Abstract
A big challenge to clinical diagnosis and therapy of colorectal cancer (CRC) is its extreme heterogeneity, and thus it would be of special importance if we could find common biomarkers besides subtype-specific biomarkers for CRC. Here, with DNA methylation data produced by different laboratories, we firstly revealed that the relative methylation-level orderings (RMOs) of CpG sites within colorectal normal tissues are highly stable but widely disrupted in the CRC tissues. This finding provides the basis for using the RankComp algorithm to identify differentially methylated (DM) CpG sites in every individual CRC sample through comparing the RMOs within the individual sample with the stable RMOs predetermined in normal tissues. For 75 CRC samples, RankComp detected averagely 4,062 DM CpG sites per sample and reached an average precision of 91.34% in terms that the hypermethylation or hypomethylation states of the DM CpG sites detected for each cancer sample were consistent with the observed differences between this cancer sample and its paired adjacent normal sample. Finally, we applied RankComp to identify DM CpG sites for each of the 268 CRC samples from The Cancer Genome Atlas and found 26 and 143 genes whose promoter regions included CpG sites that were hypermethylated and hypomethylated, respectively, in more than 95% of the 268 CRC samples. Individualized pathway analysis identified six pathways that were significantly enriched with DM genes in more than 90% of the CRC tissues. These universal DNA methylation biomarkers could be important diagnostic makers and therapy targets for CRC.
Highlights
The frequencies of somatic mutations and copy number aberrations in cancer genomes including colorectal cancer (CRC) genomes are usually very low [1,2,3], reflecting the molecular heterogeneity of CRC [4, 5]
Through the analysis of DNA methylation data produced by different laboratories, we showed that the relative methylation-level orderings (RMOs) of CpG sites are highly stable within normal colorectal samples but widely reversed in CRC tissues
Using 75 paired methylation profiles for colorectal cancer tissues and the paired adjacent normal tissues, we firstly evaluated the performance of RankComp by evaluating the identified differentially methylated (DM) CpG sites in each cancer tissue according to the observed DNA methylation level differences between the cancer tissue and its adjacent normal tissue
Summary
The frequencies of somatic mutations and copy number aberrations in cancer genomes including colorectal cancer (CRC) genomes are usually very low [1,2,3], reflecting the molecular heterogeneity of CRC [4, 5]. Different from www.impactjournals.com/oncotarget somatic mutations and copy number aberrations, DNA methylation aberrations in cancer genomes are widespread in cancer genomes [6, 7], which provides us the possibility to find common epigenetic aberrations in CRC. Current methods such as Wilcoxon rank-sum test [8] and T-test [9] can only identify differentially methylated (DM) CpG sites between a set of cancer samples and a set of normal controls. Because the highly stable REOs of genes predetermined in accumulated normal samples can represent the REOs of genes in every normal tissue, the differentially expressed genes identified by the algorithm for each disease sample are the genes that are differentially expressed in this disease sample compared with its own previous normal state
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
