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Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development.

ABSTRACT: UNLABELLED:Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development, but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the biological interrogation of germ-line polymorphisms within these sequences. In this study, through a forward genetic analysis of bona fide p53 binding sites identified by a genome-wide chromatin immunoprecipitation and sequence analysis, we discovered a SNP (rs1860746) within the motif sequence of a p53 binding site where p53 can function as a regulator of transcription. We found that the minor allele (T) binds p53 poorly and has low transcriptional regulation activity as compared to the major allele (G). Significantly, the homozygosity of the minor allele was found to be associated with an increased risk of ER negative breast cancer (OR = 1.47, P = 0.038) from the analysis of five independent breast cancer samples of European origin consisting of 6,127 breast cancer patients and 5,197 controls. rs1860746 resides in the third intron of the PRKAG2 gene that encodes the ? subunit of the AMPK protein, a major sensor of metabolic stress and a modulator of p53 action. However, this gene does not appear to be regulated by p53 in lymphoblastoid cell lines nor in a cancer cell line. These results suggest that either the rs1860746 locus regulates another gene through distant interactions, or that this locus is in linkage disequilibrium with a second causal mutation. This study shows the feasibility of using genomic scale molecular data to uncover disease associated SNPs, but underscores the complexity of determining the function of regulatory variants in human populations. ELECTRONIC SUPPLEMENTARY MATERIAL:The online version of this article (doi:10.1007/s11568-010-9138-x) contains supplementary material, which is available to authorized users.

SUBMITTER: Liu J

PROVIDER: S-EPMC2882646 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development.

Liu Jianjun J Desai Kartiki Vasant KV Li Yuqing Y Banu Shakeela S Lee Yew Kok YK Qu Dianbo D Heikkinen Tuomas T Aaltonen Kirsimari K Muranen Taru A TA Kajiji Tasneem Shabbir TS Bonnard Carine C Aittomäki Kristiina K von Smitten Karl K Blomqvist Carl C Hopper John L JL Southey Melissa C MC Brauch Hiltrud H Chenevix-Trench Georgia G Beesley Jonathan J Spurdle Amanda B AB Chen Xiaoqing X Czene Kamila K Hall Per P Nevanlinna Heli H Liu Edison T ET

The HUGO journal 20091201 1-4

<h4>Unlabelled</h4>Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development, but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the biological interrogation of germ-line polymorphisms within these sequences. In this study, through a ...[more]

PMID: 21119756

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Project description:BackgroundBone morphogenetic protein receptor I B (BMPR1B) is a transmembrane receptor mediating TGF-? signal transduction. Recent studies indicate a tumor suppressor role for BMPR1B in ovarian cancer. Polymorphism at BMPR1B 3'UTR within the miR-125b binding site alters its binding affinity toward the miRNA, which may result in insufficient post-transcriptional repression.MethodsSingle-nucleotide polymorphisms rs1970801, rs1434536, and rs11097457 near the miR-125b binding site in BMPR1B were genotyped by Taqman assay on 193 endometriosis patients and 202 healthy controls. BMPR1B and CA125 levels in ectopic endometrial tissues were evaluated by quantitative PCR and immunohistochemistry. Luciferase reporter assay was utilized to verify regulatory roles of BMPR1B 3'UTR with allelic variants of rs1434536 in a cell line model. Cell proliferation and migration were recorded, while expression of BMPR1B, CA125, glucocorticoid receptor (GCCR) and IL-1? were measured by quantitative PCR in endometrial cells transfected with wild-type or mutated miR-125b.ResultsThis study found two endometriosis-associated SNPs, rs1434536 (P?=?0.010) and rs1970801 (P?=?0.0087), located within and next to a miR-125b binding site on BMPR1B. Interestingly, patients with homozygous variant alleles at rs1434536 showed significantly lower serum CA125 levels. Immunohistochemistry staining further confirmed inverse correlation between BMPR1B and CA125 levels in three rs1434536 genotypes. Cell assays demonstrated the variant allele of rs1434536 up-regulating BMPR1B at both mRNA and protein levels, which negatively correlated with CA125 and IL-1? levels. Disruption of the binding between miR-125b and BMPR1B hampered abnormal cell proliferation.ConclusionsSNPs of BMPR1B within and next to the miR-125b binding site manifested strong correlation with endometriosis development in a Taiwanese cohort. Disrupting the binding of miR-125b toward BMPR1B would increase protein expression, diminishing abnormal cell proliferation as well as serum and cellular CA125 levels. Genetic variation at the miR-125b binding site may play functional roles to protect against endometriosis progression.

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Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development.

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Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development.

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