Glutathione S-Transferase P1 313 (A > G) Ile105Val Polymorphism Contributes to Cancer Susceptibility in Indian Population: A Meta-analysis of 39 Case-Control Studies.

GSTP1 involved in the metabolism of carcinogens and toxins, reduces damage of DNA and act as a suppressor of carcinogenesis. Many studies have reported that 313 A > G polymorphism is associated with different cancer in Indian population, but the results remain conflicting rather than conclusive. Therefore, we have performed meta-analysis to clarify the more precise association of GSPT1 313 A > G polymorphism with cancer risk in Indian population. We retrieved all relevant published literature from PubMed (Medline) and Google scholar web database and included those study only based on the established inclusion criteria. Pooled ORs and 95% CIs were used to appraise the strength of association. Publication bias and sensitivity analysis was also evaluated. A total of 6581 confirmed cancer cases and 8218 controls were included from eligible thirty nine case-controls studies. Pooled analysis suggested that the variant genotypes significantly increased the risk of cancer in allele (G vs. A: OR 1.266, 95% CI 1.129-1.418, p = 0.001), heterozygous (AG vs. AA: OR 1.191, 95% CI 1.047-1.355, p = 0.008), homozygous (GG vs. AA: OR 1.811, 95% CI 1.428-2.297, p = 0.001), dominant (GG + AG vs. AA: OR 1.276, 95% CI 1.110-1.466, p = 0.001) and recessive (GG vs. AG + AA: OR 1.638, 95% CI 1.340-2.002, p = 0.001) genetic models. The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias. This meta-analysis suggests that the GSTP1 313 A > G polymorphism may contribute to genetic susceptibility to cancer in Indian population. However, larger studies and randomized clinical trial will be required to elucidate the biological and molecular mechanism of GSTP1 gene in cancer.

Anomalies in MiRNAs Machinery Gene, GEMIN-4 Variants Suggest Renal Cell Carcinoma Risk: A Small Experimental Study from North India.

GEMIN4 is a member of the GEMIN gene family which is involved in multiple pathologies including cancer. It is located on Chr17p13.3, the most notorious chromosome and a hotspot for various carcinomas. We therefore intend to find genetic variants of GEMIN4 gene associated with renal cell carcinoma risk (RCC). This study comprised 100 patients and 225 controls. Genotyping of GEMIN4 gene variants was done using Taqman® assay. The association of GEMIN4 variants and risk prediction of RCC was done by statistical analysis. Haplotype analysis was done to see the combined effect of variants on RCC. Patients carrying variant genotype, CC of GEMIN4 T/C rs7813 showed significant association whereas in case of GEMIN4 G/C rs910925 variant genotype, CC significant risk was found. GEMIN4 rs7813 T/C variant genotype, CC showed risk with smoking (p = 0.034). Our study gives a substantive support for the association between the GEMIN4 gene variants and RCC risk.

Genetic Variant Arg399Gln G>A of XRCC1 DNA Repair Gene Enhanced Cancer Risk Among Indian Population: Evidence from Meta-analysis and Trial Sequence Analyses.

The X-ray repair cross-complementation group 1 (XRCC1) gene plays an important role in base excision repair pathway. Several studies have reported contradictory results for XRCC1 exon 10 (Arg399Gln, G23990A, rs25487) gene polymorphism and cancer risk in Indian population, making it difficult to interpret them. Therefore, we have conducted a meta-analysis to evaluate the more precise association between XRCC1 exon 10 G>A gene polymorphism and risk of cancer by published studies. We searched PubMed (Medline) and Google scholar web databases to cover all studies published on association between XRCC1 exon 10 G>A gene polymorphism and cancer risk until August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to appraise the strength of association. Heterogeneity, publication bias and sensitivity analysis were also assessed. Twenty-five published studies had fulfilled the inclusion criteria comprising 4131 confirmed cancer cases and 5013 controls. When all studies were polled together, overall significant association was found between XRCC1 exon 10 G>A polymorphism and cancer risk in variant allele carrier (A vs. G: OR 1.217, 95% CI 1.056-1.402, p = 0.007), homozygous (AA vs. GG: OR 1.359, 95% CI 1.036-1.783, p = 0.027), dominant (AA+AG vs. GG OR 1.208, 95% CI 1.006-1.450, p = 0.043) and recessive (AA vs. AG+GG: OR 1.315, 95% CI 1.029-1.680, p = 0.029) genetic models. Further sensitivity analysis supported the stability of our result by showing similar ORs before and after removal of a single study. The present meta-analysis suggested that the XRCC1 exon 10 G>A polymorphism contribute cancer risk in Indian population, and supports that individuals with risk allele A and AA genotype are at higher risk of developing cancer.

Pepsinogen-II 100 bp ins/del gene polymorphism and its elevated circulating levels are associated with gastric cancer, particularly with Helicobacter pylori infection and intestinal metaplasia.

BACKGROUND: Polymorphism in the gene of pepsinogen-II (PG-II) and its serum level are effective biomarkers for terminal differentiation of gastric mucosa into gastritis, intestinal metaplasia (IM), and gastric cancer (GC) in relationship to Helicobacter pylori infection. METHODS: Genotyping of the PG-II 100 bp insertion/deletion (ins/del) polymorphism was performed in patients with GC (n = 192) and age- and gender-matched H. pylori-associated dyspepsia (n = 180) and healthy subjects (HS, n = 240) by PCR. IgG anti-H. pylori (in all subjects) and serum PG-II levels were estimated in 145 patients each with GC and dyspepsia and in 65 healthy controls (HC) using ELISA (Biohit Oyj, Finland). RESULTS: Five alleles were amplified by PCR: allele 5 (510 bp), allele 4 (480 bp), allele 3 (450 bp), allele 2 (400 bp), and allele 1 (shorter allele, 310 bp). Allele 1 carriage was infrequent, and serum PG-II level was higher among patients with GC than in HC [OR 0.43 (95 % CI, 0.29-0.85), p < 0.001 and mean ± SD; 17.53 ± 12.60 vs. 12.77 ± 7.53 µg/l, p = 0.005, respectively], particularly in the presence of H. pylori [OR 0.42 (0.25-0.71), p = 0.001 and 18.78 ± 12.63 vs. 13.97 ± 8.14, p = 0.034]. However, allele 1 carriage and PG-II levels were comparable among patients with GC and dyspepsia. Patients with IM also carried allele 1 infrequently and had higher levels of PG-II than those without [OR 0.5 (0.29-0.85), p = 0.011 and 20.07 ± 14.22 vs. 16.61 ± 12.08, p = 0.048]. CONCLUSIONS: Carriage of the shorter allele of the PG-II 100 bp ins/del polymorphism and elevated levels of PG-II are associated with GC, particularly with H. pylori infection and IM.

Relationship of MTHFR and NQO1 Pharmacogenetics and Chemotherapy Clinical Outcomes in Breast Cancer Patients.

The study aimed at evaluating the influence of MTHFR 677C>T and NQO1 609C>T polymorphisms in toxicity and response to chemotherapy in breast cancer patients. These two genes are involved in the folate homeostasis and bioactivation of chemotherapeutic drugs, respectively. In this study, 243 patients treated with FEC/FAC/methotrexate chemotherapy regimen were recruited and followed up for toxicity (NCI-CTCAE ver. 3). While out of 243 patients, 115 patients who received neo-adjuvant chemotherapy (NACT) were followed for treatment response. Genetic analysis of MTHFR 677C>T and NQO1 609C>T was done by PCR-restriction fragment length polymorphism. We found significant association of variant genotype (TT) of NQO1 609C>T with grade 2-4 toxicity [OR 0.33 (0.13-0.88), P = 0.027] and with grade 2-4 anemia [OR 0.34 (0.12-0.95), P = 0.041]. However, no association of MTHFR 677C>T was seen with either response to NACT or drug-induced toxicity. The study provides useful information for prediction of clinical outcomes in breast cancer patients in terms of NQO1 609C>T by evaluating its association with chemotherapy-induced toxicity.

Death receptor 4 variants enhanced prostate cancer risk in North Indian population.

Death receptor 4 (DR4) is a tumor suppressor gene and plays an important mediator of apoptosis. Polymorphism in DR4 gene may reduce apoptotic capacity and provoke proliferation of cell and cancer. We evaluated genetic polymorphisms of DR4 gene in association with risk of prostate cancer (PCa) in Northern Indian population. We have recruited 192 PCa patients and 225 cancer-free ages matched unrelated healthy control of similar ethnicity. They were genotyped for DR4, 141 (G > A), 209 (C > G), and 228 (A > C) polymorphisms using amplification refractory mutation system (ARMS) method. Variant genotype AA (OR = 2.54; p = 0.007) and A allele (OR = 1.51; p = 0.015) of DR4 141 demonstrated significant increased risk for PCa. Similarly, variant genotype GG (OR = 2.58; p = 0.003) and G allele carrier (CG + GG) (OR = 1.50; p = 0.043) of DR4 209 conferred increased risk. G allele (OR = 1.50, p = 0.005) was also statistically associated with PCa risk. High risk for PCa was also observed with respect to haplotypes A-G-A (OR = 2.86; Bonferroni correction Pc = 0.008) and A-G-C (OR = 3.18, Pc = 0.008). We observed significantly enhanced risk for PCa due to interaction between DR4 209 and 228 gene polymorphisms. Furthermore, a significantly increased risk of high Gleason grade tumor was found in the combined variant allele carrier (GA + AA) of DR4 141 compared with the GG genotype (OR = 2.27, Pc = 0.052). Interaction of smoking and genotypes did not further modulate the risk of PCa. Our observations suggested that genetic variants of the DR4 gene significantly influence the risk of PCa in North Indian population and might be involved in the etiology of PCa.

No correlation between TIMP2 -418 G>C polymorphism and increased risk of cancer: evidence from a meta-analysis.

AIM: Tissue inhibitor of metalloproteinase (TIMP2) is involved in the regulation of matrix metalloproteinase 2 (MMP2) and shown to implicate in cancer development and progression. The results from the published studies based on the association between TIMP2 -418 G>C polymorphism and cancer risk are inconsistent. In this meta-analysis, we aimed to evaluate the potential association between TIMP2 -418 G>C polymorphism and cancer risk. METHODOLOGY: We searched PubMed (Medline) and EMBASE web databases to cover all studies based on relationship of TIMP2 -418 G>C polymorphism and risk of cancer until October 2013. The meta-analysis was performed for selected case-control studies and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all genetic models. RESULTS: A total of 2225 cancer cases and 2532 controls were included from ten eligible case-control studies. Results from overall pooled analysis suggested no evidence of significant risk between TIMP2 -418 G>C polymorphism and cancer risk in any of the genetic models, such as, allele (C vs. G: OR = 1.293, 95% CI = 0.882 to 1.894, p = 0.188), homozygous (CC vs. GG: OR = 0.940, 95% CI = 0.434 to 2.039, p = 0.876), heterozygous (GC vs. GG: OR = 1.397, 95% CI = 0.888 to 2.198, p = 0.148), dominant (CC+GC vs. GG: OR = 1.387, 95% CI = 0.880 to 2.187, p = 0.159) and recessive (CC vs. GG+GC: OR = 0.901, 95% CI = 0.442 to 1.838, p = 0.774) models. No evidence of publication bias was detected during the analysis. CONCLUSIONS: The present meta-analysis suggests that the TIMP2 -418 G>C polymorphism may not be involved in predisposing risk factor for cancer in overall population. However, future larger studies with group of populations are needed to analyze the possible correlation.

Genetic variants of NQO1 gene increase bladder cancer risk in Indian population and meta-analysis.

NAD(P)H: quinone oxidoreductase (NQO1) is cytosolic enzymes that plays a role in protection against natural and xenobiotic quinones. This enzyme also protects cells from oxidative damage by preventing the generation of reactive oxygen species and reducing environmental carcinogens. The study included 200 bladder cancer (BC) patients and 200 healthy control individuals that had been matched by age and sex, and were of similar ethnicity. NQO1 Exon 4 (C > T) and Exon 6 (C > T) gene polymorphisms were genotyped by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). We also performed a meta-analysis of 12 studies including the present study (2,286 cases and 2,294 controls) for NQO1 Exon 6 (C > T) polymorphism and overall BC susceptibility. Variant genotype TT of NQO1 Exon 6 (C > T) demonstrated a significant risk with BC (OR = 2.54; p = 0.016). T allele carriers (CT + TT) (OR = 1.60; p = 0.020) of NQO1 Exon 6, as well as T allele (OR = 1.60; p = 0.004) were at higher risk of BC. The diplotype C-T was observed to be associated with a significant increase BC risk (Bonferroni corrected p value, Pc = 0.02; OR = 1.61). In addition, a meta-analysis of the Exon 6 (C > T) polymorphism and BC risk showed that the variant of NQO1 Exon 6 genotypes was associated with an overall increased risk of BC, which was consistent with the results of the present study. However, none of these two polymorphisms were associated with tobacco smoking, tumor progression, and risk of BC recurrence in patients treated with BCG immunotherapy. Our results suggested that the NQO1 Exon 6 (C > T) may be associated with BC risk and could be a useful marker for primary prevention and development of BC in Indian population. Larger studies are required to validate these findings in diverse populations and of different ethnicities.

No Association of Matrix Metalloproteinase [MMP]-2 (-735C > T) and Tissue Inhibitor of Metalloproteinase [TIMP]-2 (-418G > C) Gene Polymorphisms with Cervical Cancer Susceptibility.

Matrix metalloproteinase [MMP]-2 and tissue inhibitor of metalloproteinase [TIMP]-2 are emerging as pivotal players in inflammation and carcinogenesis. The present study aimed to evaluate the role of MMP-2 (-735C > T) [rs 2285053] and TIMP-2 (-418G > C) [rs 8179090] gene polymorphisms in cervical cancer susceptibility in Indian women. We recruited 200 cervical cancer patients from North India and 200 unrelated, age-matched, cancer-free healthy female controls of similar ethnicity. Genomic DNA extraction from peripheral blood samples, collected from the study subjects, was carried out using salting-out method. MMP-2 and TIMP-2 genotyping was performed using polymerase chain reaction-based restriction fragment length polymorphism. Our findings demonstrated no significant association between MMP-2 (-735C > T) and TIMP-2 (-418G > C) gene polymorphisms and the risk of developing cervical cancer in the study population. Further stratified analysis using a case-only study approach revealed that there was no effect of MMP-2/TIMP-2 polymorphisms on early and advanced stages of cervical cancer. Further MMP-2 and TIMP-2 polymorphisms did not modulate the risk in cervical cancer patients who smoked tobacco/cigarettes. Overall, the present study demonstrated a lack of association between MMP-2 and TIMP-2 gene polymorphisms and cervical cancer susceptibility in women of Northern India.

Association of single nucleotide polymorphisms in promoter of matrix metalloproteinase-2, 8 genes with bladder cancer risk in Northern India.

OBJECTIVE: Matrix metalloproteinases (MMPs) are expressed in melanocytes and their overexpression has been linked to tumor development, progression, and metastasis. At the genetic level, following functional promoter polymorphisms are known to modify the gene transcription: -1306 C > T, -735 C > T in MMP2, and 799 C > T in MMP8 gene. Hence we hypothesize that functional polymorphisms in the 2 MMP SNPs in promoter region may modulate the risk for bladder cancer (BC) progression in North Indian population. MATERIALS AND METHODS: Genotyping for these polymorphisms were done in a group of 200 BC and 200 age matched, similar ethnicity unrelated healthy controls using PCR-based methods. Two-sided χ(2), Cox-regression was utilized to evaluate the associations between genotype and various clinical and epidemiologic factors. Multivariate analyses were conducted using logistic regression, adjusting for known BC confounders such as age and gender. Survival analysis was done using the Kaplan-Meier method and differences in survival were assessed using the log rank test. RESULTS: Individuals with MMP2 (-1306) TT genotype as well as T allele were at higher risk of BC (P, 0.042; OR, 2.85; P, 0.001; OR, 1.76). This effect was even more apparent in case of CT+TT (P < 0.001; OR, 2.61). In MMP2 (735), CT+TT demonstrated significant risk (P, 0.034; OR, 1.66). In MMP8 (799), reduced risk was observed with TT genotype (P, 0.006; OR, 0.27). Haplotype analysis showed that individuals with haplotype 735C-1306T and 735T-1306C were at 1.9- and 1.5-fold higher risk. MMP2 -1306CC in combination with MMP8 799CT genotype showed protective effect. The genotype CT and CT+TT of MMP2 1306C > T were associated with high risk of recurrence in BCG treated patients (HR, 4.32; P, 0.006 and HR, 2.06; P, 0.047) thus showing reduced recurrence free survival (CT+TT/CC = 34/45 months; log rank P, 0.039). CONCLUSION: Our data suggested that variant allele of MMP2 1306C > T was associated with high risk of tumor recurrence and reduced recurrence free survival in superficial BC patients.

Genetic variants in metabolizing genes NQO1, NQO2, MTHFR and risk of prostate cancer: a study from North India.

Quinone oxidoreductases (NAD(P)H): quinone oxidoreductase 1 (NQO1) and NRH: quinone oxidoreductase 2 (NQO2) are an antioxidant enzyme, important in the detoxification of environmental carcinogens. Methylene-tetra-hydrofolate reductase (MTHFR), plays a role in folate metabolism and may have oncogenic role through disruption of normal DNA methylation pattern, synthesis, and impaired DNA repair. In a case-control study, genotyping was done in 195 PCa and 250 age matched unrelated healthy controls of similar ethnicity to determine variants in NQO1 exon 4 (C > T, rs4986998), exon 6 (C > T, rs1800566), NQO2 -3423 (G > A, rs2070999) and MTHFR exon 4 (C > T, rs1801133) by PCR-RFLP methods. Heterozygous genotype CT and variant allele career genotype (CT + TT) of NQO1 exon 4 showed increased risk of PCa (OR = 2.06, p = 0.033; OR = 2.02, p = 0.027). Variant allele T also revealed increased risk (OR = 1.87, p = 0.029). Similarly variant genotype TT (OR = 2.71, p = 0.009), combined genotype (CT + TT) (OR = 1.59, p = 0.019) and T allele (OR = 1.63, p = 0.002) of NQO1 exon 6 demonstrated significant risk for PCa. Diplotypes of NQO1 (exon 4 and 6), C-T (OR = 1.56, Pc = 0.007) and T-T (OR = 0.011, Pc = 3.86) was associated with an increased risk for PCa. NQO2 and MTHFR did not show any risk with PCa. Our results strongly support that common sequence variants and diplotypes of NQO1 exon 4 and 6 genes may have role in PCa risk in the North Indian population, indicating the importance of genes involved in metabolism with respect to PCa risk. Additional studies on larger populations are needed to clarify the role of variation in these genes in PCa carcinogenesis.

Genetic variation in nucleotide excision repair pathway genes influence prostate and bladder cancer susceptibility in North Indian population.

BACKGROUND: Inherited polymorphisms of XPD and XPC genes may contribute to subtle variations in NER DNA repair capacity and genetic susceptibility to development of urological cancer such as prostate and bladder cancer. MATERIALS AND METHODS: We genotyped four Single Nucleotide Polymorphs (SNPs) of the DNA repair gene XPD and XPC in 195 prostate cancer (PCa) and 212 bladder cancer (BC) patients and 250 healthy controls from the same area. XPD Exon 10 (G>A) by amplification refractory mutation system and Exon 23 (A>C), XPC Intron 9 (Ins/Del) and Exon 15 (A>C) were genotyped by PCR-RFLP. RESULTS: Variant genotype of XPC demonstrated association with PCa as well as in BC (P, 0.013; P, 0.003). Combined genotype (GA+AA) revealed association with PCa and in BC (P, 0.012, P, 0.002). Variant allele also demonstrated risk in both the cancer. Diplotype of XPD and XPC was associated with a significant increase in PCa and BC risk. Variant (+/+) genotype of XPC intron 9 shown increased risk with PCa and in BC (P, 0.012; P, 0.032). CC genotype of XPC exon 15 revealed increase risk (P, 0.047) with PCa not in BC. In clinopathological grade variant allele of XPC intron 9 and 15 demonstrated risk with high grade of tumor and bone metastasis of PCa. In BC variant allele of XPD exon 10 and 15 also shown association with tumor grade. XPC intron 9 influences the risk of BC in former tobacco users in BC. CONCLUSIONS: Our result support that SNPs in XPD and XPC gene may reduce NER repair capacity and play a major role for PCa and BC in North India.

Association of Toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population.

Prostate cancer (PCa) is the most common cancer among men. It has been suggested that toll like receptors (TLRs) may contribute to PCa pathogenesis by stimulating prostate epithelial cell proliferation in response to infectious stimuli. We performed case control study to analyze the genetic variants of TLR2, 3 and 9 gene polymorphisms with PCa risk in a North Indian population. For this study we genotyped age matched, unrelated 195 PCa patients and 250 healthy controls of similar ethnicity in a case-control study. They were genotyped for TLR2 (-196 to -174 Del), TLR3 (c.1377C/T) [rs3775290] and TLR9 (G2848A) [rs352140] gene polymorphisms using polymerase chain reaction and restriction fragment length polymorphism method. Variant allele Del (D) carriers i.e. (ID + DD) of TLR2 (-196 to -174 Del) SNP, demonstrated 1.57 fold increased risk (p = 0.040; OR = 1.57, 95% CI = 1.02-2.24) as compared to Ins (I) allele, suggesting a dominant effect model involved in the risk of this polymorphism in PCa. However, variants of TLR3 and 9 gene polymorphisms were not associated with PCa risk. Our results suggested the low penetrance variant of TLR2 (-196 to -174 Del) to be at increased PCa risk in North Indian population. Functional studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in identifying the disease-associated variants for PCa etiology.

Association studies of Toll-like receptor gene polymorphisms with allograft survival in renal transplant recipients of North India.

Organ transplantation itself inevitably activates the innate immune system by Toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the possible association of TLR2, TLR3, and TLR9 polymorphisms of donor-recipient pairs and acute rejection in renal transplant patients of North India. TLR2 (-196 to -174 del), TLR3 (c.1377C/T; rs 3775290), and TLR9 (+2848 G/A; rs 352140) were genotyped using DNA samples from 200 donor-recipient pairs of live donor kidney transplantation by applying Restriction Fragment Length Polymorphism (RFLP) methodology. The variant allele frequency of TLR2 (-196 to -174 del) was significantly different between recipients and donors (7.5% vs. 5.0%; p = 0.049; OR = 3.9; 95% CI = 1.01-15.32). However, no significant association for allograft rejection was observed in transplant recipients for TLR3 and TLR9. Interestingly, a low prevalence of AA genotype of TLR9 + 2848 G>A was observed in rejecters when compared with non-rejecters, demonstrating protective association with allograft rejection (OR = 0.30, 95% CI = 0.12-0.88, p = 0.028). An allele in patients was also observed to be associated with higher rejection-free survival (log-rank = 0.044). These TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with renal graft rejection.

Polymorphisms and haplotypes in caspases 8 and 9 genes and risk for prostate cancer: a case-control study in cohort of North India.

OBJECTIVE: Despite the potential importance of apoptosis pathways in prostate tumor etiology, little has been published regarding prostate tumor risk associated with common gene variants in caspases (CASP). Normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. MATERIALS AND METHODS: Using data from a hospital-based case-control study conducted by Sanjay Gandhi Post Graduate Institute of Medical Science, India, from 2007 to 2009, we evaluated risk of prostate cancer (CaP) in 165 patients and age-matched 205 healthy controls. We genotyped the functional IVS12-19G/A, D302H, -678del, and -652 6N ins/del polymorphisms in the promoter of CASP 8 and -293del, -1263A/G in CASP 9 genes. RESULTS: A significant increased risk for CaP was found for the CASP 8 IVS12-19G/A heterozygous genotype (P = 0.02; OR = 1.69) as well as for the variant allele carriers (P = 0.04; OR = 1.56). Also the CASP 9 -1263A/G showed lower risk for both heterozygous and variant allele carrier genotypes (P = 0.002; OR = 0.45 and P = 0.05; OR = 0.66 respectively). CASP 9 -1263A/G was also found to be associated with increased risk with bone metastasis. Furthermore, a significant additive interaction between CASP 8 IVS12-19G/A polymorphism and tobacco smoking was observed with CaP risk. CONCLUSION: These results suggested that the CASP 8 IVS12-19G/A and CASP 9 -1263 polymorphism may be involved in etiology of CaP and thus could be implicated as a marker for genetic susceptibility in North Indian population.

Association of p53 codon 248 (exon7) with urinary bladder cancer risk in the North Indian population.

p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stresses including UVR-induced DNA damage and regulates many downstream genes to initiate cell-cycle arrest, DNA repair or apoptosis. p53 gene variants at codon 11, Pro47Ser and codon 248 (exon 7) were evaluated for bladder cancer (BC) risk in North Indians. In the present study, the above encoding regions in p53 genes were analyzed in a hospital based study in 200 BC and 200 healthy controls age and gender matched and of similar ethnicity. The genotyping was assessed by the polymerase chain reaction restriction fragment length polymorphism technique and statistically evaluated using SPSS software ver. 15.0. A significant association was found with p53 codon 248 polymorphism and BC risk whereas p53 codon 11 and p53 Pro47Ser polymorphism showed no association with BC risk. The individuals carrying the heterozygous genotype (Arg/Trp-Arg/Gln) in the p53 codon 248 polymorphism showed high BC risk (p < 0.001). Combinations with heterozygous and variant genotypes also showed a high risk for BC (p < 0.001). The minor allele (Trp/Gln) carriers of the p53 codon 248 demonstrated a 1.7-fold risk for BC. Furthermore, haplotype analysis revealed that the Glu-Pro-Trp/Gln haplotype is associated with a 1.9-fold risk for BC. A protective role was observed with tumor stage/grade of BC patients with p53 codon 248 (p = 0.003; OR = 0.32). Thus, it is evident from our study that of all the 3 single nucleotide polymorphisms evaluated, only p53 codon 248 (exon7) gene polymorphism has an implication for risk in BC in the North Indian population.

Polymorphisms in COX-2 gene influence prostate cancer susceptibility in a northern Indian cohort.

BACKGROUND AND AIMS: Cyclooxygenase-2 (COX-2) converts arachidonic acid to prostaglandins, which are important mediators of cell proliferation and inflammation. Evidence indicates that COX-2 plays a role in carcinogenesis and that it is overexpressed in prostate tumors. We examined whether sequence variants in the COX-2 gene were associated with prostate cancer (PCa) risk. METHODS: In a hospital-based case/control study, 195 subjects with PCa and 250 healthy controls were investigated for the association of COX-2 -765 G>C (rs20417) and +8473 T>C (rs5275) promoter polymorphism with PCa susceptibility using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULT: Variant allele 'C' carriers of COX-2 -765 G>C polymorphism were associated with a 1.7-fold increased risk for PCa (p = 0.016; OR = 1.74). The variant genotype CC of COX-2 +8473 T>C polymorphism was found to be significantly associated with the overall higher risk of PCa (p = 0.045; OR = 1.82). Combined genotype (TC + CC) also demonstrated a 1.5-fold significant risk with PCa (p = 0.040; OR = 1.52). The diplotype C-C was observed to be associated with a significant increase in PCa risk (Bonferroni corrected p value, Pc = 0.004; OR = 4.26). Stratification of cases based on clinical pathological grade of tumors revealed no association with PCa risk. CONCLUSIONS: Our findings suggest COX-2 -765G>C and +8473 T>C polymorphism and diplotype C-C to be a risk factor for PCa. However, further validation in large population-based studies is needed to confirm the finding.

Impact of total and ionized serum calcium on prostate cancer risk in North Indian men.

INTRODUCTION: Calcium has anti-proliferative and pro-differentiation effects on cells in vitro and can inhibit the development of various cancers. While there is some epidemiologic evidence for an inverse relation between dietary calcium intake and prostate cancer risk, only few have focused on serum calcium levels in this respect. MATERIALS AND METHODS: We assayed total serum calcium and ionized serum calcium in a pilot study of 40 prostate cancer patients and compared with 40 healthy controls. RESULTS: Our observations provided evidence for an association between prostate cancer risk and total and ionized serum calcium levels(p=0.020 and p≤0.001 respectively). The mean difference of total serum calcium was also significant in patients with serum PSA >20ng/ ml (p=0.017). CONCLUSION: This is an important and interesting finding which requires further exploration into mechanism involved in calcium channel and prostate cancer risk in a larger cohort of different ethnic population.

Genetic polymorphisms in MHC-encoded antigen processing gene TAP2: a case-control study in end-stage renal disease patients of North India.

AIM: TAP2 genes are involved in antigen presentation by MHC class I molecules, especially in the transport of endogenous peptides. As for most MHC genes, a polymorphism has been described and the possibility that it could influence the recipient immune response by modulating antigen presentation in renal disorders. The aim of our study was to analyze TAP2 gene polymorphism in between ESRD (end stage renal disease) patients and healthy controls in our North Indian population. MATERIALS AND METHOD: We analyzed 3 polymorphisms in the TAP2 gene viz. 565 (G→A, Ala→Thr), 379 (G→A, Val→Ile) and 665 (A→G, Thr→Ala), by amplification refractory mutation system-polymerase chain reaction, (ARMS-PCR) methodology using SPSS 11.0 (Chicago, IL, U.S.A.) in a hospital based case-control study in 148 ESRD cases and 230 healthy controls. They were age and sex matched and were of similar ethnicity. RESULTS: Our results showed that only TAP2 G>A 379 Val/Ile was found to be significant for end stage renal disease patients. Furthermore, 2 haplotypes, Ile(379)-Thr(665) and Ile(379)-Ala(665) (p=0.001; OR=0.28 and p=0.030; OR=4.30 respectively) were also associated with the disease and on the other hand gene combination effect revealed protective pattern with ESRD (Val/Ile(379)-Thr/Thr(665) p=0.007; OR=0.30). These results suggested that the currently described polymorphism in the limited coding region of TAP2 genes individually does not influence end stage renal disease risk. It however, proposes a strong link when in combination with each other. CONCLUSION: The study suggests that the possibility exists that some alleles, in the TAP genes, might confer susceptibility or protection in patients with ESRD which might prove to be helpful in identifying individuals at a higher risk for progressive renal insufficiency.

Prostate cancer predisposition loci and risk of metastatic disease and prostate cancer recurrence.

PURPOSE: Genome-wide association studies (GWAS) have identified multiple novel prostate cancer predisposition loci. Whether these common genetic variants are associated with incident metastatic prostate cancer or with recurrence after surgical treatment for clinically localized prostate cancer is uncertain. EXPERIMENTAL DESIGN: Twelve single nucleotide polymorphisms (SNPs) were selected for study in relation to prostate metastatic cancer and recurrence, based on their genome-wide association with prostate cancer in the Cancer Genetic Markers of Susceptibility (CGEMS). To assess risk for metastatic disease, we compared genotypes for the 12 SNPs by logistic regression of 470 incident metastatic prostate cancer cases and 1,945 controls in 3 case-control studies. To assess the relationship of these SNPs to risk for prostate cancer recurrence, we used Cox regression in a cohort of 1,412 men treated for localized prostate cancer, including 328 recurrences, and used logistic regression in a case-case study, comparing 450 recurrent versus 450 nonrecurrent prostate cancer cases. Study-specific relative risks (RRs) for risk of metastatic disease and recurrence were summarized using meta-analysis, with inverse variance weights. RESULTS: MSMB rs10993994 (per variant allele summary RR = 1.24, 95% CI = 1.05-1.48), 8q24 rs4242382 (RR = 1.40, 95% CI = 1.13-1.75), and 8q24 rs6983267 (RR = 0.67, 95% CI = 0.50-0.89) were associated with risk for metastatic prostate cancer. None of the 12 SNPs was associated with prostate cancer recurrence. CONCLUSIONS: SNPs in MSMB and 8q24 which predispose to prostate cancer overall are associated with risk for metastatic prostate cancer, the most lethal form of this disease. SNPs predictive of prostate cancer recurrence were not identified, among the predisposition SNPs. GWAS specific to these 2 phenotypes may identify additional phenotype-specific genetic determinants.