VEGF-2578C/A, -460T/C Polymorphisms and Gastrointestinal Tract Cancer Risk: An Updated Meta-Analysis.

Functional polymorphisms in the vascular endothelial growth factor (VEGF) alter the susceptibility toward different gastrointestinal tract (GIT) cancers. In this study, we explored the association of VEGF-2578C/A and VEGF-460T/C polymorphisms with esophageal cancer (EC) risk. In total, 330 patients with EC and 330 controls for VEGF-2578C/A polymorphism and 316 patients with EC and 316 controls for VEGF-460T/C polymorphism were genotyped. AA genotype (p = 0.01) and A allele (p = 0.02) of VEGF-2578C/A and CC genotype (p = 0.04) and C allele (p = 0.04) of VEGF-460T/C polymorphism were significantly associated with an increased risk of EC. VEGF-2578C/A and VEGF-460T/C polymorphisms have been studied in different GIT cancers, but results are inconclusive. Therefore, we performed a meta-analysis to assess the association of these polymorphisms with the risk of GIT cancers. The PubMed, ScienceDirect, and Google Scholar databases were used to search the articles. Twenty-one studies on VEGF-2578C/A and 20 studies on VEGF-460T/C polymorphism were included in this meta-analysis. VEGF-2578C/A polymorphism was associated with the decreased risk of GIT cancer in the overall population under the overdominant model (p = 0.009). A significant association of VEGF-2578C/A polymorphism with GIT cancer risk has been observed in the middle easterners, Caucasians, and Asians under different genetic models. VEGF-460T/C polymorphism was significantly associated with an increased risk of GIT cancers in Caucasians. Stratification of the data on the basis of cancer type showed a significant association of VEGF-2578C/A polymorphism with the risk of gallbladder cancer, whereas VEGF-460T/C polymorphism was associated with the risk of hepatocellular cancer, gastric cancer, and colorectal cancer. Our meta-analysis suggested that VEGF-2578C/A and VEGF-460T/C polymorphisms were associated with GIT cancer risk.

miR-107 and miR-126 and Risk of Breast Cancer: A Case-Control Study.

Background: Micro RNAs are new diagnostic markers and therapeutic targets in breast cancer research. miR-107 and miR-126 have been reported to be linked with the pathogenesis of breast cancer. The present study investigates the levels of expression of miR-107 and miR-126 in patients with breast cancer to find their correlation with the risk of breast cancer in Amritsar, Punjab, Northwest India. Material and Methods: In total, 200 subjects, 100 patients with breast cancer and 100 controls, were enrolled to screen the expression of miR-107 and miR-126 using quantitative reverse transcription polymerase chain reaction (RT-PCR) technique. The Livak method (2-ΔΔCt) was used to calculate the fold change of the expression of micro RNAs. Student t-test was used to calculate the significant change in the expression of miRNAs in patients as compared with controls. Spearman rank correlation coefficient and ROC were conducted. The value of p < 0.05 was considered to indicate a statistically significant difference. Results: miR-107 was downregulated in patients with breast cancer as compared with controls (fold change = 0.467; p = 0.114) but not statistically significant. The expression of miR-126 was found to be 5.37 times elevated in patients with breast cancer, specifically in stage I and stage III patients (p = 0.009), compared with controls, which may indicate its oncogenic activity. The ROC analyses revealed that miR-126 could be a potential diagnostic marker. In conclusion oncogenic behavior of miR-126 is suggestive of its role in pathogenesis in patients with breast cancer.

Association of ATG10 rs1864183, ATG16L1 rs2241880 and miR-126 with esophageal cancer.

BACKGROUND: In India, esophageal cancer (EC) is among the major cause of cancer-related deaths in both sexes. In recent past, autophagy has emerged as one of the crucial process associated with cancer. In the development of EC, the role of autophagy and the precise molecular mechanism involved has yet to be fully understood. Recently, a small number of studies have proposed how variations in autophagy genes affect the growth and development of EC. Micro-RNA's are also known to play a critical role in the development of EC. Here, we examined the relationship between the risk of EC and two single-nucleotide polymorphisms (SNPs) in the key autophagy genes, ATG10 rs1864183 and ATG16L1 rs2241880. We also analyzed the association of miR-107 and miR-126 with EC as these miRNA's are associated with autophagy. METHODS AND RESULTS: A total of 230 EC patients and 230 healthy controls from North-west Indian population were enrolled. ATG10 rs1864183 and ATG16L1 rs2241880 polymorphism were analyzed using TaqMan genotyping assay. Expression levels of miR-107 and miR-126 were analyzed through quantitative PCR using SYBR green chemistry. We found significant association of CT + CC genotype (OR 0.64, p = 0.022) in recessive model for ATG10 rs1864183 polymorphism with decreased EC risk. For ATG16L1 rs2241880 polymorphism significant association for AG genotype (OR 1.48, p = 0.05) and G allele (OR 1.43, p = 0.025) was observed for increased EC risk. Expression levels of miR-126 were also found to be significantly up regulated (p = 0.008). CONCLUSION: Our results suggest that ATG10 rs1864183, ATG16L1 rs2241880 and miR-126 may be associated with esophageal carcinogenesis and warrant further investigation.

Association of VEGF-116G/A Promoter Polymorphism with Esophageal Cancer Risk: A Case-Control study and an Updated Meta-Analysis on Gastrointestinal Tract Cancers.

OBJECTIVE: The present study aimed to investigate the potential association of VEGF-116G/A promoter polymorphism with esophageal cancer risk in North-West Indians and to perform a comprehensive meta-analysis of VEGF-116G/A polymorphism in Gastrointestinal Tract (GIT) cancers. METHODS: A total of 679 DNA samples (333 esophageal cancer patients and 346 healthy controls) were genotyped for VEGF-116G/A polymorphism using Sanger sequencing. In silico analysis was carried out to predict the impact of VEGF-116G/A polymorphism on transcription factor binding sites. Ten studies including 2157 patients and 2307 controls on different GIT cancers were included in the meta-analysis.  Results: The AA genotype and A allele of VEGF -116G/A polymorphism was significantly associated with an increased risk of esophageal cancer. In silico analysis predicted that A allele of VEGF-116G/A polymorphism created new binding sites for STAT4, c-Ets-1 and Elk-1 transcription factors. The meta-analysis results showed that VEGF-116G/A polymorphism was associated with an increased risk of GIT cancer under the recessive and AA vs GG genetic model in the overall population. Stratification of the studies by ethnicity revealed an increased risk of GIT cancers in Asians under allele contrast, recessive, AA vs GG and AA vs AG model. Analysis based on cancer type revealed an increased risk of esophageal cancer under allele contrast, recessive, AA vs GG and AA vs AG comparison model and increased risk of oral cancer was observed under the allele contrast model and dominant model. CONCLUSION: VEGF-116G/A polymorphism was associated with esophageal cancer risk in North- West Indians. The findings of the present meta-analysis showed a significant association of VEGF-116G/A polymorphism with GIT cancer risk.

Association of RAD51, XRCC1, XRCC2, and XRCC3 Polymorphisms with Risk of Breast Cancer.

Background: DNA repair genes are among the low-penetrance genes implicated in breast cancer. However variants of DNA repair genes may alter their protein function thus leading to carcinogenesis. Breast cancer is the most common cancer among women in India. The aim of the present study was to identify association, if any, of single nucleotide polymorphisms (SNP's) in four genes involved in DNA repair pathways including, RAD51 rs1801320, XRCC1 rs25487, XRCC2 rs3218536, and XRCC3 rs861539 with the risk of breast cancer. Materials and Methods: In this case-control study 611 female subjects (311 breast cancer patients and 300 healthy controls) were screened for four SNPs using polymerase chain reaction-restriction fragment length polymorphism analyses. Multifactor dimensionality reduction (MDR) analysis was performed to estimate the gene-gene interaction. Protein-protein interaction network analysis were studied using the STRING database. Results: The GC genotype (p = 0.018) and the combined GC+CC (p = 0.03) genotypes of RAD51 rs1801320 were significantly associated with reduced risk of breast cancer. The CT genotype (p = 0.0001), the combined CT+TT genotypes (p = 0.0002), and the T allele (p = 0.0019) of XRCC3 rs861539 polymorphism were associated with reduced risk of the breast cancer. No association of XRCC1 rs25487 and XRCC2 rs3218536 polymorphisms with breast cancer was observed. MDR analysis indicated a positive interaction between XRCC3 and XRCC2. String network analysis showed that the RAD51, XRCC1, XRCC2, and XRCC3 proteins are in strong interaction with each other and other breast cancer-related proteins such as BRCA2. Conclusion: RAD51 rs1801320 and XRCC3 rs861539 polymorphisms were associated with reduced risk of breast cancer. There is evidence of positive interactions among XRCC1, XRCC2, XRCC3, and RAD51.

RAD51 135G>C polymorphism in esophageal cancer and meta-analysis in gastrointestinal tract cancers.

Background: A functional single-nucleotide polymorphism (SNP), 135G>C in the 5'UTR of the RAD51 gene, affects gene transcription activity with implications for the repair of damaged DNA related to tumorigenesis. Previous limited reported genetic studies to link the 135G>C polymorphism of RAD51 gene to the risk of gastrointestinal tract (GIT) cancers, especially esophageal cancer (EC), have been inconclusive. Materials and Methods: The polymorphism was evaluated by RFLP-PCR in 252 EC patients and 252 healthy controls from Amritsar, Punjab, India, for case-control study. For a meta-analysis, a total of 78 studies on GIT cancers were assessed, out of which 14 eligible studies (including the present study) comprising 2842 cases and 3224 controls were included. Odds ratios (ORs) with 95% confidence intervals (CIs) and Chi-square test were used to assess the association in different inheritance models. Results: The GC genotype (OR: 0.45, 95% CI: 0.29-0.68) and C allele (OR: 0.52, 95% CI: 0.36-0.75) were significantly lower (P = 0.0005) in cases as compared to controls. There was no significant association with any genetic model in the meta-analysis. Conclusion: C allele provides protection for EC in the studied population contrary to previous reports in Polish, Chinese population probably due to ethic differences. Compared with previous meta-analysis on individual GIT cancers, present meta-analysis included all GIT cancers but found no association.

Association of MTHFR 677C>T polymorphism with breast cancer risk: A case-control study and meta-analysis.

Background and Objectives: Breast cancer is a complex, multifactorial disease that arises as a result of interactions between multiple genes and environmental factors. Methylenetetrahydrofolate reductase (MTHFR) is a low susceptibility gene, involved in folate metabolism. It assists in conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate which further leads to DNA methylation. 5,10-methylenetetrahydrofolate assists in conversion of uracil to thymine and purine synthesis for DNA synthesis. MTHFR 677C>T polymorphism alters the activity of MTHFR enzyme potentially effecting DNA repair and synthesis, hence a potential risk for cancer like breast cancer. Hence, the present study was conducted to evaluate association of MTHFR 677C>T polymorphism and breast cancer in Punjabi population. Moreover, a meta-analysis was conducted to address the same. Materials and Methods: A total of 247 breast cancer patients and 247 controls were selected from Punjabi population for analysis using PCR-RFLP method. For meta-analysis, 67 studies were selected, and allele contrast, homozygous, heterozygous, dominant, and recessive models were used to evaluate the association between MTHFR 677C>T and breast cancer. Results: The frequencies of CC, CT, and TT genotype were 68.4% versus 74.5%, 28.7% versus 23.5%, and 2.9% versus 2.0% in patients and controls, respectively. There was no significant difference found. In meta-analysis, significant association was found in overall and Asian population while no significant association was found in Caucasians. Interpretation and Conclusions: MTHFR 677C>T polymorphism is not a risk factor for breast cancer in Punjabi population. Inconsistency with the meta-analysis can be due to ethnic diversity.

Impact of VEGFA promoter polymorphisms on esophageal cancer risk in North-West Indians: a case-control study.

BACKGROUND: Angiogenesis play a critical role in the development and progression of tumors in solid tumors. Vascular endothelial growth factor (VEGF) is one of the most important endothelial cell mitogen which plays a critical role in normal physiological and tumor angiogenesis. OBJECTIVES: The objective of this case-control study was to investigate the association of VEGF-2578C/A, -2549 I/D, and -460T/C promoter polymorphisms with esophageal cancer risk in North-West Indians. METHODS: In this study, 200 sporadic esophageal cancer patients and 200 healthy, unrelated, age and gender matched controls were analyzed. The genomic DNA was extracted from blood samples using phenol chloroform method. Genotyping of VEGF- 2549I/D polymorphism was carried out by direct polymerase chain reaction (PCR) whereas VEGF -2578C/A and VEGF-460T/C) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: AA genotype (p = 0.005) and A allele (p = 0.005) VEGF -2578 C/A, II genotype (p = 0.011) and I allele (p = 0.012) of VEGF - 2549 I/D and CC genotype (p = 0.013) and C allele of VEGF-460T/C polymorphisms were significantly associated with increased risk of esophageal cancer. Stratification of data on the basis of gender showed that VEGF -2578 AA genotype (p = 0.001) and A allele (p = 0.001); VEGF -2549 II genotype (p = 0.002) and I allele (p = 0.002) and VEGF- 460CC genotype (p = 0.001) and C allele (p = 0.002) was significantly associated with increased risk of esophageal cancer in female group. Haplotype analysis revealed that A-2578 I- 2549 C- 460 haplotype was significantly associated with increased risk for esophageal cancer in total samples (p = 0.008) as well as in female group (p = 0.001). CONCLUSIONS: The results of present study indicate that VEGF -2578C/A, - 2549I/D and -460T/C polymorphisms were significantly associated with increased risk of esophageal cancer in North-West Indians.

Association of VEGF haplotypes with breast cancer risk in North-West Indians.

BACKGROUND: Angiogenesis is a complex and coordinated process regulated by different growth factors and is one of the hallmark features of cancer. VEGF is one of the most important endothelial cell mitogen and has a critical role in normal physiological and tumor angiogenesis. The objective of this study was to investigate the potential association of haplotypes of six VEGF polymorphisms with breast cancer risk in North-West Indians. METHODS: Samples of 250 breast cancer patients and 250 age and sex matched controls were genotyped for VEGF -2578C/A, -2549I/D, -460T/C, +405C/G, -7C/T and +936C/T polymorphisms. Haplotypes were generated to determine the better contribution of VEGF polymorphisms to breast cancer risk. RESULTS: Haplotypes CDTCCC (OR = 0.56, 95%CI, 0.38-0.81; p = 0.003) and CDTGCC (OR = 0.63, 95%CI, 0.44-0.92; p = 0.018) of VEGF -2578C/A, -2549I/D, -460T/C, +405C/G, -7C/T and +936C/T polymorphisms were significantly associated with decreased risk of breast cancer. CDTCCC haplotype was also significantly associated with reduced risk of breast cancer in pre and post menopausal as well as both obese and non obese patients. Haplotype CDTGCC was marginally associated (p = 0.07) with reduced risk of breast cancer in non-obese patients as compared with non-obese controls where as haplotype AICGTC was marginally associated (p = 0.09) with reduced risk of breast cancer in obese patients when compared with non-obese patients. The CDTGCC haplotype was significantly associated with increased risk of breast cancer in premenopausal obese patients (OR = 1.98, 95%CI, 1.10-3.56; p = 0.02). CONCLUSIONS: Our data indicated that CDTCCC and CDTGCC haplotypes of VEGF -2578C/A, -2549I/D, -460T/C, +405C/G, -7C/T and +936C/T polymorphisms were significantly associated with breast cancer risk in North-West Indians. Further studies on multiethnic groups with larger sample size are required to confirm our results.

In silico pathway analysis based on chromosomal instability in breast cancer patients.

BACKGROUND: Complex genomic changes that arise in tumors are a consequence of chromosomal instability. In tumor cells genomic aberrations disrupt core signaling pathways involving various genes, thus delineating of signaling pathways can help understand the pathogenesis of cancer. The bioinformatics tools can further help in identifying networks of interactions between the genes to get a greater biological context of all genes affected by chromosomal instability. METHODS: Karyotypic analyses was done in 150 clinically confirmed breast cancer patients and 150 age and gender matched healthy controls after 72 h Peripheral lymphocyte culturing and GTG-banding. Reactome database from Cytoscape software version 3.7.1 was used to perform in-silico analysis (functional interaction and gene enrichment). RESULTS: Frequency of chromosomal aberrations (structural and numerical) was found to be significantly higher in patients as compared to controls. The genes harbored by chromosomal regions showing increased aberration frequency in patients were further analyzed in-silico. Pathway analysis on a set of genes that were not linked together revealed that genes HDAC3, NCOA1, NLRC4, COL1A1, RARA, WWTR1, and BRCA1 were enriched in the RNA Polymerase II Transcription pathway which is involved in recruitment, initiation, elongation and dissociation during transcription. CONCLUSION: The current study employs the information inferred from chromosomal instability analysis in a non-target tissue for determining the genes and the pathways associated with breast cancer. These results can be further extrapolated by performing either mutation analysis in the genes/pathways deduced or expression analysis which can pinpoint the relevant functional impact of chromosomal instability.

Screening of BRCA1 variants c.190T>C, 1307delT, g.5331G>A and c.2612C>T in breast cancer patients from North India.

The polymorphic variants of BRCA1, which lead to amino acid substitutions, have a known pathogenic role in breast cancer. The present study investigated in North Indian breast cancer patients the association of risk with four reported pathogenic variants of BRCA1: c.190T>C (p.Cys64Arg), 1307delT, g.5331G>A (p.G1738R) and c.2612C>T (p.Pro871Leu). Genotyping was done by PCR-RFLP method in 255 clinically confirmed breast cancer patients and 255 age and gender matched healthy individuals. For c.190T>C, 1307delT and g.5331G>A, all the patients and controls had the wild-type genotype indicating no association with breast cancer risk. For c.2612C>T polymorphism, the frequency of the CC, CT, and TT genotypes was 14.5 vs 15.7%, 59.6 vs 53.7% and 25.9 vs 30.6% in breast cancer patients and controls respectively. The frequency of heterozygotes (CT genotype) was higher in cases than controls but the difference was not statistically significant. Genetic model analysis showed no association of the four analyzed BRCA1 variants with breast cancer risk with any model. The studied variants were not associated with the risk of breast cancer in Punjab, North west India, suggesting a need for further screening of other BRCA1 variants. It is the first reported study on these 4 variants from India.

Association of XRCC1, XRCC2 and XRCC3 Gene Polymorphism with Esophageal Cancer Risk.

AIM: The X-ray repair cross-complementing (XRCC) gene polymorphisms influence esophageal carcinogenesis by altering the DNA repair capacity. The present study was designed to screen five single nucleotide polymorphisms (SNPs) of XRCC genes for their susceptibility to esophageal cancer (EC) risk. There is no previous report on these polymorphisms for EC from India, where EC frequency is high. METHODS: The present study included 497 subjects (213 EC patients and 284 healthy controls). The polymorphisms were screened using the PCR-RFLP method and allele and genotype distribution were compared using chi-square test. Association analysis was done by haplotype analysis and linkage disequilibrium (LD) analysis. Gene-gene interactions were identified using multifactor dimensionality reduction (MDR). The risk was calculated using binary logistic regression. RESULTS: For XRCC1 p.Arg399Gln, a decreased risk for EC was associated with the AA genotype [OR (95% CI): 0.53 (0.3-0.95), p=0.03] even after adjusting for various covariates [OR (95% CI): 0.49 (0.26-0.9), p=0.024] and with the recessive model [OR (95% CI): 0.49 (0.27-0.8), p=0.016]. The GA genotype of p.Arg280His was associated with an increased risk for EC [OR (95% CI): 1.7 (1.0-2.82), p= 0.045] after adjustments. The two XRCC1 polymorphisms, p.Arg399Gln and p.Arg194Trp were in slight LD among EC patients (D̍́=0.845, r 2=0.042). XRCC2 and XRCC3 polymorphisms were not associated with EC risk. CONCLUSION: XRCC1 p.Arg399Gln plays a protective role in the development of the EC. The study is the first report from India, providing baseline data about genetic polymorphisms in DNA repair genes XRCC1, XRCC2 and XRCC3 modulating overall EC risk.

Linkage disequilibrium and haplotypes of five TP53 polymorphisms in oesophageal cancer patients.

The aim of present study was to evaluate the linkage disequilibrium (LD) of p.R72P, PIN3 Ins16bp, p.P47S, p.R213R and r.13494g[a polymorphism of TP53 and their haplotypes association with oesophageal cancer risk in patients from Punjab, northwest India. A total of 466 samples, including 233 oesophageal cancer patients and 233 healthy individuals were analysed. Data analysis revealed the gender specific association. In female group, arginine-proline (RP) genotype (P = 0.08) and P allele (P = 0.07) of p.R72P polymorphism was marginally associated with increased risk of oesophageal cancer. A1A2 genotype (P = 0.06) and A2 allele (P = 0.07) of PIN3 Ins16bp polymorphism was marginally associated with decreased risk of oesophageal cancer in male group. A1A2-GA genotype combination (P = 0.04) of PIN3 and r.13494g[a polymorphisms was significantly associated with decreased risk of oesophageal cancer in male group. In female group, PP-GA genotype combination (P = 0.02) of p.R72P and r.13494g[a polymorphisms and RP-A1A1-GG genotype combination (P = 0.04) of p.R72P, PIN3 and r.13494g[a polymorphisms was significantly associated with increased risk of oesophageal cancer. We observed moderate LD between two intronic polymorphisms PIN3 Ins16bp and r.13494g[a (D´ = 0.90; r2 = 0.68). Haplotype analysis revealed that none of the haplotype combination was associated with oesophageal cancer risk when both the genders were considered. Stratification on the basis of gender showed that P-A2-P-A-A haplotype of p.R72P, PIN3 Ins16bp, p.P47S, p.R213R and r.13494g[a polymorphisms was marginally associated with reduced oesophageal cancer risk in male group (P = 0.08). Replication of these findings in independent cohorts may be insightful for the role of TP53 in oesophageal cancer pathogenesis.

Risk Factor Analysis for Breast Cancer in Premenopausal and Postmenopausal Women of Punjab, India.

OBJECTIVE: Amritsar, the second largest town of agrarian state of Punjab, India reports high number of breast cancer cases every year. The present study investigated the etiology of breast cancer using various obesity indices and other epidemiological factors among breast cancer patients residing in and around Amritsar city. METHODS: In this case control study, risk factors for breast cancer were analyzed in 542 female subjects: 271 females with breast cancer patients and 271 unrelated healthy females matched for age as control females. RESULTS: Bivariate analysis for risk factors in cases and controls showed a lower risk (OR=0.65, 95% CI 0.43-0.99, p=0.04) in obese cases with BMI≥25kg/m2 as compared to subjects with normal BMI. Risk factor analysis showed that parameter which provided risk for cancer in postmenopausal women was obesity and in premenopausal women was parity. Postmenopausal women with BMI (overweight: OR=0.39, 95% CI 0.17-0.92, p=0.03; obese: OR= 0.26, 95% CI 0.13-0.52, p=0.00), WC (OR=0.17, 95% CI 0.05-0.52, p=0.00) and WHtR (p=0.02) had highr risk. Premenopausal women with 3 or less than 3 children had a higher risk (OR=5.54, 95 % CI 2.75-11.19, p=0.00) than postmenopausal women when compared to women with more than 3 children. Binary logistic regression analysis revealed that low parity (≤3) substantially increased the risk for breast cancer (OR=4.80, 95% CI 2.34-9.85, p=0.00) in premenopausal women. CONCLUSION: Obesity, parity associated breast cancer risk and reduced breastfeeding cumulatively predispose the premenopausal women of this region to higher risk of breast cancer.
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Association of the -2518 A/G Polymorphism of MCP-1 with Breast Cancer in Punjab, North-West India.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a major chemokine thought to be responsible for monocyte and T-lymphocyte recruitment in acute inflammatory conditions and recruitment of macrophages in tumors. It is also implicated in cardiovascular disease, rheumatoid arthritis and chronic obstructive pulmonary disease. The aim of the present study was to investigate the correlation between MCP-1 -2518 A/G polymorphism and breast cancer risk in patients from Amritsar city of Punjab state in North-West India. MATERIALS AND METHODS: We screened DNA samples of 200 sporadic breast cancer patients and 200 age and gender matched unrelated healthy individuals for MCP-1 -2518 A/G polymorphism using the PCR-RFLP method. RESULTS: A significantly increased frequency of the GG genotype was observed in patients as compared to controls. Individuals carrying the MCP1 -2518GG genotype had a two fold risk for breast cancer (OR=2.06, 95%CI, 1.06-3.98; p=0.03). Genetic models analysis revealed a significant association between MCP-1 -2518 A/G polymorphism and cancer risk in homozygous co-dominant (OR=2.06, 95%CI, 1.06-3.98; p=0.03) and recessive (OR=1.97, 95%CI, 1.05-3.70; p=0.03) models. CONCLUSIONS: We conclude that the GG genotype of the MCP-1-2518 A/G polymorphism is associated with increased risk to breast cancer in Punjab, North-West India.

No Association between the CCR5Δ32 Polymorphism and Sporadic Esophageal Cancer in Punjab, North-West India.

BACKGROUND: Chemokines and their receptors influence carcinogenesis and cysteine-cysteine chemokine receptor 5 (CCR5) directs spread of cancer to other tissues. A 32 base pair deletion in the coding region of CCR5 that might alter the expression or function of the protein has been implicated in a variety of immune-mediated diseases. The action of antiviral drugs being proposed as adjuvant therapy in cancer is dependent on CCR5 wild type status. In the present study, distribution of CCR5Δ32 polymorphism was assessed in North Indian esophageal cancer patients to explore the potential of using chemokine receptors antagonists as adjuvant therapy. MATERIALS AND METHODS: DNA samples of 175 sporadic esophageal cancer patients (69 males and 106 females) and 175 unrelated healthy control individuals (69 males and 106 females) were screened for the CCR5Δ32 polymorphism by direct polymerase chain reaction (PCR). RESULTS: The frequencies of wild type homozygous (CCR5/CCR5), heterozygous (CCR5/Δ32) and homozygous mutant (Δ32/Δ32) genotypes were 96.0 vs 97.72%, 4.0 vs 1.71% and 0 vs 0.57% in patients and controls respectively. There was no difference in the genotype and allele frequencies of CCR5Δ32 polymorphism in esophageal cancer patients and control group. CONCLUSIONS: The CCR5Δ32 polymorphism is not associated with esophageal cancer in North Indians. As the majority of patients express the wild type allele, there is potential of using antiviral drug therapy as adjuvant therapy.

Association of VEGF and VEGFR1 polymorphisms with breast cancer risk in North Indians.

The aim of present study was to evaluate the relationship between vascular endothelial growth factor (VEGF) -2578C/A, -2549I/D, -460T/C and -7C/T and VEGFR1 -710C/T polymorphisms with risk to breast cancer in North Indians. A total of 204 sporadic breast cancer patients and 204 controls were recruited for this case-control study. Significantly increased frequency of II genotype of -2549I/D polymorphism was observed in patients as compared to control individuals (odds ratio (OR) = 2.76, 95 % confidence interval (CI), 1.55-4.92; p = 0.0005). VEGF -2578AA genotype (OR = 2.87; 95 % CI, 1.61-5.10; p = 0.0003) and A allele (OR = 1.65, 95 % CI, 1.25-2.18; p = 0.0004) were found to be associated with increased risk for breast cancer. Individuals carrying CC genotype (OR = 2.23, 95 % CI, 1.25-3.97) and C allele (OR = 1.42, 95 % CI, 1.07-1.87) of VEGF -460T/C polymorphism were at higher risk of breast cancer. There was no significant difference in genotype and allele distribution of VEGF -7C/T and VEGFR1 -710C/T polymorphisms between cases and control individuals (p > 0.05). Linkage disequilibrium analysis showed a strong linkage between VEGF -2549I/D and -2578C/A polymorphisms (Lewontin's [Formula: see text] = 0.99; r (2) = 0.97), -2549I/D and -460T/C ([Formula: see text] = 0.94; r (2) = 0.84), and -2578C/A and -460T/C polymorphisms ([Formula: see text] = 0.93; r (2) = 0.83). In the present study, we concluded that VEGF -2549I/D, -2578C/A and -460T/C polymorphisms are associated with risk to breast cancer in Punjab, North India.

No association of hypoxia inducible factor-1α gene polymorphisms with breast cancer in North-West Indians.

BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1α) is the key regulator of cellular responses to hypoxia and plays a central role in tumour growth. Presence of Single nucleotide polymorphisms (SNPs) in the critical regulatory domains of HIF-1α may result in the overexpression of the protein and subsequent changes in the expression of the downstream target genes. The aim of study was to investigate the association of three SNPs (g.C111A, g.C1772T and g.G1790A) of HIF-1α with the risk of breast cancer in North Indian sporadic breast cancer patients. MATERIALS AND METHODS: A total of 400 subjects, including 200 healthy controls and 200 patients with breast cancer were recruited in this study. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The CC and CA genotype frequency of HIF-1α g.C111A polymorphism was 100 vs 99% and 0 vs 1% in breast cancer patients and healthy controls respectively. The frequencies of CC, CT and TT genotype of g.C1772T polymorphism were 76 vs 74.5%, 19 vs 21% and 5 vs 4.5% in breast cancer patients and control individuals respectively. There was no significant difference in genotype and allele frequencies of HIF-1α g.C1772T polymorphism between cases and control individuals (p>0.05). For g.G1790A genotypes, all patients and controls had only GG genotype. CONCLUSIONS: The three HIF-1α polymorphisms (g.C111A, g.C1772T and g.G1790A) are not associated with breast cancer risk in North-West Indian patients.

Analysis of TP53 polymorphisms in North Indian sporadic esophageal cancer patients.

BACKGROUND: To investigate the relationship of five TP53 polymorphisms (p.P47S, p.R72P, PIN3 ins16bp, p.R213R and r.13494g>a) with the esophageal cancer (EC) risk in North Indians. MATERIALS AND METHODS: Genotyping of p.P47S, p.R72P, PIN3 ins16bp, p.R213R and r.13494g>a polymorphisms of TP53 in 136 sporadic EC patients and 136 controls using polymerase chain reaction and PCR-RFLP. RESULTS: The frequencies of genotype RR, RP and PP of p.R72P polymorphism were 16.91 vs 26.47%, 58.82 vs 49.27% and 24.27 vs 24.27% among patients and controls respectively. We observed significantly increased frequency of RP genotype in cases as compared to controls (OR=1.87, 95% CI, 1.01-3.46, p=0.05). The frequencies of genotype A1A1, A1A2 and A2A2 of PIN3 ins16bp polymorphism were 69.12 vs 70.59%, 27.20 vs 25% and 3.68 vs 4.41% among patients and controls. There was no significant difference among genotype and allele distribution between patients and controls. The frequencies of genotype GG, GA and AA of r.13494g>a polymorphism were 62.50 vs 64.70%, 34.56 vs 30.15% and 2.94 vs 5.15% among patients and controls respectively. No significant difference between genotype and allele frequency was observed in the patients and controls. For p.P47S and p.R213R polymorphisms, all the cases and controls had homozygous wild type genotype. The RP-A1A1-GG genotype combination shows significant risk for EC (OR=2.01, 95%CI: 1.01-3.99, p=0.05). CONCLUSIONS: Among the five TP53 polymorphisms investigated, only p.R72P polymorphism may contributes to EC susceptibility.

Vascular endothelial growth factor (VEGF) gene polymorphisms and breast cancer risk in Punjabi population from North West India.

The purpose of this study was to evaluate the association of seven VEGF promoter polymorphisms with breast cancer risk in Punjabi population from North West India. We screened DNA samples of 102 sporadic breast cancer patients and 102 unrelated healthy, gender, and age-matched individuals for seven VEGF promoter polymorphisms [-417 C/T (rs833062), -172 C/A (rs59260042), -165 C/T (rs79469752), -160 C/T, -152 G/A (rs13207351), -141 A/C (rs28357093) and -116 G/A (rs1570360)] by direct sequencing. The frequency of GG, GA, and AA genotype of -152 G/A polymorphism was 26.47 vs 38.34%, 46.08 vs 51.96%, and 27.45 vs 9.80%, in patients and controls, respectively. VEGF -152 AA genotype was significantly associated with increased risk for breast cancer (OR = 4.04, 95%CI, 1.69-9.68, p = 0.001; recessive model OR = 3.48, 95%CI, 1.59-7.63, p = 0.001). For VEGF -116 G/A polymorphism, G and A allele frequencies were 65.2 vs 76.47% and 34.8 vs 23.53% in patients and controls, respectively. Individuals having -116 AA genotype (OR = 3.40; 95%CI, 1.24-9.37; p = 0.014) and A allele (OR = 1.73; 95%CI, 1.12-2.67; p = 0.012) were associated with increased risk for breast cancer. VEGF -165 C/T and -141 A/C polymorphisms were associated with reduced risk for breast cancer. There was significantly decreased frequency of CT genotype (4.90 vs 18.63%; p = 0.002) and T allele (2.45 vs 9.31%; p = 0.003) of -165 C/T polymorphism among breast cancer patients as compared to controls. VEGF -141 A and C allele frequency were 96.57 vs 91.18% and 3.43 vs 8.82% in patients and controls, respectively. Significant reduced risk for breast cancer was observed with AC genotype (OR = 0.34, 95%CI, 0.14-0.86; p = 0.019) and C allele (OR = 0.37; 95%CI, 0.15-0.89; p = 0.023) of -141 A/C polymorphism. We did not observe association of VEGF -417 T/C, -172 C/A, -160 C/T polymorphisms with breast cancer risk in the studied subjects (p > 0.05). The VEGF -152 G/A and -116 G/A polymorphisms were found to be significantly associated with increased risk for breast cancer while -165 C/T and -141 A/C polymorphisms were found to be associated with decreased risk for breast cancer in Punjabi population from North West India.