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Open Access 01-12-2011 | Research article

Variants on the promoter region of PTEN affect breast cancer progression and patient survival

Authors: Tuomas Heikkinen, Dario Greco, Liisa M Pelttari, Johanna Tommiska, Pia Vahteristo, Päivi Heikkilä, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna

Published in: Breast Cancer Research | Issue 6/2011

Abstract

Introduction

The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.

Methods

We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.

Results

All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.

Conclusions

Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.

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Title: Variants on the promoter region of PTEN affect breast cancer progression and patient survival
Authors: Tuomas Heikkinen
Dario Greco
Liisa M Pelttari
Johanna Tommiska
Pia Vahteristo
Päivi Heikkilä
Carl Blomqvist
Kristiina Aittomäki
Heli Nevanlinna
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 6/2011
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr3076

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