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Association of PIN3 16-bp duplication polymorphism of TP53 with breast cancer risk in Mali and a meta-analysis.

ABSTRACT: BACKGROUND:Breast cancer, the most common tumor in women in Mali and worldwide has been linked to several risk factors, including genetic factors, such as the PIN3 16-bp duplication polymorphism of TP53. The aim of our study was to evaluate the role of the PIN3 16-bp duplication polymorphism in the susceptibility to breast cancer in the Malian population and to perform a meta-analysis to better understand the correlation with data from other populations. METHODS:We analyzed the PIN3 16-bp duplication polymorphism in blood samples of 60 Malian women with breast cancer and 60 healthy Malian women using PCR. In addition, we performed a meta-analysis of case-control study data from international databases, including Pubmed, Harvard University Library, Genetics Medical Literature Database, Genesis Library and Web of Science. Overall, odds ratio (OR) with 95% CI from fixed and random effects models were determined. Inconsistency was used to assess heterogeneity between studies and publication bias was estimated using the funnel plot. RESULTS:In the studied Malian patients, a significant association of PIN3 16-bp duplication polymorphism with breast cancer risk was observed in dominant (A1A2?+?A2A2 vs. A1A1: OR?=?2.26, CI 95%?=?1.08-4.73; P?=?0.02) and additive (A2 vs. A1: OR?=?1.87, CI 95%?=?1.05-3.33; P?=?0.03) models, but not in the recessive model (P?=?0.38). In the meta-analysis, nineteen (19) articles were included with a total of 6018 disease cases and 4456 controls. Except for the dominant model (P?=?0.15), an increased risk of breast cancer was detected with the recessive (OR?=?1.46, 95% CI?=?1.15-1.85; P?=?0.002) and additive (OR?=?1.11, 95% CI?=?1.02-1.19; P?=?0.01) models. CONCLUSION:The case-control study showed that PIN3 16-bp duplication polymorphism of TP53 is a significant risk factor for breast cancer in Malian women. These findings are supported by data from the meta-analysis carried out on different ethnic groups around the world.

SUBMITTER: Diakite B

PROVIDER: S-EPMC7333399 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Association of PIN3 16-bp duplication polymorphism of TP53 with breast cancer risk in Mali and a meta-analysis.

Diakite Brehima B Kassogue Yaya Y Dolo Guimogo G Kassogue Oumar O Keita Mamadou Lassine ML Joyce Brian B Neuschler Erin E Wang Jun J Musa Jonah J Traore Cheick Bougari CB Kamate Bakarou B Dembele Etienne E Nadifi Sellama S Isichei Mercy M Holl Jane L JL Murphy Robert R Doumbia Seydou S Hou Lifang L Maiga Mamoudou M

BMC medical genetics 20200703 1

<h4>Background</h4>Breast cancer, the most common tumor in women in Mali and worldwide has been linked to several risk factors, including genetic factors, such as the PIN3 16-bp duplication polymorphism of TP53. The aim of our study was to evaluate the role of the PIN3 16-bp duplication polymorphism in the susceptibility to breast cancer in the Malian population and to perform a meta-analysis to better understand the correlation with data from other populations.<h4>Methods</h4>We analyzed the PI ...[more]

PMID: 32620097

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Project description:BackgroundPreviously we have suggested that cancer cells develop a mechanism(s) which allows for either: silencing of the wild-type TP53 transcription, degradation of the wild-type TP53 mRNA, or selective overproduction of the mutated TP53 mRNA, which is the subject of this article. Sequencing of TP53 on the respective cDNA and DNA templates from tumor samples were found to give discordant results. DNA analysis showed a pattern of heterozygous mutations, whereas the analysis of cDNA demonstrated the mutated template only. We hypothesized that different TP53 gene expression levels of each allele may be caused by the polymorphism within intron 3 (PIN3). The aim of this study was to test if one of the polymorphic variants of PIN3 (A1 or A2) in the heterozygotes is associated with a higher TP53 expression, and therefore, responsible for the haploinsufficiency phenomenon.Methods250 tumor samples were tested. To analyze the involvement of PIN3 polymorphic variant (A1 or A2) on TP53 mRNA expression regulation, bacterial subcloning combined with sequencing analyses, dual luciferase reporter assays and bioinformatic analysis were performed.ResultsHaplotype analysis showed the predominance of the mutated template during the cDNA sequencing in all samples showing a heterozygous TP53 mutation and PIN3 heterozygosity. Out of 30 samples (from the total of 250 tested samples) which carried TP53 mutations and had a bias in allelic expression 6 were heterozygous for the A1/A2 polymorphism, and all 6 (p = 0.04) samples carried the mutation within the PIN3 longer allele (A2). Reporter assays revealed higher luciferase activity in cells transfected with the plasmid containing A2 construct than A1 and control. A2/A1 ratio ranged from 1.16 for AD293 cell line (p = 0.019) to 1.59 for SW962 cell line (p = 0.0019). Moreover, bioinformatic analyses showed that PIN3 duplication stabilized secondary DNA structures - G-quadruplexes.ConclusionTP53 alleles are not equivalent for their impact on the regulation of expression of TP53 mRNA. Therefore, in PIN3-heterozygous cases a single TP53 mutation of the longer allele might sufficiently destabilize its function. Secondary DNA structures such as quadruplexes can also play a role in PIN3-dependent TP53 haploinsufficiency.

Dataset Information

Association of PIN3 16-bp duplication polymorphism of TP53 with breast cancer risk in Mali and a meta-analysis.

Publications

Association of PIN3 16-bp duplication polymorphism of TP53 with breast cancer risk in Mali and a meta-analysis.

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