Abstract
BackgroundKLK10 exon 3 hypermethylation correlated to tumor-specific lack of KLK10 expression in cancer cell lines and primary tumors. In the present study we investigate the possible role of KLK10 exon 3 methylation in ovarian tumor diagnosis and prognosis.ResultsQualitative methylation-specific PCR (MSP) results did not show statistically significant differences in patient group samples (normal and tumor) where all samples were positive only for the unmethylated-specific PCR except for two malignant samples that were either doubly positive (serous carcinoma) or doubly negative (Sertoli-Leydig cell tumor) for the two MSP tests. However, KLK10 exon 3 unmethylated PCR product concentration (ng/μl) showed statistically significant differences in benign and malignant patient group samples; mean ± SD (n): tumor: 0.077 ± 0.035 (14) and 0.047 ± 0.021 (15), respectively, p-value = 0.011; and normal: 0.094 ± 0.039 (7) and 0.046 ± 0.027 (6), respectively, p-value = 0.031. Moreover, ROC curve analysis of KLK10 exon 3 unmethylated PCR product concentration in overall patient group samples showed good diagnostic ability (AUC = 0.778; p-value = 0.002). Patient survival (living and died) showed statistically significant difference according to preoperative serum CA125 concentration (U/ml); median (n): 101.25 (10) and 1252 (5), respectively, p-value = 0.037, but not KLK10 exon 3 unmethylated PCR product concentration (ng/μl) in overall malignant patient samples; mean ± SD (n): 0.042 ± 0.015 (14) and 0.055 ± 0.032 (7), p-value = 0.228.ConclusionTo the best of our knowledge, this is the first report on KLK10 exon 3 unmethylated PCR product concentration as potential early epigenetic diagnostic marker in primary ovarian tumors. Taken into account the limitations in our study (small sample size and semi-quantitative PCR product analysis) further studies are strongly recommended.
Highlights
Kallikrein-related peptidase10 gene (KLK10) exon 3 hypermethylation correlated to tumor-specific lack of KLK10 expression in cancer cell lines and primary tumors
There were no statistically significant differences of patient age mean ± SD according to disease grade (1, 2 and 3): mean ± SD (n): 36.8 ± 11.2 (5), 48.0 ± 19.6 (5) and 46.5 ± 11.0 (6), respectively; p-value = 0.422, or disease stage (I/II and III/IV): mean ± SD (n): 42.5 ± 16.4 (9) and 45.7 ± 11.7 (7), respectively; p-value = 0.675
Our results showed statistically significant positive correlation between KLK10 exon 3 unmethylated Polymerase chain reaction (PCR) product concentration and patient age by Spearman’s correlation and on comparing its mean ± SD in overall samples and in malignant samples according to age groups (Table 4)
Summary
KLK10 exon 3 hypermethylation correlated to tumor-specific lack of KLK10 expression in cancer cell lines and primary tumors. In the present study we investigate the possible role of KLK10 exon 3 methylation in ovarian tumor diagnosis and prognosis. DNA methylation is one of the well-studied epigenetic modifications in DNA/chromatin metabolism. It is a dynamic process and involves the reversible and heritable methylation of the 5′ carbon of cytosine residues to yield 5-methylcytosine (5-MC) [1]. In DNA the cytosine residues occur either in frequencies that are far less than expected or in CpG-rich short stretches (0.5–4 kbp) in gene promoters and other regulatory regions known collectively as CpG islands. The effect of DNA methylation on gene regulation may differ according to the context in which it occurs; in CpG-rich gene promoters it is well known to share in gene silencing [8]. Aberrant gene methylation in cancer can be a promising diagnostic and prognostic target in tumor and naked DNA samples; e.g. in lung cancer [10]
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