Deletions in chromosome 4 differentially associated with the development of cervical cancer: evidence of slit2 as a candidate tumor suppressor gene.
The aim of this study was to locate the candidate tumor suppressor genes (TSGs) loci in the chromosomal 4p15-16, 4q22-23 and 4q34-35 regions associated with the development of uterine cervical carcinoma (CA-CX). Deletion mapping of the regions by microsatellite markers identified six discrete areas with high frequency of deletions, viz. 4p16.2 (D1: 40%), 4p15.31 (D2: 35-38%), 4p15.2 (D3: 37-40%), 4q22.2 (D4: 34%), 4q34.2-34.3 (D5: 37-59%) and 4q35.1 (D6: 40-50%). Significant correlation was noted among the deleted regions D1, D2 and D3. The deletions in D1, D2, D5 and D6 regions are suggested to be associated with the cervical intraepithelial neoplasia (CIN), and deletions in the D2, D3, D5 and D6 regions seems to be associated with progression of CA-CX. The deletions in the D2 and D6 regions showed significant prognostic implications (P = 0.001; 0.02). The expression of the candidate TSG SLIT2 mapped to D2 region gradually reduced from normal cervix uteri -->CIN --> CA-CX. SLIT2 promoter hypermethylation was seen in 28% CIN samples and significantly increased with tumor progression (P = 0.04). Significant correlation was seen between SLIT2 deletion and its promoter methylation (P = 0.001), indicating that both these phenomena could occur simultaneously to inactivate this gene. Immunohistochemical analysis showed reduced expression of SLIT2 in cervical lesions and CA-CX cell lines. Although no mutation was detected in the SLIT2 promoter region (-432 to + 55 bp), CC and AA haplotypes were seen in -227 and -195 positions, respectively. Thus, it indicates that inactivation of SLIT2-ROBO1 signaling pathway may have an important role in CA-CX development.
Singh
Ratnesh Kumar
RK
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700026, India.
Indra
Dipanjana
D
Mitra
Sraboni
S
Mondal
Ranajit Kumar
RK
Basu
Partha Sarathi
PS
Roy
Anup
A
Roychowdhury
Susanta
S
Panda
Chinmay Kumar
CK
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000098552:Slit Homolog 2 Protein
D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000098552:Slit Homolog 2 Protein