Evaluation of folate receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers.

Sara Notaro,Gabriel Schmid,Alain Gustave Zeimet,Annamarie Wiedemair,Heidi Fiegl,Julia Rössler,Christian Marth,Daniel Reimer

doi:10.1186/s12885-016-2637-y

Sara Notaro, Gabriel Schmid + Show 6 more

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https://doi.org/10.1186/s12885-016-2637-y

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Abstract

BackgroundIn this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer.MethodsTwo hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique.ResultsNo correlation between FOLR1 mRNA expression and its specific promoter DNA methylation was found neither in type I nor in type II cancers, however, high FOLR1 mRNA expression was found to be correlated with global DNA hypomethylation in type II cancers (p = 0.033). Strong FOLR1 mRNA expression was revealed for Grades 2-3, FIGO stages III-IV, residual disease > 0, and serous histotype. High FOLR1 expression was found to predict increased platinum sensitivity in type I cancers (odds ratio = 3.288; 1.256-10.75; p = 0.020). One-year survival analysis showed in type I cancers an independent better outcome for strong expression of FOLR1 in FIGO stage III and IV. For the entire follow up period no significant independent outcome for FOLR1 expression was revealed. In type I cancers LINE 1 DNA hypomethylation was found to exhibit a worse PFS and OS which were confirmed to be independent in multivariate COX regression model for both PFS (p = 0.026) and OS (p = 0.012).ConclusionNo correlations were found between FOLR1 expression and its specific promoter methylation, however, high FOLR1 mRNA expression was associated with DNA hypomethylation in type II cancers. FOLR1 mRNA expression did not prove to predict clinical outcome in type II cancers, although strong FOLR1 expression generally denotes ovarian cancers with highly aggressive phenotype. In type I cancers, however, strong FOLR1 expression has been found to be a reliable indicator of improved platinum responsiveness reflecting a transient better one-year follow up outcome in highly FOLR1 expressing type I cancers. An independent prognostic role of global DNA hypomethylation was demonstrated in type I tumours.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2637-y) contains supplementary material, which is available to authorized users.

Highlights

In this retrospective study we evaluated the respective correlations and clinical relevance of folate receptor 1 (FOLR1) mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer
FOLR1 mRNA expression in ovarian cancer In the unselected cohort of examined ovarian cancers, FOLR1 mRNA expression with a median value of 9.14 was significantly stronger than in borderline tumours and in healthy controls (Fig. 1a)
Two orders of magnitude can be distinguished regarding FOLR1 expression: one is the clustering of type I cancers together with borderline tumours and healthy ovarian epithelium and the second is the merging of type II cancers with healthy fallopian epithelium

Summary

Introduction

In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer. Folic acid is an essential component in DNA synthesis, replication and repair, protein synthesis and methylation reactions. This is especially true for rapidly dividing cells [2]. Three different mechanisms exist for cellular folate uptake: one via the membrane-associated Folate Receptor (FOLR) and the physiologically more important mechanism via the Reduced Folate Carrier (RFC). FOLR internalizes folates by means of receptor mediated endocytosis and RFC uses a bidirectional anionexchange mechanism to transport folates into cytoplasm [5, 6]. Human FOLR is encoded by a family of genes whose homologous products are the FOLR types -α, -β and –γ

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