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(FOLR1) Mrna Expression, Its Specific Promoter

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(FOLR1) Mrna Expression, Its Specific Promoter Notaro et al. BMC Cancer (2016) 16:589 DOI 10.1186/s12885-016-2637-y RESEARCH ARTICLE Open Access 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 Notaro1,2, Daniel Reimer1, Heidi Fiegl1, Gabriel Schmid1, Annamarie Wiedemair1, Julia Rössler1, Christian Marth1 and Alain Gustave Zeimet1* Abstract Background: 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. Methods: Two 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. Results: No 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). Conclusion: No 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. Keywords: Ovarian cancer, Folate receptor 1, FOLR1, FOLR1 promoter methylation, Global DNA hypomethylation, Type I, Type II, Platinum sensitivity * Correspondence: [email protected] 1Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Notaro et al. BMC Cancer (2016) 16:589 Page 2 of 13 Background role in tumorigenesis. Two distinct DNA methylation Ovarian carcinomas account for the highest mortality abnormalities are observed in cancer. The first is a global among all gynecological cancers in the world [1]. Despite genome-wide reduction of DNA methylation (global DNA aggressive treatment including highly offensive surgical hypomethylation) and the second is hypo- or hyper- cytoreduction and multiagent chemotherapy, the prog- methylation within the CpG islands within specific gene nosis of patients with advanced ovarian cancer remains promoters. Promoter hypomethylation is believed to in- unacceptably poor. duce proto-oncogene activation, and global DNA hypome- Folic acid is an essential component in DNA synthesis, thylation is strongly related to chromosomal instability. replication and repair, protein synthesis and methylation Regional hypermethylation is strongly associated with reactions. This is especially true for rapidly dividing cells transcriptional silencing of specific genes (e.g., tumour [2]. Three different mechanisms exist for cellular folate suppressor genes) [16]. A global decrease in the amount of uptake: one via the membrane-associated Folate Receptor cellular cytosine methylation is observed in many neoplas- (FOLR) and the physiologically more important mechan- tic tissues and is related to poor prognosis or clinical sever- ism via the Reduced Folate Carrier (RFC). More recently, ity in several cancer types, including ovarian cancer [17]. a third, the proton-coupled folate transporter, responsible The majority of global DNA hypomethylation occurs at exclusively for the intestinal uptake of folate, was identi- repetitive elements, such as long interspersed nuclear ele- fied [3, 4]. FOLR internalizes folates by means of receptor ments (LINEs) [18]. Genome-wide DNA hypomethylation mediated endocytosis and RFC uses a bidirectional anion- at LINE1 elements during tumorigenesis is presumed to exchange mechanism to transport folates into cytoplasm contribute crucially to chromosomal instability [19]. [5, 6]. Human FOLR is encoded by a family of genes Some authors [20–22] have proposed a potential role of whose homologous products are the FOLR types -α,-β epigenetic regulation in FOLR1 expression through methy- and –γ. lation, but the evidence was not conclusive. Nevertheless, Principally FOLR isoforms α and β are capable of epigenetic changes can offer a plausible explanation for transporting folate into cells, but generally the ubiqui- elevated FOLR1 expression in some tumours [23]. tously expressed RFC is exclusively used for this purpose The purpose of the study presented here was to ana- by adult tissues [7]. In fact, most normal tissues virtually lyse the clinical relevance of FOLR1 mRNA expression lack FOLR, and its physiologic importance appears to be and its possible influence on global DNA methylation confined to situations where the availability of folate is status in ovarian cancer. Furthermore, we were inter- limited [8]. ested in elucidating whether FOLR1 mRNA expression In contrast, the ability of FOLR1 (encodes for folate is mainly regulated by DNA methylation of its promoter. receptor α) to bind folate has been demonstrated in In addition, the role of FOLR1 expression was assessed malignant tissue [9, 10]. Under such pathological as predictive markers of platinum responsiveness. We circumstances FOLR1 may be overexpressed to increase were especially interested in conducting these analyses folate uptake in order to cope with the augmented turn- regarding the histologic subtypes and the ovarian cancer over of nucleic acid synthesis and reparation during dualistic typology proposed by Kurman et al. [24, 25]. accelerated cellular growth [11, 12]. FOLR1 was found to be strongly expressed in renal, pancreatic, endometrial Methods carcinomas, squamous cervical cancer and ovarian cancer Patients and samples [13]. Furthermore, FOLR1 is reported to be expressed in Two hundred fifty four ovarian cancer samples were the majority of non-mucinous epithelial ovarian cancers at retrospectively analysed from 1989 to 2010 at the levels 10- to 100-fold higher than its normal expression in Medical University of Innsbruck. The study was per- the kidney and on lung and breast epithelial cells [14]. formed in accordance with the principles of the Helsinki Recently, it was shown that FOLR1 can be exploited for Declaration after approval by the local ethics committee. specific delivery of drugs linked to folic acid into ovarian Median age was 61.58 years. Median follow-up was cancer cells. Proof of principle was provided with folate- 55 months (1-289 m). After surgery patients mostly desacetyl vinblastine monohydrazide (Vintafolide®) in the received chemotherapy as a standard treatment. A clinical PRECEDENT trial in ovarian cancer. Moreover, minority of them (12 pts) underwent neoadjuvant companion diagnostics with radio-labelled folate (Etarfola- treatment (at least three courses of chemotherapy tide®) -based tumour imaging has been found to predict followed by interval debulking surgery); these patients response to Vintafolide® [15]. were excluded from the platinum response risk analysis. Furthermore, folic acid is crucially involved in DNA The majority received adjuvant chemotherapy platinum- methylation via metabolic cycling of methionine towards based therapy. Staging was performed according to the homocysteine. Epigenetic modifications of DNA through International Federation of Gynecology and Obstetrics CpG site methylation are recognized to play a fundamental (FIGO) classification. All FIGO stages and all histotypes Notaro et al. BMC Cancer (2016) 16:589 Page 3 of 13 were included. The clinico-pathological characteristics mucinous tumours. Nine patients had FIGO stage I and are reported in Table 1. According to the dualistic
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