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A genetic variation of the p38? promoter region is correlated with an increased risk of sporadic colorectal cancer.

ABSTRACT: p38 plays a critical role in the proliferation, survival, migration and metastasis of colorectal cancer (CRC) cells. The present study assessed the correlation between a single nucleotide polymorphism (SNP) in the p38? promoter region (rs2235356, -1628A>G) and the predisposition of individuals to sporadic CRC in a case-control study. A genotyping method was developed to detect this SNP, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A logistic regression analysis was used to determine the odds ratio (OR) and 95% confidence interval (CI). It was revealed that the -1628G variant allele was correlated with an increased risk of CRC (OR, 1.99; 95% CI, 1.60-2.47; P<0.0001). An in silico analysis revealed several transcription factors that either acquired or lost the ability to bind to -1628AA in the p38? promoter region due to the SNP. Therefore, this allelic variant may be a genetic modifier for CRC susceptibility.

SUBMITTER: Huang Q

PROVIDER: S-EPMC3742754 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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A genetic variation of the p38β promoter region is correlated with an increased risk of sporadic colorectal cancer.

Huang Qinghua Q Chen Dianke D Song Shunxin S Fu Xinhui X Wei Yisheng Y Lu Jiachun J Wang Lei L Wang Jianping J

Oncology letters 20130508 1

p38 plays a critical role in the proliferation, survival, migration and metastasis of colorectal cancer (CRC) cells. The present study assessed the correlation between a single nucleotide polymorphism (SNP) in the p38β promoter region (rs2235356, -1628A>G) and the predisposition of individuals to sporadic CRC in a case-control study. A genotyping method was developed to detect this SNP, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A logistic regre ...[more]

PMID: 23946768

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Project description:BackgroundColorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect.Methodology/principal findingsWe examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene.ConclusionsThese results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.

Dataset Information

A genetic variation of the p38? promoter region is correlated with an increased risk of sporadic colorectal cancer.

Publications

A genetic variation of the p38β promoter region is correlated with an increased risk of sporadic colorectal cancer.

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