Dataset Information

Intron 3 sixteen base pairs duplication polymorphism of p53 contributes to breast cancer susceptibility: evidence from meta-analysis.

ABSTRACT:

Background

P53 is a tumor suppressor gene and plays important role in the etiology of breast cancer. Intron 3 sixteen-bp duplication polymorphism of p53 has been reported to be associated with breast cancer risk. However, the reported results remain conflicting rather than conclusive.

Methods

A meta-analysis including 19 case-control studies was performed to address this issue. Odds ratios (ORs) with 95% confidence intervals (CIs) were adopted to evaluate the association.

Results

The overall results suggested that the variant genotypes were associated with a significantly increased breast cancer risk (Del/Ins vs Del/Del: OR?=?1.18, 95% CI: 1.00-1.40; Ins/Ins vs Del/Del: OR?=?1.42, 95% CI?=?1.09-1.84; Ins/Ins+Del/Ins vs Del/Del: OR?=?1.21, 95% CI?=?1.03-1.41). When stratifying by sample size of studies, a significantly elevated risk was also observed among large sample studies (>500 subjects) but not among small sample studies (?500 subjects).

Conclusion

These results suggested that the 16-bp duplication polymorphism of p53 may contribute to susceptibility to breast cancer. Additional well-designed large studies were required to validate this association in different populations.

SUBMITTER: Wu D

PROVIDER: S-EPMC3631160 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Intron 3 sixteen base pairs duplication polymorphism of p53 contributes to breast cancer susceptibility: evidence from meta-analysis.

Wu Dongmei D Zhang Zhizhong Z Chu Haiyan H Xu Ming M Xue Yao Y Zhu Haixia H Zhang Zhengdong Z

PloS one 20130419 4

<h4>Background</h4>P53 is a tumor suppressor gene and plays important role in the etiology of breast cancer. Intron 3 sixteen-bp duplication polymorphism of p53 has been reported to be associated with breast cancer risk. However, the reported results remain conflicting rather than conclusive.<h4>Methods</h4>A meta-analysis including 19 case-control studies was performed to address this issue. Odds ratios (ORs) with 95% confidence intervals (CIs) were adopted to evaluate the association.<h4>Resul ...[more]

PMID: 23620777

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Project description:Organic cation transporter 1 (OCT1, SLC22A1) is localized in the sinusoidal membrane of human hepatocytes and mediates hepatic uptake of weakly basic or cationic drugs and endogenous compounds. Common amino acid substitutions in OCT1 were associated with altered pharmacokinetics and efficacy of drugs like sumatriptan and fenoterol. Recently, the common splice variant rs35854239 has also been suggested to affect OCT1 function. rs35854239 represents an 8 bp duplication of the donor splice site at the exon 7-intron 7 junction. Here we quantified the extent to which this duplication affects OCT1 splicing and, as a consequence, the expression and the function of OCT1. We used pyrosequencing and deep RNA-sequencing to quantify the effect of rs35854239 on splicing after minigene expression of this variant in HepG2 and Huh7 cells and directly in human liver samples. Further, we analyzed the effects of rs35854239 on OCT1 mRNA expression in total, localization and activity of the resulting OCT1 protein, and on the pharmacokinetics of sumatriptan and fenoterol. The 8 bp duplication caused alternative splicing in 38% (deep RNA-sequencing) to 52% (pyrosequencing) of the minigene transcripts when analyzed in HepG2 and Huh7 cells. The alternatively spliced transcript encodes for a truncated protein that after transient transfection in HEK293 cells was not localized in the plasma membrane and was not able to transport the OCT1 model substrate ASP+. In human liver, however, the alternatively spliced OCT1 transcript was detectable only at very low levels (0.3% in heterozygous and 0.6% in homozygous carriers of the 8 bp duplication, deep RNA-sequencing). The 8 bp duplication was associated with a significant reduction of OCT1 expression in the human liver, but explained only 9% of the general variability in OCT1 expression and was not associated with significant changes in the pharmacokinetics of sumatriptan and fenoterol. Therefore, the rs35854239 variant only partially changes splicing, causing moderate changes in OCT1 expression and may be of only limited therapeutic relevance.

Dataset Information

Intron 3 sixteen base pairs duplication polymorphism of p53 contributes to breast cancer susceptibility: evidence from meta-analysis.

Background

Methods

Results

Conclusion

Publications

Intron 3 sixteen base pairs duplication polymorphism of p53 contributes to breast cancer susceptibility: evidence from meta-analysis.

Similar Datasets

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