Search

Abstract: Objective: Prostate cancer (CaP) is a heterogeneous, multifactorial, and multifocal disease. Therefore, the search for a combination of functional polymorphisms using cell cycle and apoptotic genes as tumor markers is fundamental for a more precise and reliable diagnosis. In the present study, we investigated the diagnostic value of 3 different genes associated with CaP carcinogenesis, encoding for cell cycle (MDM2, CCND1) and apoptotic (Fas) genes that are differentially expressed in CaP. Methods: In a hospital-based case control study of northern India, blood samples were obtained from 192 CaP patients and 224 cancer-free age matched unrelated healthy controls of similar ethnicity. They were genotyped for MDM2 G309T, CCND1 G870A, Fas A670G, and G1377A polymorphisms using polymerase chain restriction fragment length polymorphism (PCR-RFLP) method. Results: MDM2 309GG variant was at reduced risk for developing CaP (P = 0.041; OR, 0.59). Whereas CCND1 AA genotype demonstrated increased risk (P = 0.018; OR, 1.86). The diplotype analysis of Fas G670A and G1377A (G-A) was observed to be associated with a significant increase in CaP risk (P = 0.024; OR, 1.63). Conclusion: Findings based on current sample size our results suggested a positive association of CCND1AA genotype and diplotype analysis of Fas G670A and G1377A (G-A) to be associated with CaP risk that could influence the pathophysiology, thereby modulating the risk of CaP. [Copyright &y& Elsevier]

Background and Aims: P53 gene variants BstUI RFLP at codon 72 in exon 4, 16-bp tandem repeat in intron 3 and Msp I RFLP in intron 6 and P73 gene variants of G4C14-to-A4T14 (GC/AT), exon 2 polymorphism, which respectively codes for four functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms. We undertook this study to evaluate the role of P53 and P73 SNPs in prostate cancer in a Northern Indian population. Methods: P53 and P73 genotypes were assessed in a hospital-based case-control study comprised of 177 prostate cancer cases and 265 healthy controls. After the extraction of genomic DNA from blood, genotyping was done using PCR-RFLP and PCR-CTPP methods, respectively. Results: A significant association was found in P53 intron 6 G>A and P53 R72P G>C polymorphism with PCa risk. In P53 intron 6 G>A polymorphism the heterozygous genotype (GA) showed marginal risk with the disease (OR = 1.48, 95% CI = 0.999–2.220). Individuals with heterozygous genotype only (GC) of P53 R72P G>C polymorphism demonstrated PCa risk (OR = 1.5, 95% CI = 1–2.199). Haplotypes G-C-D and A-G-D (OR = 1.58, 95% CI = 1.125–2.241 and OR = 2.70, 95% CI = 1.767–4.143, respectively) were also found to be associated with an increased risk of PCa. Conclusions: Our study provided evidence that the P53 intron 6 G>A and R72P G>C polymorphisms were associated with a higher risk of prostate cancer in a Northern Indian population. [ABSTRACT FROM AUTHOR]

OBJECTIVE • To investigate, by genotyping CASP8 (- 652 6N del/ins) and CASP9 (-1263 A > G; - 293 19N del/ins), whether inactivation of apoptosis by genetic polymorphism of caspases 8 and 9 play an integral role in the mechanism of cancer development. • To investigate the role of these polymorphisms in susceptibility to early development of hormone refractory prostate cancer. PATIENTS AND METHODS • The study included 175 histologically confirmed cases of prostate cancer and 198 age and ethnicity matched healthy controls. • CASP9 - 1263 A > G polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. • CASP9 - 293 del/ins and CASP8 - 652 del/ ins polymorphisms were genotyped and the deletion pattern analysed by polyacrylamide gel electrophoresis. RESULTS • Our results demonstrated that presence of CASP9 - 1263 G allele was associated with reduced risk for prostate cancer (odds ratio 0.6, 95%CI 0.39-0.92, P = 0.02). Other variant CASP9 was not associated with prostate cancer risk. • Coincidentally, the presence of CASP9 - 1263 G allele was associated with increased risk for progression of prostate cancer to bone metastasis (odds ratio - 2.28, 95%CI 1.14-4.53, P = 0.02). • CASP8-652 ( + / - ) genotype was associated with increased hazard for early development of hormone refractory prostate cancer (hazard ratio 2.44, 95%CI 1.2-5.85, P = 0.045). CONCLUSION • Our results support the hypothesis that variants of CASP9 may influence the susceptibility to prostate cancer and its progression to bone metastasis. • CASP8 polymorphism may influence the progression of prostate cancer disease to a hormone refractory state. [ABSTRACT FROM AUTHOR]

Purpose: The proinflammatory cytokine tumor necrosis factor-α has an important role in the pathogenesis of prostate cancer. Single nucleotide polymorphisms in the promoter region of the TNF-A gene alter tumor necrosis factor-α transcription. Thus, we studied the association of 4 SNPs in the promoter region of TNF-A gene, including −1031T>C, −863C>A, −857 C>T and −308 G>A, in a North Indian cohort of patients with prostate cancer. Materials and Methods: The study involved 453 subjects. All 197 case and 256 control samples were genotyped for the 4 promoter polymorphisms in the TNF-A gene using allele specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. Results: Results showed an increased risk of prostate cancer for the TNF-A −1031 CC genotype (OR 2.01, p = 0.03). No significant association was observed for the TNF-A −863 C>A, TNF-A −857 C>T or −308 G>A polymorphisms. Haplotype analysis revealed that TNF-A −1031C-863C-857T-308G was significantly associated with prostate cancer risk (OR 2.22, p = 0.013). Moreover, the TNF-A −1031 C and −857 T alleles were associated with higher tumor grade and an increased risk of tumor progression and metastasis. Conclusions: These results show that TNF-A polymorphisms have an important role in prostate cancer pathogenesis. Results are in line with findings in other studies from the West and to our knowledge for the first time from India indicating the involvement of immune system genes in prostate cancer pathogenesis. [Copyright &y& Elsevier]

Abstract: Purpose: Matrix metalloproteinases (MMPs) have been implicated in progression and metastases of different tumors. The balance between the MMPs and their natural inhibitors (tissue inhibitors of matrix metalloproteinases; TIMP) seem to be an important factor related to its role. The purpose of this study was to evaluate polymorphisms in the MMP-3 and TIMP-3 genes for their associations with prostate cancer (PCa) risk in North Indians. Materials and methods: Genotypes were determined by PCR-RFLP (Polymerase Chain Reaction Restriction Fragment Length Polymorphism) method in 150 PCa patients and 200 age matched controls of similar ethnicity. Results: We found significant association in the MMP-3(1171)5A/6A and TIMP-3 (1298) C/T polymorphism with PCa risk. Variant genotype (5A/5A) of MMP-3(1171)5A/6A polymorphism had a high PCa risk (p =0.037, OR=3.52, 95%CI=1.08–11.5). Individuals with TIMP-3 (1298) CT genotype as well as T allele showed reduced risk of PCa (p <0.001; OR=0.31; 95%CI=0.18–0.52, and p =0.001; OR=0.49; 95%CI=0.32–0.75). This effect was even more evident in case of T allele carrier (CT+TT) (p <0.001; OR=0.36; 95%CI=0.22–0.59). Overall no significant association was observed statistically in MMP-3 and TIMP-3 with any of the grading stages and smoking habits in PCa. Haplotype analysis of MMP-3 showed that A-5A-A was associated with three folds (OR=3.06; 95%CI=1.71–5.47; p <0.001) increased risk in PCa patients. Conclusion: This is the first reported association between polymorphisms in the MMP-3 and TIMP-3 gene and PCa risk and supports the hypothesis that the protease/antiprotease balance has an important role. Due to the small sample size further investigations need to be done to prove a statistical significant correlation between the MMP/TIMP expression and clinicopathological parameters. [Copyright &y& Elsevier]

Abstract: IL-12 and IL-18 are immunomodulatory cytokines that play important roles in host immune response against cancers. Variation in DNA sequence in gene promoter may lead to altered IL-18 production and/or activity, and hence can modulate an individual''s susceptibility to BC. To test this hypothesis, we investigated the relationship of IL-18 gene promoter −137 G/C and −607C/A polymorphisms and IL12 (−16974) A/C with the risk of BC in North Indian population. Polymorphisms in IL-18 and IL-12 genes were analyzed in 200 BC patients and 200 age, ethnicity and sex-matched controls, using restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) and amplification refractory mutation specific-polymerase chain reaction (ARMS) method. The concentrations of IL-18 in serum were determined by ELISA. Significant association was observed with IL18 (−137) G/C heterozygous genotype (GC) with 1.96 folds risk of BC as well at C allele carrier and variant C allele having 2 fold and 1.6 fold risk for BC respectively. IL18 (−607) C/A, heterozygous CA genotype also showed a high risk (OR=1.59) for BC. While IL12 (−16974) A/C heterozygote genotype and C allele carrier demonstrated reduced risk of BC. Hetero genotype of IL18 (−137) G/C was associated with risk of recurrence (HR=2.35) in superficial BC patients receiving BCG treatment thus showing least survival. The distributions of IL-18 gene haplotypes were not significantly different between patients and controls. Serum IL-18 levels were significantly higher in BC patients than in the healthy subjects (p=0.025). Serum IL-18 levels was also significantly associated with IL18 (−137) G/C in heterozygous genotype (GC) (p=0.048). Our results suggest that IL-18 gene polymorphism contributes to bladder cancer risk whereas IL-12 is protective. A relation between IL18 (−137) G/C in heterozygous genotype with elevated IL-18 serum level and bladder cancer risk has been registered in the present study. [Copyright &y& Elsevier]

Background and Aims: The importance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in tumor progression is well documented. MMP2/TIMP2 system has a significant impact on the development and progression of cancer and genetic polymorphisms in the promoters of MMP2 (−1306C/T, 735C/T) and TIMP2 (−418G/A, −303C/T) are correlated with decreased enzyme activity. We sought to determine whether genetic polymorphisms in MMP2 and TIMP2 polymorphisms may be associated with varying risk of prostate cancer (PCa) in men in North India. Methods: Genotyping was done by PCR-restriction fragment length polymorphism method in 190 histologically confirmed PCa patients and 200 unrelated, healthy, age-matched individuals of similar ethnicity. Results: Patients with MMP2 (-1306) CT genotype as well as T allele were at higher risk of PCa (p = 0.018; OR = 1.68 and p = 0.015; OR = 1.52). This effect was even more evident in the case of the T allele carrier (CT + TT) (p = 0.011; OR = 1.71). MMP2 (735) C>T, TIMP2 (−418) G>C and TIMP2 (−303) C>T polymorphism demonstrated no association. However, TIMP2 (−418) GC was found to be involved in progression of PCa but not in initiation. Haplotype results demonstrated that MMP2 (1306T–735C) and TIMP2 (418G-303T) were associated with a 1.5- and 1.8-fold increased risk, respectively. Conclusions: Our data indicated that MMP2-1306C>T gene polymorphism contributes to PCa susceptibility. These findings suggested MMP2 variants as a predictor of PCa progression risk among North Indian men. We assume that analysis of these gene polymorphisms can help identify patient subgroups at high risk of poor disease outcome. [ABSTRACT FROM AUTHOR]

Background & objectives: Genetic variation in the DNA repair genes might be associated with altered DNA repair capacities (DRC). Reduced DRC due to inherited polymorphisms may increase the susceptibility to cancers. Base excision and nucleotide excision are the two major repair pathways. We investigated the association between two base excision repair (BER) genes (APE1 exon 5, OGG1 exon 7) and two nucleotide excision repair (NER) genes (XPC PAT, XPC exon 15) with risk of prostate cancer (PCa). Methods: The study was designed with 192 histopathologically confirmed PCa patients and 224 age matched healthy controls of similar ethnicity. Genotypes were determined by amplification refractory mutation specific (ARMS) and PCR-restriction fragment length polymorphism (RFLP) methods. Results: Overall, a significant association in NER gene, XPC PAT Ins/Ins (I/I) genotype with PCa risk was observed (Adjusted OR- 2.55, 95%C1-1.22-5.33, P=0.012). XPC exon 15 variant CC genotypes presented statistically significant risk of PCa (Adjusted OR- 2.15, 95% CI-1.09-4.23, P=0.026). However, no association was observed for polymorphism with BER genes. Diplotype analysis of XPC PAT and exon 15 revealed that the frequency of the D-C and I-A dipiotype was statistically significant in PC a. The variant genotypes of NER genes were also associated with high Gleason grade. Interpretation & conclusions: The results indicated that there was a significant modifying effect on the association between genotype XPC PAT and exon 15 polymorphism and PCa risk which was further confirmed by diplotype analysis of XPC PAT and exon 15 in north Indian population. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Polymorphisms in DNA repair genes may be associated with altered DNA repair capacity, thereby influencing an individual''s susceptibility to smoking-related cancers such as bladder cancer. Therefore, we sought to examine the correlation between single nucleotide polymorphisms in DNA repair genes and bladder cancer. Methodology: We undertook a case-control study of 212 urothelial bladder cancer (UBC) cases and 250 controls to investigate the association between OGG1 (C1245G rs1052133), XRCC3 (C18067T, rs861539) and XRCC7 (G6721T, rs7003908) polymorphisms and bladder cancer susceptibility by PCR–RFLP and the ARMS method. We also investigated gene-environment interactions. Results: The OGG1 GG genotype was associated with an elevated risk of urothelial bladder cancer (UBC) (OR, 2.10; p, 0.028). XRCC7 +6721 GG was also associated with increased susceptibility to UBC (OR, 4.45; p, 0.001). In a recessive model, the OGG1 GG genotype showed an increased risk of TaG2,3 +T1G1–3 tumors. Additionally, the OGG1 GG genotype in non-smokers represented a 2.46-fold greater risk (OR, 2.46; p, 0.035) in bladder cancer patients. Subsequent analysis demonstrated more pronounced association of XRCC7 with smokers (OR, 4.39; p, 0.001). XRCC7 also showed increased association with TaG2,3 +T1G1–3 tumors and muscle invasive tumors (OR, 3.16; p, 0.001 and OR, 4.24; p, 0.001, respectively). Multiple Cox regression analysis in non-muscle invasive bladder tumor (NMIBT) patients demonstrated an association of the OGG1 GG polymorphism with a high risk of recurrence in patients on cystoscopic surveillance (HR, 4.04; p, 0.013). Subsequently, shorter recurrence-free survival (log rank p, 0.024; CC/GG, 42/24) was observed. Conclusion: Our data suggest association of a variant (GG) genotype of OGG1 with increased UBC susceptibility and a high risk of tumor recurrence in NMIBT patients on cystoscopic surveillance. XRCC7 G allele carriers (TG+GG) are also at an elevated risk for susceptibility to UBC as evidenced by a high odds ratio throughout the analysis. [Copyright &y& Elsevier]

Abstract: Background: Patients with chronic kidney disease manifest an inflammatory state in comparison to healthy individuals. Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine involved in initiation and progression of renal injury. We examined the 2-promoter region polymorphism of TNF-α gene G to A at −308 and at +488 sites in end-stage renal disease (ESRD) subjects. Methods: The TNF-α −308 G/A and +488 G/A polymorphisms were genotyped in 231 patients aged 36.5±10, and in 180 matched controls (34.96±11.3) by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and amplification refractory mutation system (ARMS–PCR) method, respectively. Results: The genotypic distribution of TNF-α −308 and +488 were significantly different between patients and controls (P <0.001 and P <0.006), respectively. The AA genotype was more frequent in ESRD patients than controls for both the sites (42% vs. 2.8% and 17.3% vs. 2.2%), respectively. The allelic frequency of TNF-α ⁎A was also higher in cases than in controls for both the sites (P <0.001; OR=2.96; 95% CI=2.228–3.945 and P <0.013; OR=1.422; 95% CI=1.078–1.876). Significant difference was observed for haplotype frequency distribution between ESRD patients and controls and ‘A–G#’ haplotype showed >9-fold higher risk (OR=9.886, 95% CI=4.408–22.172). The two polymorphisms were in linkage disequilibrium in the control group (D′=0.8047, P <0.001). Conclusion: Both the variants of TNF-α (−308 and +488) polymorphism had significant association and may thus be a strong predisposing risk factor for ESRD in a cohort of north Indian population. Further, individuals with haplotypes A–G# may be at higher risk for ESRD. [Copyright &y& Elsevier]