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. 2009 Oct;22(4):853-61.

Identification of candidate epigenetic biomarkers for ovarian cancer detection

Yi-Wen Huang  1 , Rachel A Jansen, Enrica Fabbri, Dustin Potter, Sandya Liyanarachchi, Michael W Y Chan, Joseph C Liu, Anne P G Crijns, Robert Brown, Kenneth P Nephew, Ate G J van der Zee, David E Cohn, Pearlly S Yan, Tim H-M Huang, Huey-Jen L Lin
Affiliations

Identification of candidate epigenetic biomarkers for ovarian cancer detection

Yi-Wen Huang et al. Oncol Rep. 2009 Oct.

Abstract

Ovarian cancer ranks the most lethal among gynecologic neoplasms in women. To develop potential biomarkers for diagnosis, we have identified five novel genes (CYP39A1, GTF2A1, FOXD4L4, EBP, and HAAO) that are hypermethylated in ovarian tumors, compared with the non-malignant normal ovarian surface epithelia, using the quantitative methylation-specific polymerase chain reactions. Interestingly enough, multivariate Cox regression analysis has identified hypermethylation of CYP39A1 correlated with an increase rate of relapsing (P=0.032, hazard ratio >1). Concordant hypermethylation in at least three loci was observed in 50 out of 55 (91%) of ovarian tumors examined. The test sensitivity and specificity were assessed to be 96 and 67% for CYP39A1; 95 and 88% for GTF2A1; 93 and 67% for FOXD4L4; 81 and 67% for EBP; 89 and 82% for HAAO, respectively. Our data have identified, for the first time, GTF2A1 alone, or GTF2A1 plus HAAO are excellent candidate biomarkers for detecting this disease. Moreover, the known functions of these gene products further implicate dysregulated transcriptional control, cholesterol metabolism, or synthesis of quinolinic acids, may play important roles in attributing to ovarian neoplasm. Molecular therapies, by reversing the aberrant epigenomes using inhibitory agents or by abrogating the upstream signaling pathways that convey the epigenomic perturbations, may be developed into promising treatment regimens.

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Figures

Figure 1
Figure 1
Significant hypermethylation was observed in ovarian tumors, as opposed to nOSE. (A) Amplification of corresponding pairs of primers resulted in specific amplicons of the correct sizes. The target DNA employed in this assay was extracted from either pooled ovarian tumors (OVCA) or from nOSE. Noticeably, SssI DNA served as a positive control (SssI), while reactions devoid of target DNA (water) served as negative control. (B) After equalizing the quantity of DNA samples by normalization to the internal control loci COL2A1, the relative level of methylation was expressed as percentage (%), in relation to a standard curve generated from SssI in which methylation was set as 100%. All samples were assayed in triplicates and the tumor-specific methylation in ovarian tumors, in relation to nOSE samples (underlined), was analyzed by Wilcoxon rank-sum test and significance was granted if the P-value was <0.05. In the panel of CYP39A1, three samples denoted with black bars were further assessed for DNA copy numbers.
Figure 2
Figure 2
Concordant DNA hypermethylation can be observed in ovarian cancer. (A) By aligning the level of DNA methylation to ovarian tumors and nOSE samples, a heat map was generated. Ovarian tumors harboring the highest magnitude of methylation (in black) observed in the greatest number of loci were shown at the top, as opposed to tumor samples with the lowest level of methylation (in white and grey), observed in the least number of genes, are shown in bottom panel. Because nOSE samples retain a negligible level of methylation in all four loci, they were placed on the farthest bottom section. (B) Scatterplot manifested concurrent hypermethylation (P<0.001; Pearson's correlation coefficient, r=0.6408) observed in two loci (CYP39A1 and GTF2A1) in ovarian tumors. Scales on X- and Y-axis represent % of methylation for CYP39A1 and GTF2A1, respectively (shown in Fig. 1B).
Figure 3
Figure 3
Aberrant methylation in ovarian cancer cell lines represses target gene expression. (A) qMSP method has assessed elevated methylation in 3 loci observed in ovarian cancer cell lines, in relation to the IOSE. As described in the legend of the Fig. 1B, by comparing to SssI which was set as 100%, the methylation level of three loci was appraised in ovarian cancer cell lines. (B) To evaluate if an aberrant epigenome is one of the causes attributing to down-regulated expression, cells were treated with 5-aza-2′-deoxycytidine (ADC) alone, trichostatin A (TSA) alone, or both ADC plus TSA. Forty-eight hours later, mRNA expression was assessed by RT-PCR. Equal quantity of mRNA was assured by normalizing to the internal control GAPDH. Relative expression of a given locus in treated cells was obtained by comparing mRNA level in treated cells to that in vehicle DMSO treated cells (control) which was set as 1.*Indicates statistic significance between treated and control samples, which is denoted by the P-value (<0.05) derived from Student's t-test.
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References

    1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66. - PubMed
    1. Bast RC, Jr, Badgwell D, Lu Z, Marquez R, Rosen D, Liu J, Baggerly KA, Atkinson EN, Skates S, Zhang Z, Lokshin A, Menon U, Jacobs I, Lu K. New tumor markers: CA125 and beyond. Int J Gynecol Cancer. 2005;15(Suppl 3):274–281. - PubMed
    1. Urban N, McIntosh MW, Andersen M, Karlan BY. Ovarian cancer screening. Hematol Oncol Clin North Am. 2003;17:989–1005. ix. - PubMed
    1. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415–428. - PubMed
    1. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4:143–153. - PubMed

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