Relevance of PTEN Loss in Brain Metastasis Formation in Breast Cancer Patients

Overview

Journal Breast Cancer Res

Specialty Oncology

Date 2012 Mar 21

PMID 22429330

Citations 59

Authors

Harriet Wikman

Katrin Lamszus

Niclas Detels

Liubov Uslar

Michaela Wrage

Christian Benner

Ina Hohensee

Bauke Ylstra

Kathrin Eylmann

Marc Zapatka

Guido Sauter

Dirk Kemming

Markus Glatzel

Volkmar Muller

Manfred Westphal

Klaus Pantel

Affiliations

Soon will be listed here.

Abstract

Introduction: With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer.

Methods: Patterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations.

Results: The array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P < 0.01; false discovery rate (fdr) < 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases.

Conclusions: These results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation.

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