Alterations of the P16 gene in uterine cervical carcinoma from Indian patients

In our analysis, alterations in the P16 tumor suppressor gene were seen in 33% (15/46) of sampled uterine cervical lesions. Among the alterations, mutations in P16 were detected in 15% (7/46) of the samples. One mutation occurred at intron 1/exon 2 splice junction. All the other mutations were in exon 2 with three of them as silent mutations. The promoter hypermethylation and homozygous deletion of P16 gene were detected in 6.5% (3/46) and 8.7% (4/46) of the samples respectively. Loss of heterozygosity and microsatellite size alterations at the P16 locus were seen in 17% (8/46) of the samples. HPV16/18 infection was detected in 76% (35/46) of the samples. But no association was found between P16 alterations and HPV infection. Thus, it seems that P16 inactivation may be associated with the development of some uterine cervical carcinoma

Frequent Deletion and Methylation in SH3GL2 and CDKN2A Loci are Associated with Early- and Late-onset Breast Carcinoma

This study attempts to understand the association of candidate tumour suppressor genes SH3GL2, CDKN2A (p16–p14) and CDKN2B (p15) in development of earlyonset (group A) and late-onset (group B) breast carcinoma (BC). Deletion, methylation, and mutation of the candidate tumour suppressor genes (TSGs) were analysed in 47 group A and 59 group B samples. Immunohistochemical analysis was used to identify the expression status of SH3GL2 and p16. Clinicopathological correlation of the alterations was analysed by the chi-square and log-rank tests. Higher frequency of overall alterations (46–62%) in SH3GL2 and p16-p14 than p15 (22–26%) indicated their importance in BC. Deletion frequencies were in the following order: group A: p14 (43%) > p16 (42%) > SH3GL2 (38%) > p15 (33%) and group B: p14 (36%) > p16 (33%) > SH3GL2 (31%) > p15 (14%) while, methylation frequencies were: group A: SH3GL2 (34%) > p16 (28%) > p14 (26%) > p15 (15%) and group B: SH3GL2 (36%) > p16 (31%) > p14 (29%) > p15 (15%). Infrequent mutation was observed only in CDKN2A common exon-2. Immunohistochemical analysis showed significant association between expression of SH3GL2 and p16 with their deletion (P = 0.01 and 0.02, respectively) and methylation status (P = 0.007 and 0.01, respectively). In group A, overall alterations of SH3GL2 showed significant association with CDKN2A locus with significant prognostic implications, whereas CDKN2A and CDKN2B loci were associated in both groups.The molecular mechanisms involving CDKN2A inactivation seem to follow similar pathway in the pathogenesis of both age groups of BC while significant association of SH3GL2 with CDKN2A might play a synergistic role in the development of group A

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 fi CIN fi 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