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PMID: 20338046 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response.

Molecular cancer ·Vol. 9 ·2010-03-25 ·Pages 68

Dejeux E, Rønneberg JA, Solvang H, Bukholm I, Geisler S, Aas T, Gut IG, Børresen-Dale AL, Lønning PE, Kristensen VN, Tost J

Abstract

Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment. We investigated quantitatively the methylation patterns in the promoter regions of 14 genes (ABCB1, ATM, BRCA1, CDH3, CDKN2A, CXCR4, ESR1, FBXW7, FOXC1, GSTP1, IGF2, HMLH1, PPP2R2B, and PTEN) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters.Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the FOXC1 promoter. Absence of methylation at the ABCB1 promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of GSTP1, FOXC1 and ABCB1 correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis GSTP1 and FOXC1 methylation status proved to be independent prognostic markers associated with survival. Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the ABCB1 or GSTP1 promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while FOXC1 methylation might be a protective factor against tumour invasiveness. FOXC1 proved to be general prognostic factor, while ABCB1 and GSTP1 might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions.

MeSH Terms
Adult Aged Aged, 80 and over Antineoplastic Agents/therapeutic use Breast Neoplasms/drug therapy,genetics,mortality DNA Methylation/genetics Doxorubicin/therapeutic use Drug Resistance, Neoplasm/genetics Female Gene Expression Gene Expression Profiling Humans Kaplan-Meier Estimate Middle Aged Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic/genetics
Chemicals
Antineoplastic Agents Doxorubicin
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Dejeux Emelyne
Laboratory for Epigenetics, Centre National de Génotypage, CEA - Institut de Génomique, Evry, France. [email protected]
Rønneberg Jo Anders
Solvang Hiroko
Bukholm Ida
Geisler Stephanie
Aas Turid
Gut Ivo G
Børresen-Dale Anne-Lise
Lønning Per Eystein
Kristensen Vessela N
Tost Jörg
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Article Info
Journal
Molecular cancer
Abbr.
Mol Cancer
ISSN
1476-4598
DOI
10.1186/1476-4598-9-68
Email
[email protected]
Published
2010-03-25
Epub
2010-00-25
Pages
68
Language
English
Region
England
NLM ID
101147698
PMCID
PMC2861056
Subset
IM
External Links
PubMed source DOI: 10.1186/1476-4598-9-68 PMC Full Text View journal details
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