Promoter CpG island hypermethylation and down regulation of XRCC1 gene can augment in the gastric carcinogenesis events.

Gastric cancer (GC) is a multistep process characterized by a gradual accumulation of genetic and epigenetic alterations in genes at various stages of progression. Epigenetic alterations like DNA methylation play an important role in cancer and may serve as a biomarker for cancer. The present study was aimed to investigate the promoter hypermethylation, expression profile, and Arg399Gln gene polymorphism of DNA repair gene XRCC1 (X-ray repair cross complimentary group I) in GC patients. A total of 60 histopathologically confirmed GC subjects were recruited in the study. Information on various dietary, lifestyle and environmental factors was obtained in face-to-face interviews using a structured questionnaire from each subject. Tissue samples were taken along with adjacent non-cancerous tissues for analysis. Promoter methylation status and expression of XRCC1 gene was evaluated using MS-PCR and western blotting respectively; while as Arg399Gln polymorphism was analyzed by PCR-RFLP. We found that the XRCC1 gene promoter of 38.3% cancerous tissues were methylated compared to 13.3% of adjacent normal tissues. The promoter hypermethylation status of the gene was found to be significantly associated with the loss of protein expression (P < 0.0001, OR = 14.63; 95% CI 4.01-53.43). However, we did not find any significant association of polymorphism of XRCC1 Arg399Gln with promoter methylation or protein expression. Further, comparison of methylation status and protein expression with clinical parameters like age, smoking status, etc. was also not significant (P > 0.05). The present study indicates that XRCC1 undergoes aberrant promoter hypermethylation with subsequent loss of protein expression in gastric cancer.

Impact of catechol-O-methyltransferase gene variants on methylation status of P16 and MGMT genes and their downregulation in colorectal cancer.

Globally, colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second most commonly diagnosed cancer in females, with 1.4 million new cases and almost 694 000 deaths estimated to have occurred in 2012. The development and progression of CRC is dictated by a series of alterations in diverse genes mostly proto-oncogenes and tumor suppressor genes. In this dreadful disease disturbances different from mutations called as epigenetic regulations are also taken into consideration and are thoroughly investigated. The present study was designed to analyze the promoter hypermethylation of CpG (cytosine, followed by guanine nucleotide) islands of cyclin-dependent kinase inhibitor 2A (P16) and O-methylguanine-DNA methyltransferase (MGMT) genes and its subsequent effect on the protein expression in CRC. The impact of the common functional polymorphism of the catechol-O-methyltransferase (COMT) gene, Val158Met, on promoter hypermethylation of P16 and MGMT genes in CRC was also investigated. The study included 200 CRC cases and equal numbers of normal samples. DNA was extracted using the kit method and methylation specific-PCR was performed for analysis of the promoter hypermethylation status. Total protein was isolated form all CRC cases and western blotting was performed for P16 and MGMT proteins. The COMT Val158Met polymorphism was analyzed by a PCR-restriction fragment length polymorphism assay. Epigenetic analysis showed that unlike other high-risk regions, the Kashmiri population has a different promoter hypermethylation profile of both P16 and MGMT genes, with frequent and significant promoter hypermethylation of both in CRC. The frequency of promoter hypermethylation of both genes was significantly higher in males and was insignificantly found to be higher in stage III/IV. The degree of P16 and MGMT promoter hypermethylation increased significantly with increasing severity of the lesion. We also found a significant correlation between P16 and MGMT promoter hypermethylation and loss of protein expression in CRC. A significant association was found between COMT polymorphism (homozygous variant) and P16 methylation status. Similar results were also found for MGMT hypermethylated cases.

DNA Repair Gene XRCC1 and XPD Polymorphisms and Gastric Cancer Risk: A Case-Control Study Outcome from Kashmir, India.

Coding polymorphisms in several DNA repair genes have been reported to affect the DNA repair capacity and are associated with genetic susceptibility to many human cancers, including gastric cancer. An understanding of these DNA repair gene polymorphisms might assess not only the risk of humans exposed to environmental carcinogens but also their responses to different therapeutical approaches, which target the DNA repair pathway. In the present study, polymorphic variants of two DNA repair genes, XRCC1 Arg399Gln and XPD Lys751Gln, were chosen to be studied in association with gastric cancer susceptibility in the Kashmiri population. A total of 180 confirmed cases of gastric cancer (GC) and 200 hospital-based controls from Government Shri Maharaja Hari Singh Hospital, Srinagar, were included in the study. The genotyping for XRCC1 and XPD genes was carried out by polymerase chain reaction-restriction fragment length polymorphism. We found that tobacco smoking is strongly associated with GC risk (OR = 25.65; 95% CI: 5.49-119.7). However, we did not find any association of polymorphism of XRCC1 Arg399Gln (OR = 1.56; 95% CI: 0.32-7.82) and XPD Lys751Gln (OR = 0.46; CI: 0.10-2.19) with GC risk in the study population. The combination of genotypes and gender stratification of XRCC1 and XPD genotypic frequency did not change the results. Consumption of large volumes of salt tea was also not associated with gastric cancer risk. Polymorphic variants of XRCC1 Arg399Gln and XPD Lys751Gln are not associated with the risk of gastric cancer in the Kashmiri population. However, replicative studies with larger sample size are needed to substantiate the findings.

Psychiatric Co-morbidity in Patients With Irritable Bowel Syndrome at a Tertiary Care Center in Northern India.

BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is a chronic psycho-physiological disorder. It is considered to be the most common functional gastrointestinal disorder, and about 50-90% of IBS patients have associated psychiatric co-morbidity. We aimed to study psychiatric co-morbidities in patients with IBS visiting a tertiary care center. METHODS: This was a cross-sectional case-control study conducted over a duration of one and a half years from January 2014 to July 2015. Patients were selected from the out-patient department of gastroenterology. About 160 patients with IBS who fulfilled the inclusion criteria and who gave written informed consent were selected as study cases. The healthy attendants of cases were selected as controls. A total of 200 controls were selected. Rome-III criteria were used to diagnose IBS. For diagnosing psychiatric disorders, we used the Mini International Neuropsychiatric Interview Schedule Plus. RESULTS: Mean age of our cases and controls was 39.7 ± 11.4 and 37.7 ± 9.6 years, respectively. Females outnumbered males in our cases as well as their controls by a ratio of 2:1 approximately. Psychiatric disorders were seen in 84.4% of IBS patients as compared to 41.5% in controls. Major psychiatric disorders seen in our patients were generalized anxiety disorders (30.0%) and depression (28.0%). CONCLUSIONS: The majority of patients with IBS who present to a tertiary care center have co-morbid psychiatric disorders. We need to screen these patients for such co-morbidities and develop a holistic approach for better outcome in such cases.

Evaluation of iron deficiency anaemia for gastrointestinal causes in patients without GI symptoms in high prevalent GI malignancy zones.

BACKGROUND AND STUDY AIMS: Gastric cancer is highly prevalent in Kashmir, as are lower gastrointestinal (LGI) malignancies. Colonic cancer, gastric cancer, and coeliac disease are the most important gastrointestinal (GI) causes of iron deficiency anaemia (IDA) worldwide. Approximately 9% of patients with IDA present with a suspicious lesion in the GI tract upon examination. However, the absence of GI symptoms and a possible lesion accounting for blood loss in IDA have not been studied in this zone with a high prevalence of GI malignancy. We aimed to examine IDA patients without GI symptoms to determine the most plausible cause of their blood loss. PATIENTS AND METHODS: A total of 100 patients with IDA and 250 control subjects without IDA and referred for gastrointestinal endoscopy were enrolled in a cross-sectional, comparative study. Patients presenting with a significant lesion proportionate to their anaemia in the upper GI tract were not examined further, if no further strong indications were present. RESULTS: Twenty-nine patients (29%) were found to have malignancy: 13 with gastric cancer and 16 with colonic malignancies. Other apparent causes of GI blood loss included peptic ulcer disease in 10 (10%) patients, haemorrhoids in 22 (25%), polyps in eight (three in the upper GI tract and five in the LGI tract), gastric erosions in eight (8%), and angiodysplasia, diverticulitis, and trichuriasis in two (2%) each. CONCLUSION: In light of the high incidence of GI malignancies in this patient group, a low threshold for GI screening as well as mass screening for IDA is needed.

Role of the VDR Bsm I and Apa I polymorphisms in the risk of colorectal cancer in Kashmir.

OBJECTIVE: A case-control study aiming to evaluate the relationship between Bsm I and Apa I restriction fragment gene polymorphisms and colorectal cancer (CRC) was carried out in Kashmir, including a total of 368 subjects (180 cases and 188 controls). METHODS: DNA samples extracted from the blood of the subjects were analyzed for 3' untranslated region (3' UTR) Apa I and Bsm I polymorphisms using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). RESULTS: A statistically significant 2.7-fold increased risk was observed in individuals found homozygous for the presence of the 'b' allele, in comparison to subjects homozygous for the 'B' allele (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.49-4.86 (Bsm I)), and a statistically insignificant 2-fold increased risk was found among individuals with the 'aa' genotype, as compared to subjects with the 'AA' genotype (OR 2.017, 95% CI 0.86-4.7). Our study also yielded statistically significant results when the Apa I polymorphism was stratified by age (≤ 50 years) and dwelling area (rural area), and the Bsm I polymorphism by gender (male gender), suggesting a possible role of Apa I and Bsm I polymorphisms in the etiology of CRC in Kashmir. CONCLUSION: We conclude that Apa I and Bsm I single-nucleotide polymorphisms (SNPs) in the vitamin D receptor gene (VDR) might be associated with susceptibility to CRC among Kashmiris.