TY - JOUR
T1 - Deletions in chromosome 4 differentially associated with the development of cervical cancer
T2 - Evidence of slit2 as a candidate tumor suppressor gene
AU - Singh, Ratnesh Kumar
AU - Indra, Dipanjana
AU - Mitra, Sraboni
AU - Mondal, Ranajit Kumar
AU - Basu, Partha Sarathi
AU - Roy, Anup
AU - Roychowdhury, Susanta
AU - Panda, Chinmay Kumar
N1 - Funding Information:
Acknowledgment We are thankful to the Director, Chittaranjan National Cancer Institute (CNCI), Kolkata-700026, India. We are also grateful to Professor H. Z. Hausen and E. M. de Villiers for their generous gift of HPV-16/18 plasmids. Financial support for this work was provided by grant [no. 27 (0111)/00/EMR-II] from CSIR, Govt. of India to Dr. C. K. Panda and CSIR-JRF/NET Fellowship grant (no. 9/30 (026)/2002-EMR-I) to Mr. R. K. Singh.
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34447277390&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447277390&partnerID=8YFLogxK
U2 - 10.1007/s00439-007-0375-6
DO - 10.1007/s00439-007-0375-6
M3 - Article
C2 - 17609981
AN - SCOPUS:34447277390
SN - 0340-6717
VL - 122
SP - 71
EP - 81
JO - Human genetics
JF - Human genetics
IS - 1
ER -