Genetic analysis identifies putative tumor suppressor sites at 2q35-q36.1 and 2q36.3-q37.1 involved in cervical cancer progression.
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 PPP1R7 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.
Narayan
Gopeshwar
G
Department of Pathology, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
Pulido
Hugo Arias
HA
Koul
Sanjay
S
Lu
Xin-Yan
XY
Harris
Charles P
CP
Yeh
Y Albert
YA
Vargas
Hernan
H
Posso
Hector
H
Terry
Mary Beth
MB
Gissmann
Lutz
L
Schneider
Achim
A
Mansukhani
Mahesh
M
Rao
Pulivarthi H
PH
Murty
Vundavalli V V S
VV
D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053455:Caspase 10; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2; D002893:Chromosomes, Human, Pair 3; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D000072200:Ku Autoantigen; D009693:Nucleic Acid Hybridization; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
D034961:Antigens, Nuclear; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D053455:Caspase 10; D020169:Caspases; C506438:CASP10 protein, human; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen