Aberrant DNA methylation has shown promise as a biomarker for the early detection of cancer. To discover novel genes frequently methylated at an early stage in colorectal cancer (CRC), DNA microarray analysis coupled with enriched methylated DNA was performed in primary tumors and compared with adjacent nontumor tissues of 12 patients with CRC at stages I to IV. Stepwise filtering for candidate selection in microarray data analysis yielded a set of genes that are highly methylated across all CRC tumors and that can be used as a composite biomarker for CRC detection. Verification assay identified the SDC2 gene as a potential methylation biomarker for early CRC detection. In clinical validation in tissues from 139 CRC patients, a much higher level of aberrant SDC2 methylation was measured in most primary tumors (97.8%), compared with corresponding nontumor tissue of CRC patients, irrespective of clinical stage. Clinical validation of SDC2 methylation in serum DNA from CRC patients (n = 131) at stages I to IV and from healthy individuals (n = 125) by quantitative methylation-specific PCR demonstrated a high sensitivity of 87.0% (95% CI, 80.0% to 92.3%) in detecting cancers, with a specificity of 95.2% (95% CI, 89.8% to 98.2%). Importantly, sensitivity at stage I was 92.3%, indicating the potential of SDC2 methylation as a blood-based DNA test for early detection of CRC.
Pre-mRNA splicing further increases protein diversity acquired through evolution. The underlying driving forces for this phenomenon are unknown, especially in terms of gene expression. A rice alternatively spliced transcript detection microarray (ASDM) and RNA sequencing (RNA-Seq) were applied to differentiate the transcriptome of 4 representative organs of Oryza sativa L. cv. Ilmi: leaves, roots, 1-cm-stage panicles and young seeds at 21 days after pollination. Comparison of data obtained by microarray and RNA-Seq showed a bell-shaped distribution and a co-lineation for highly expressed genes. Transcripts were classified according to the degree of organ enrichment using a coefficient value (CV, the ratio of the standard deviation to the mean values): highly variable (CVI), variable (CVII), and constitutive (CVIII) groups. A higher index of the portion of loci with alternatively spliced transcripts in a group (IAST) value was observed for the constitutive group. Genes of the highly variable group showed the characteristics of the examined organs, and alternatively spliced transcripts tended to exhibit the same organ specificity or less organ preferences, with avoidance of ‘organ distinctness’. In addition, within a locus, a tendency of higher expression was found for transcripts with a longer coding sequence (CDS), and a spliced intron was the most commonly found type of alternative splicing for an extended CDS. Thus, pre-mRNA splicing might have evolved to retain maximum functionality in terms of organ preference and multiplicity.
Abstract. Aberrant DNA methylation occurs early and frequently in tumorigenesis. Identification of DNA methylation biomarkers is a field that provides potential for improving the clinical process of breast cancer diagnosis. We utilized a genome-wide technique, methylated DNA isolation assay (MeDIA), in combination with high-resolution CpG microarray analysis to identify hypermethylated genes in breast cancer. Among differentially methylated genes between tumor and adjacent normal tissues, 3 candidate genes (LHX2, WT1 and OTP) were finally selected through a step-wise filtering process and examined for methylation status in normal tissues, primary tumor, and paired adjacent normal-appearing tissues from 39 breast cancer patients. Based on the calculated cut-off values, all genes showed significantly higher frequencies of aberrant hypermethylation in primary tumors (43.6% for LHX2, 89.7% for WT1 and 100% for OTP, P<0.05) while frequencies were intermediate in paired adjacent normal tissues and absent in normal tissues. On further analysis, the methylation level in primary tumors was not significantly correlated with clinicopathological features. Interestingly, DNA methylation of a novel gene OTP was detected in adjacent normal tissues even 6 cm away from primary tumors, suggesting that OTP methylation may qualify as a biomarker for the early detection of breast cancer. In conclusion, we successfully identified a novel gene OTP frequently methylated in breast cancer by genomewide screening. Our results suggest that the OTP gene may play a crucial role in breast carcinogenesis, although further clinical validation will be needed to evaluate the potential application of OTP in the early detection of breast cancer.
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