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Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers.

ABSTRACT: Aberrant DNA methylation is more prominent in proximal compared with distal colorectal cancers. Although a number of methylation markers were identified for colon cancer, yet few are available for rectal cancer.DNA methylation differences were assessed by a targeted DNA microarray for 360 marker candidates between 22 fresh frozen rectal tumour samples and 8 controls and validated by microfluidic high-throughput and methylation-sensitive qPCR in fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples, respectively. The CpG island methylator phenotype (CIMP) was assessed by MethyLight in FFPE material from 78 patients with pT2 and pT3 rectal adenocarcinoma.We identified and confirmed two novel three-gene signatures in fresh frozen samples that can distinguish tumours from adjacent tissue as well as from blood with a high sensitivity and specificity of up to 1 and an AUC of 1. In addition, methylation of individual CIMP markers was associated with specific clinical parameters such as tumour stage, therapy or patients' age. Methylation of CDKN2A was a negative prognostic factor for overall survival of patients.The newly defined methylation markers will be suitable for early disease detection and monitoring of rectal cancer.

SUBMITTER: Exner R

PROVIDER: S-EPMC4651135 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers.

Exner Ruth R Pulverer Walter W Diem Martina M Spaller Lisa L Woltering Laura L Schreiber Martin M Wolf Brigitte B Sonntagbauer Markus M Schröder Fabian F Stift Judith J Wrba Fritz F Bergmann Michael M Weinhäusel Andreas A Egger Gerda G

British journal of cancer 20150903 7

<h4>Background</h4>Aberrant DNA methylation is more prominent in proximal compared with distal colorectal cancers. Although a number of methylation markers were identified for colon cancer, yet few are available for rectal cancer.<h4>Methods</h4>DNA methylation differences were assessed by a targeted DNA microarray for 360 marker candidates between 22 fresh frozen rectal tumour samples and 8 controls and validated by microfluidic high-throughput and methylation-sensitive qPCR in fresh frozen and ...[more]

PMID: 26335606

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Project description:Background: DNA methylation is a common event in the early development of various tumors, including breast cancer (BRCA), which has been studies as potential tumor biomarkers. Although previous studies have reported a cluster of aberrant promoter methylation changes in BRCA, none of these research groups have proved the specificity of these DNA methylation changes. Here we aimed to identify specific DNA methylation signatures in BRCA which can be used as diagnostic and prognostic markers. Methods: Differentially methylated sites were identified using the Cancer Genome Atlas (TCGA) BRCA data set. We screened for BRCA-differential methylation by comparing methylation profiles of BRCA patients, healthy breast biopsies and blood samples. These differential methylated sites were compared to nine main cancer samples to identify BRCA specific methylated sites. A BayesNet model was built to distinguish BRCA patients from healthy donors. The model was validated using three Gene Expression Omnibus (GEO) independent data sets. In addition, we also carried out the Cox regression analysis to identify DNA methylation markers which are significantly related to the overall survival (OS) rate of BRCA patients and verified them in the validation cohort. Results: We identified seven differentially methylated sites (DMSs) that were highly correlated with cell cycle as potential specific diagnostic biomarkers for BRCA patients. The combination of 7 DMSs achieved ~94% sensitivity in predicting BRCA, ~95% specificity comparing healthy vs. cancer samples, and ~88% specificity in excluding other cancers. The 7 DMSs were highly correlated with cell cycle. We also identified 6 methylation sites that are highly correlated with the OS of BRCA patients and can be used to accurately predict the survival of BRCA patients (training cohort: likelihood ratio = 70.25, p = 3.633 × 10-13, area under the curve (AUC) = 0.784; validation cohort: AUC = 0.734). Stratification analysis by age, clinical stage, Tumor types, and chemotherapy retained statistical significance. Conclusion: In summary, our study demonstrated the role of methylation profiles in the diagnosis and prognosis of BRCA. This signature is superior to currently published methylation markers for diagnosis and prognosis for BRCA patients. It can be used as promising biomarkers for early diagnosis and prognosis of BRCA.

Project description:BackgroundBreast cancer is a highly heterogeneous disease resulting in diverse clinical behaviours and therapeutic responses. DNA methylation is a major epigenetic alteration that is commonly perturbed in cancers. The aim of this study is to characterize the relationship between DNA methylation and aberrant gene expression in breast cancer.MethodsWe analysed DNA methylation and gene expression profiles from breast cancer tissue and matched normal tissue in The Cancer Genome Atlas (TCGA). Genome-wide differential methylation analysis and methylation-gene expression correlation was performed. Gene expression changes were subsequently validated in the METABRIC dataset. The Oncoscore tool was used to identify genes that had previously been associated with cancer in the literature. A subset of genes that had not previously been studied in cancer was chosen for further analysis.ResultsWe identified 368 CpGs that were differentially methylated between tumor and normal breast tissue (∆β > 0.4). Hypermethylated CpGs were overrepresented in tumor tissue and were found predominantly (56%) in upstream promoter regions. Conversely, hypomethylated CpG sites were found primarily in the gene body (66%). Expression analysis revealed that 209 of the differentially-methylated CpGs were located in 169 genes that were differently expressed between normal and breast tumor tissue. Methylation-expression correlations were predominantly negative (70%) for promoter CpG sites and positive (74%) for gene body CpG sites. Among these differentially-methylated and differentially-expressed genes, we identified 7 that had not previously been studied in any form of cancer. Three of these, TDRD10, PRAC2 and TMEM132C, contained CpG sites that showed diagnostic and prognostic value in breast cancer, particularly in estrogen-receptor (ER)-positive samples. A pan-cancer analysis confirmed differential expression of these genes together with diagnostic and prognostic value of their respective CpG sites in multiple cancer types.ConclusionWe have identified 368 DNA methylation changes that characterize breast cancer tumor tissue, of which 209 are associated with genes that are differentially-expressed in the same samples. Novel DNA methylation markers were identified, of which cg12374721 (PRAC2), cg18081940 (TDRD10) and cg04475027 (TMEM132C) show promise as diagnostic and prognostic markers in breast cancer as well as other cancer types.

Dataset Information

Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers.

Publications

Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers.

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