Search

Jagjeet Kaur, 1 Vasudha Sambyal, 1 Kamlesh Guleria, 1 Neeti Rajan Singh, 2 Manjit Singh Uppal, 2 Mridu Manjari, 3 Meena Sudan 4 1Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, India; 2Department of Surgery; 3Department of Pathology; 4Department of Radiotherapy, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, IndiaCorrespondence: Vasudha SambyalDepartment of Human Genetics, Guru Nanak Dev University, Amritsar 143001, Punjab, India Tel +911832258803-09 ext 3448Email vasudhasambyal@yahoo.co.inAim: 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.Keywords: XRCC1, XRCC2, XRCC3, polymorphisms, esophageal cancer

Medication adherence has long been viewed as a patient issue, but what if we shift this perspective? What if medications could adjust to the needs and context of patients, instead of the other way around? We used design thinking to create a contextually sensitive digital health mobile application to improve medication adherence in older adults. We define contextual sensitivity as sensitivity to the context of patient needs. Through persona and scenario ideation, interviews, evaluations of existing solutions, prototypes, and consultations with subject matter experts, we uncovered key barriers to medication adherence. We outline 4 key challenges: alert fatigue, poor health literacy, lack of social support, and lack of behavior change and motivation, which are specific to older adults. The resulting application features reminders and alerts, a dashboard and calendar, educational resources, social sharing, and reward features. These 5 elements emphasize the significance of design thinking, contextual sensitivity, trimodal alerts, and co-interventions in developing effective digital health solutions for medication adherence among older adults.

Coronary Artery Disease (CAD) is a global health concern, with diagnostic modalities and risk factors that exhibit regional variations. This study, conducted at the Islamabad Diagnostic Center, Pakistan, aimed to provide a comprehensive assessment of CAD prevalence, severity, and associated risk factors, while also evaluating the diagnostic accuracy of Computed Tomography Coronary Test (CTT) and Exercise Treadmill Test (ETT) in a cohort of 2909 patients. Among the patients assessed via CT Coronary scans, CAD was universally observed, presenting with varying degrees of severity. Our findings indicated that 24.5% of patients had mild CAD, 28.6% exhibited mild to moderate CAD, 16.3% were diagnosed with moderate CAD, 18.4% demonstrated moderate to severe CAD, and 20.4% displayed severe CAD. This spectrum underscores the diverse nature of CAD within the study population. In addition to CTT, we conducted a detailed evaluation of ETT results in 49 patients. These results revealed that 55.1% of patients tested positive for ischemia during the exercise test, emphasizing the prevalence of cardiac stress and underlying CAD. Conversely, 32.7% of patients exhibited negative ETT results, indicating favorable cardiac tolerance during physical activity. A subset of patients yielded non-diagnostic or inconclusive results, necessitating further clinical assessment. Disease history analysis showed a dichotomy within the cohort, with 20.4% having a known medical history and 79.6% possessing an unknown disease history, highlighting the importance of comprehensive medical records in clinical practice. Hypertension, a critical cardiovascular risk factor, was identified in 87.8% of patients, underscoring its significance. Smoking history displayed notable variation, with 69.4% categorized as smokers, 14.3% as ex-smokers, and 10.2% as non-smokers. Lipid profile analysis indicated that 69.4% of patients had abnormal lipid levels. To assess the diagnostic accuracy of CTT and ETT, we calculated Positive Predictive Values (PPV) and Negative Predictive Values (NPV). CTT exhibited a PPV of approximately 5.99% and an NPV of approximately 4.40%, whereas ETT displayed a higher PPV of around 26.44% and a substantially higher NPV of about 49.24%. This study offers valuable insights into CAD prevalence, severity, and associated risk factors in a Pakistani cohort, emphasizing the importance of holistic risk assessment and tailored interventions in clinical practice. Our findings also highlight the diagnostic utility of ETT in CAD assessment.

Background & objectives Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors which stimulates tumour progression induction of endothelial cell migration and division, inhibition of the apoptosis of endothelial cells, induction of serine protease activity and enhancement of vascular permeability. This study aimed to investigate the correlation of VEGF+405G/C,-7C/T and+936C/T polymorphisms with oesophageal cancer risk. Methods DNA samples of 464 subjects (231 sporadic oesophageal cancer affected individuals and 233 controls) were genotyped forVEGF+936C/T,+405G/C and-7C/T polymorphisms. VEGF+936C/T and +405G/C polymorphisms were genotyped by PCR-RFLP method whereas VEGF-7C/T polymorphism was genotyped using Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Results CT genotype of VEGF-7C/T polymorphism was significantly associated with reduced risk of oesophageal cancer. VEGF-7C/T polymorphism was significantly associated with reduced risk of oesophageal cancer underdominant, co-dominant, over dominant and log-additive genetic models in total patients and in the female group. C+936G+405T-7 haplotype was significantly associated with decreased risk (P=0.01)of oesophageal cancer in total patients and also in the male group (P=0.02). Interpretation & conclusions In future, replication of the findings of the present study in a larger sample from different ethnic groups, along with functional analysis, may be insightful for the role of VEGFA polymorphisms in the pathogenesis of oesophageal cancer. Identification of the correlation of VEGF variants with specific therapy in oesophageal cancer may help in better selection of patients and monitoring treatment response in VEGF-therapy.

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.

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.

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., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

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.

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 .

Common copy number variations often contain cancer-related genes and are likely to play a role in carcinogenesis. Different mechanisms of tumorigenesis are suggested in female and male breast cancer because of different molecular profiles. The cytogenetic analysis of GTG-banded chromosomes was performed in six male patients with infiltrating ductal carcinoma and six healthy male controls matched for age. Single-nucleotide polymorphism (SNP) array analysis was performed in male breast cancer (MBC) patients. Cytogenetic analysis found aberrations previously implicated in cancer. SNP array analysis in patients revealed a gain of Xp11.23, 8p23.2, Yq11.221, Yq11.3 (AZF region), 12p11.21, 18q12.1, and 17q21.3; a loss of Yq11.222 and 7q11.21; and a loss of heterozygosity of 4p16.3, 6p12.3, 6p22.2-p21.31, 7p14.2-14.1, 18q11.2-q12.1, 20p11.23-11.1, 20q11.21-11.23, 1q25.2-q25.3, 2q11.1-q11.2, 5q23.1-23.2, 11p15.4-15.3, and 22q13.1-13.31. Some of these variations, especially those of the Y-chromosome, have not been reported earlier. Chromosomal loci identified by SNP array harbor genes were reported to be associated with cancer progression and metastasis, indicating their involvement in MBC also.

The national burden of HCV has significantly mounted over the period of last few decades placing Pakistan at the worst placement of second largest burden of HCV globally. Herein for the first time from Pakistan, we examined clinical correlation of potential biomarkers with HCV. Nation-wide study was conducted on 13,348 suspected HCV patients during 2018-2022. During pre-COVID-19 era of 2018-2019, prevalence of HCV remained 30%. During 2018, among HCV positive patients, 91% of ALT, 63% of AST, 67% of GGT, 28% of Bili T, 62% of HB, 15% of HBA1C, 25% of CREAT, 15% of PT, 15% of aPTT and 64% of AFP were abnormal. During 2019, among HCV infected 74.47% of ALT, 63.54% of AST, 70.24% of GGT, 24.71% of Bili T, 8.77% of HB and 75% of AFP were raised. CT/CAT scan revealed 4.65% liver complications (mild 13.04%, moderate 30.43% and severe 56.52%). During 2020, HCV prevalence remained 25%. 65.17% of ALT, 64.20% of AST, 68.75% of GGT, 31.25% of Bili T, 20.97% of HB, 4.65% of CREAT and 73.68% of AFP levels were raised. CAT analysis revealed liver complications among 4.41% (14.81% mild, 40.74% moderate, and 44.44% sever). 85.71% of participants diabetes was out of control. During 2021, HCV prevalence remained 27.1%. ALT (73.86%), AST (50.6%), GGT (67.95%), Bili T (28.21%), HB (20%), CREAT (5.8%) and AFP (82.14%) levels were abnormal. During 2022, the levels of ALT (56.06%), AST (56.36%), GGT (56.6%), Bili T (19.23%), HB (43.48%), HBA1C (14.81), CREAT (18.92%), AFP (93.75%) were abnormal. CAT analysis revealed 7.46% liver complications (25% mild, 30.36% moderate, and 42.86% sever). During 2021-2022, 83.33% of subject's diabetes was not controlled.

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., Competing Interests: None

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., Competing Interests: None

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., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

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., (© 2021. The Author(s).)

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.

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.

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; r 2 = 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.

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., .

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.

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.

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.

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.

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.

Background: Vascular endothelial growth factor (VEGF), an endothelial cell specific mitogen, has been implicated as a critical factor influencing tumor related angiogenesis. The aim of present study was to evaluate the relationship between VEGF +936C>T and +405C>G polymorphisms of VEGF with risk of breast cancer in Punjab, India., Materials and Methods: We screened DNA samples of 192 sporadic breast cancer patients and 192 unrelated healthy, gender and age matched control individuals for VEGF +936C>T and +405C>G polymorphisms using the PCR-RFLP method., Results: For the VEGF +405C>G polymorphism, we observed significantly increased frequency of GG genotype in cases as compared to controls and strong association of +405GG genotype was observed with three fold risk for breast cancer (OR=3.07; 95%CI 1.41-6.65; p=0.003). For the +936C>T polymorphism, significant associations of CT and combined CT+TT genotypes were observed with elevated risk of breast cancer (p=0.021; 0.023). The combined genotype combinations of GG-CC and GG- CT of +405C>G and +936C>T polymorphisms were found to be significantly associated with increased risk of breast cancer (p=0.04; 0.0064)., Conclusions: The findings of the present study indicated significant associations of VEGF +936C>T and +405C>G polymorphisms with increased breast cancer risk in patients from Punjab, North India.

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.

Background: The purpose of this study was to evaluate the potential association of five (p.P47S, p.R72P, PIN3 Ins16bp, p.R213R and r.13494g>a) polymorphisms of TP53 with the risk of developing breast cancer in North Indian Punjabi population., Methods: We screened DNA samples of 200 sporadic breast cancer patients (197 females and 3 males) and 200 unrelated healthy, gender and age matched individuals for the polymorphisms., Results: For the p.P47S polymorphism, we observed the PP genotype in 99.5% of the patients and PS genotype in only 1 patient. All the controls had the wild type PP genotype. The frequency of RR, RP and PP genotype of p.R72P was 23.5% vs 33.5%, 51.5% vs 45.5% and 25% vs 21% in patients and controls respectively. Heterozygous (RP) genotype was increased in breast cancer patients as compared to controls (51.5 vs 45.5%) and showed 1.61 fold significantly increased risk for breast cancer (OR=1.61, 95% CI, 1.01-2.58, p=0.04). In breast cancer patients the frequencies of A1A1, A1A2 and A2A2 genotypes of PIN3 Ins16bp polymorphism were 67%, 26% and 7% respectively whereas in controls the genotype frequencies were 68.5%, 27.5% and 4% respectively, with no significant difference. For p.R213R (c.639A>G), all individuals had homozygous wild type genotype. The frequencies of GG, GA and AA genotypes of TP53 r.13494g>a polymorphism were 62 vs 67.5%, 33 vs 28% and 5 vs 4.5% in patients and controls respectively, again without significant difference. We observed that RP- A1A1 genotype combination of p.R72P and PIN3 Ins16bp and RP-GG combination of p.R72P and r.13494g>a polymorphism showed significant risk of breast cancer (OR=1.65, 95%CI: 0.98-2.78, p=0.05; OR=1.72, 95%CI: 1.01-2.92, p=0.04)., Conclusion: The results of present study indicated that among the five TP53 polymorphisms investigated, the p.R72P polymorphism, and the RP-A1A1 and RP-GG genotype combination contribute to breast cancer susceptibility in North Indians.

Aims: The aim of the present study was to assess the role of the vascular endothelial growth factor (VEGF) -2549 insertion/deletion (I/D) polymorphism in susceptibility to sporadic breast cancer., Methods: DNA samples of 94 breast cancer patients and 94 unrelated healthy control individuals with matched age and gender from the same geographical region of Punjab, North West India were screened for the -2549 I/D polymorphism. Serum VEGF-C (sVEGF-C) levels of breast cancer patients and healthy controls were measured using an enzyme-linked immunosorbent assay., Results: The frequency of the II, ID, and DD genotype was 23.40 versus 10.64%, 48.94 versus 52.13%, and 27.66 versus 37.23%, in patients and controls, respectively. A statistically significant difference was observed for genotype distribution among the patients and controls (χ(2)=6.039, p=0.049). There was a significant increase in the I allele frequency in the patients as compared with controls (47.86 versus 36.70%, p=0.028). The sVEGF-C levels were also considerably higher in patients as compared to healthy controls (p<0.01)., Conclusions: The VEGF -2549 I/D polymorphism has a role in the susceptibility to breast cancer in the Amritsar region of Punjab, India.

Background: The present study aimed to find the prognostic implications of two polymorphisms in TP53 (p.R72P, PIN3 Ins16bp) and one in CCR5 (CCR5/32) in sporadic breast cancer patients., Methods: DNA samples of 80 breast cancer patients and 80 age and gender matched unrelated healthy control individuals from Punjab, North West India were analyzed., Results: For p.R72P, the genotype frequency was 13.8% (RR), 58.8% (RP), 27.5% (PP) in patients and 33.9% (RR), 40.0% (RP), 26.5% (PP) in controls. For PIN3 Ins16bp, the genotype frequencies were 53.75% (A1A1), 37.5% (A1A2), 8.75% (A2A2) in patients and 66.3% (A1A1), 31.3% (A1A2), 2.5% (A2A2) in controls. Only 4 (5%) breast cancer patients were heterozygous for CCR5Δ32 deletion. Common RR-A1A1-WT/WT genotype was lower while RP-A1A2-WT/WT genotype was higher in patients as compared to controls. RP-A1A1-WT/WT genotype was significantly higher in patients as compared to control individuals (p = 0.008)., Conclusion: Though a clear association of any particular genotype with sporadic breast cancer or stage was not apparent, the results of present study were suggestive that sporadic breast cancer patients with RR-A1A1-WT/WT genotype might have a better response to chemotherapy, thus improving their chances of survival.

In 1385 adults with primary untreated hyperlipidemia and in a population study of 339 adults (Princeton Follow-up Study [PFS]), we hypothesized that homeostasis model assessment (HOMA) insulin resistance (IR) was a significant explanatory variable for triglycerides (TG) and that IR rose in a stepwise fashion, independent of age, race, sex, and body mass index (BMI), whereas TG categories rose from less than 150 to 150 to 200, to 200 to 500, and to more than 500 mg/dL. A third hypothesis was that TG, BMI, and the ratio of TG to high-density lipoprotein cholesterol (TG/HDL-C) were significant explanatory variables for IR and that IR was inversely associated with HDL-C quintiles and positively associated with non-HDL-C quintiles. By stepwise multiple regression with age, race, sex, BMI, and IR as explanatory variables, in the 1385 patients, positive explanatory variables for TG included BMI (partial R = 1.3%, P < 0.0001), sex (men higher, partial R = 1.1%, P = 0.0001), and IR (partial R = 0.4%, P = 0.012). In the 339 PFS subjects, positive explanatory variables for TG were IR (partial R = 11.4%, P < 0.0001), race (whites higher, partial R = 2.1%, P = 0.005), and sex (men higher, partial R = 1.4%, P = 0.019). After adjusting for age, race, sex, and BMI, in 1385 patients, HOMA IR rose while TG categories rose, with least square means of 2.64 for the TG category less than 150 mg/dL, 3.27 for 150 to 200 mg/dL, 3.85 for 200 to 500 mg/dL, and 4.12 for more than 500 mg/dL. Similarly, in the PFS, while TG categories rose, the least square means of HOMA IR rose, with 1.68 for the TG category less than 150 mg/dL, 2.34 for 150 to 200 mg/dL, and 3.03 for 200 to 500 mg/dL. Body mass index, TG, and TG/HDL-C were significant explanatory variables for IR. Homeostasis model assessment IR is a significant, potentially reversible explanatory variable for TG in patients referred because of hyperlipidemia and in population subjects.

A rare example of an intralobar sequestration (ILS) containing a fungal mycetoma is reported. This finding indicates the presence of a communication between the ILS and the airways, thus supporting the theory that ILSs are acquired lesions, rather than congenital malformations.