Dataset Information

Polymorphism within the distal RAD51 gene promoter is associated with colorectal cancer in a Polish population.

ABSTRACT: Colorectal cancer (CRC) is one of the most common cancers in developed countries. Annually, over one million of new cases in the world are recorded. Majority of CRCs occur sporadically with dominant phenotype of chromosomal instability (CIN). Permanent exposure to DNA damaging agents such as ionizing radiation result in DNA double-stranded breaks, which create favorable conditions for chromosomal aberration to arise. Homologous recombination repair (HRR) is the leading process engaged in maintaining of the genome integrity. RAD51 protein was recognized as crucial in HRR. Single nucleotide polymorphisms are the primary source of genetic variation which presence in the RAD51 promoter region can affect on its expression and consequently modulate HR efficiency.The aim of this study was to analyze the distribution of genotypes and allele frequencies of -4791A/T and -4601A/G RAD51 gene polymorphisms, followed by an assessment of their relationship with the risk of CRC.The study included 115 patients with confirmed CRC. Control group was consisted of 118 cancer-free individuals with a negative family history. The genotypes were identified by PCR-RFLP method.This study revealed statistically significant association between appearance of G/A genotype in position -4601 of RAD51 gene and CRC risk.

SUBMITTER: Mucha B

PROVIDER: S-EPMC4637713 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Polymorphism within the distal RAD51 gene promoter is associated with colorectal cancer in a Polish population.

Mucha Bartosz B Kabzinski Jacek J Dziki Adam A Przybylowska-Sygut Karolina K Sygut Andrzej A Majsterek Ireneusz I Dziki Lukasz L

International journal of clinical and experimental pathology 20150901 9

<h4>Background</h4>Colorectal cancer (CRC) is one of the most common cancers in developed countries. Annually, over one million of new cases in the world are recorded. Majority of CRCs occur sporadically with dominant phenotype of chromosomal instability (CIN). Permanent exposure to DNA damaging agents such as ionizing radiation result in DNA double-stranded breaks, which create favorable conditions for chromosomal aberration to arise. Homologous recombination repair (HRR) is the leading process ...[more]

PMID: 26617897

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Project description:BACKGROUND:Colorectal cancer (CRC) is categorized by alteration of vital pathways such as ?-catenin (CTNNB1) mutations, WNT signaling activation, tumor protein 53 (TP53) inactivation, BRAF, Adenomatous polyposis coli (APC) inactivation, KRAS, dysregulation of epithelial to mesenchymal transition (EMT) genes, MYC amplification, etc. In the present study an attempt was made to screen CTNNB1 gene in colorectal cancer samples from Pakistani population and investigated the association of CTNNB1 gene mutations in the development of colorectal cancer. METHODS:200 colorectal tumors approximately of male and female patients with sporadic or familial colorectal tumors and normal tissues were included. DNA was extracted and amplified through polymerase chain reaction (PCR) and subjected to exome sequence analysis. Immunohistochemistry was done to study protein expression. Molecular dynamic (MD) simulations of CTNNB1WT and mutant S33F and T41A were performed to evaluate the stability, folding, conformational changes and dynamic behaviors of CTNNB1 protein. RESULTS:Sequence analysis revealed two activating mutations (S33F and T41A) in exon 3 of CTNNB1 gene involving the transition of C.T and A.G at amino acid position 33 and 41 respectively (p.C33T and p.A41G). Immuno-histochemical staining showed the accumulation of ?-catenin protein both in cytoplasm as well as in the nuclei of cancer cells when compared with normal tissue. Further molecular modeling, docking and simulation approaches revealed significant conformational changes in the N-terminus region of normal to mutant CTNNB1 gene critical for binding with Glycogen synthase kinase 3-B (GSK3) and transducin containing protein1 (TrCp1). CONCLUSION:Present study on Pakistani population revealed an association of two non-synonymous polymorphisms in the CTNNB1 gene with colorectal cancer. These genetic variants led to the accumulation of the CTNNB1, a hallmark of tumor development. Also, analysis of structure to function alterations in CTNNB1 gene is crucial in understanding downstream biological events.

Dataset Information

Polymorphism within the distal RAD51 gene promoter is associated with colorectal cancer in a Polish population.

Publications

Polymorphism within the distal RAD51 gene promoter is associated with colorectal cancer in a Polish population.

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