high-resolution deletion mapping of the long arm of chromosome 2 (2q) in invasive cervical carcinoma (CC). The CGH analyses on 52 CCs identified genetic losses at 2q33-q36, gain of 3q26-q29, and frequent chromosomal amplifications. Characterization of 2q deletions by loss of heterozygosity (LOH) in 60 primary tumors identified two sites of minimal deleted regions at 2q35-q36.1 and 2q36.3-q37.1. To delineate the stage at which these genetic alterations occur in CC progression, we analysed 33 cervical intraepithelial neoplasia (CIN) for LOH. We found that 89% of high-grade (CINII and CINIII) and 40% of low-grade (CINI) CINs exhibited LOH at 2q. To identify the target tumor suppressor gene (TSG), we performed an extensive genetic and epigenetic analyses of a number of candidate genes mapped to the deleted regions. We did not find inactivating mutations in CASP10, BARD1, XRCC5, or PPP1R7 genes mapped to the deleted regions. However, we did find evidence of downregulated gene expression in CFLAR, CASP10 and PPPIR7 in CC cell lines. We also found reactivated gene expression in CC cell lines in vitro after exposure to demethylating and histone deacetylase (HDAC) inhibiting agents. Thus, these data identify frequent chromosomal amplifications in CC, and sites of TSGs at 2q35-q36.1 and 2q36.3-q37.1 that are critical in CC development.