A Study on Association of XRCC3 Gene Polymorphism in Gastric cancer risk

Gastric Cancer (GC) is among the common and fatal cancer in the world. DNA repair plays a critical role in protecting the genome of the cell from insults of cancer-causing agents. Inherited polymorphisms of DNA repair genes may contribute to variations in DNA Repair capacity (DRC) and genetic susceptibility to different c ancers. Mammalian cells are constantly exposed to a wide variety of genotoxic a gents from both endogenous and exogenous sources. In human beings, 70 genes are involve d in the five major DNA repair pathways: direct repair, NER, BER, mismatch repa ir and double-strand break repair. The X-ray repair complementing defective repa ir in Chinese hamster cells 3 (XRCC3) gene is a member of the RAD51 gene fami ly. It encodes an important protein that functions in the homologous rec ombination repair of DNA double-strand break. The Kashmir valley has an eleva ted incidence of GC and its etiology is not understood fully yet, though, we are ethni cally and demographically different from the other states of the country and world. The aim of this study was to determine whether single nucleotide poly morphism (SNP) of XRCC3 gene (Thr241Met) of exon7, can influence the risk of gastric cancer in Kashmiri population. About 80 histopathologically confirmed GC case s and 70 healthy controls, age ,gender, ethnicity matched for known genotypes of XRCC3 exon7 were analyzed. Patients medical history and dietary habits were taken for the study as well. The ge notype for this variant was determined using polymerase chain reaction- restriction fra gment length polymorphisms (PCR-RFLP) in 80 histologically confirmed GC patients and 70 frequency-matched healthy controls in Department of Biochemistr y, Government Medical College srinagar. The XRCC3 genotype and allele frequencies were not significantly different between cases and controls (P= 0.92 for ge notype; P= 0:72 for allele). The XRCC3 241Met allele frequency (6.6%) was signifi cantly lower in healthy Kashmiri controls than previously reported healthy US Caucasian controls (38.9%). Compared with the XRCC3241Thr/Thr genoty pe, the variant XRCC3241Thr/Met and Met/Met genotypes were not associated with an increased risk of gastric cancer (adjusted odds ratio (ORa), 1.19; 95% confiden ce interval (CI), 0.44-3.18). These finding s suggest that polymorphisms of XRCC3 Thr241Met may not play a role in the etiology of GC. Further studies with a larger number of subjects and simultaneous measurement of different pol ymorphisms in DNA repair genes in the same pathway are needed

Elucidation of etiology of colorectal cancer: A study on silencing of p16 gene by promoter hypermethylation

Colorectal cancer (CRC), commonly known as bowel cancer is the third most common cause of cancer-related deaths in the western world. Colorectal cancer is one of the leading malignancies worldwide. CRC has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. The usual treatment is surgery and subsequent chemotherapy and radiotherapy. Cancer development and progression is dictated by series of alterations in genes such as tumor suppressor genes, DNA repair genes, oncogenes and others. In colorectal carcinogenesis disturbances different from mutations called an epigenetic regulation are also taken into consideration. The aim of this study was to study the promoter hypermethylation of CpG islands of p16 gene in colorectal cancer patients among the Kashmiri population. The study included 70 surgically obtained colorectal samples among which 50 were obtained from colorectal cancer patients and 20 were histopathologically normal colorectal samples. All the samples were histopathologically confirmed before further processing. DNA was extracted from all the samples and was modified using bisulphite modification kit. Methylation-specific polymerase (MSP) chain reaction was used for analysis of the promoter hypermethylation status of p16 gene. The genetic analysis of the cases and controls by MSP- PCR method, for checking the promoter hypermethylation of CpG islands of p16 gene revealed that unlike other high risk regions, Kashmiri population has a different promoter hypermethylation profile of p16 gene. 66% of the cases showed p16 promoter hypermethylation while as 34% of the cases were nonhypermethylated. The study also revealed that 20% of the normal cases also had promoter hypermethylation of p16 gene and 80% did not showed promoter hypermethylation of p16 gene. The association of promoter hypermethylation with colorectal cancer was evaluated by χ2 (Chi square) test with Odds ratio and was found to be significant. Among 29 male cases and 21 female cases, the association of promoter hypermethylation with colorectal cancer was evaluated using Fisher’s exact test and was found to be significant in both males and females. Occurrence of p16 promoter hypermethylation was found to be unequally distributed in males and females with more frequency in males than in females but the difference was not statistically significant. When the frequency of p16 promoter hypermethylation was compared with clinical staging of the disease, p16 promoter hypermethylation was found to be certainly higher in Stage III/IV (83.33%) compared to Stage I/ II (56.25%) but the difference was not statistically significant. Also, the degree of p16 promoter hypermethylation increased with the increasing severity of the lesion but the difference was not again statistically significant. These results clearly suggest that p16 aberrant promoter hypermethylation in Kashmiri population contributes to the process of carcinogenesis in colorectal cancer and is reportedly one of the commonest epigenetic changes in the development of human CRC. It also demonstrates that hypermethylation of p16 gene can be designated as epigenetic biomarker for the screening, diagnosis and prognosis of colorectal cancer. The data gives a clue that p16 gene expression can be readily and fully restored and growth rate of cancer cells decreased by treatment of cancer cells with demethylating agents and DNA methylation inhibitors