Genetic analysis identifies putative tumor suppressor sites at 2q35-q36.1 and 2q36.3-q37.1 involved in cervical cancer progression

被引:63
作者
Narayan, G
Pulido, HA
Koul, S
Lu, XY
Harris, CP
Yeh, YA
Vargas, H
Posso, H
Terry, MB
Gissmann, L
Schneider, A
Mansukhani, M
Rao, PH
Murty, VVVS
机构
[1] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Inst Canc Genet, New York, NY 10032 USA
[3] Inst Nacl Canerol, Dept Genet, Santa Fe De Bogota, Colombia
[4] Inst Nacl Canerol, Dept Pathol, Santa Fe De Bogota, Colombia
[5] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA
[6] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA
[7] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany
[8] Univ Jena, Dept Obstet & Gynecol, D-6900 Jena, Germany
关键词
cervical carcinoma; chromosome; 2; CGH; gene amplification; LOH; cervical intraepithelial neoplasia;
D O I
10.1038/sj.onc.1206432
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3489 / 3499
页数:11
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