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

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.

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

“…This may promote tumor development and progression by changing the global heterochromatin structure and activating proto-oncogenes or germline specific genes [ 31 , 49 ]. Furthermore, global hypomethylation is associated with a poor prognosis in cancer entities, such as myeloma or type I ovarian cancers [ 35 , 44 ] and increases during the malignant transformation of meningioma [ 13 ]. This might be associated with the even more aggressive behavior of ATRT-SMARCA4 compared to SMARCB1 mutated ones.…”

BRCA1 and BRCA2 mRNA-expression prove to be of clinical impact in ovarian cancer

“…Bisulfite modification and MethyLight analysis were performed as described previously. 14 For BRCA1 DNA-methylation two different MethyLight PCR primer sets were used, Primers and probes for BRCA1 were determined with the assistance of the computer program Primer Express version 2.0.0 (Applied Biosystems, Foster City, CA, USA) to produce a 86-base-pair PCR amplicon (located at +57 to +142 relative to transcription start site of BRCA1 ). Genomic DNA not treated with bisulfite (unmodified) was not amplified with the primers (data not shown).…”

A novel isolation method for cancer prognostic factors via the p53 pathway by a combination of in vitro and in silico analyses

“…All 40 genes, however, did not affect prognosis in patients with TP53 mutant cancer (Figure 6B , Supplementary Figure 1 ), demonstrating a dependence on TP53 mutational status. The genes selected using this method included NCOA3 [ 34 , 35 ], HOXA1 [ 36 ], FOLR1 [ 37 ], SOCS1 [ 38 ], and PIK4CA [ 39 ], which showed similar expression patterns related to survival in patients with cancer. This result suggested that our method was a relatively simple method for identification of genes functionally associated with the p53 pathway.…”