DNA methylation markers for diagnosis and prognosis of common cancers

Abstract

The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis.

Plasma mSEPT9: A novel circulating cell-free DNA-based epigenetic biomarker to diagnose hepatocellular carcinoma

“…Epigenetic alterations are a common hallmark of human cancer (Moran et al, 2017;Hao et al, 2017). Several lines of evidence suggest that the septin 9 gene (SEPT9) is a key regulator of cell division and a tumor suppressor whose hypermethylation is associated with liver carcinogenesis (Scott et al, 2005;Kakehashi et al, 2011;Villanueva et al, 2015).…”

MethSurv: A Web Tool to Perform Multivariable Survival Analysis Using DNA Methylation Data

“…Such a rich collection of data gathered from a large number of patients have a great potential to be used in robust statistical analyses, thereby enabling improved survival prediction. Therefore, several studies [35,36,43,[47][48][49][50] rely on TCGA as a complementary resource for biomarker assessment. We believe that MethSurv will be a promising tool for similar studies to explore methylation-based biomarkers and to perform in silico validation as illustrated in the case studies section.…”

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

“…DNA methylation signatures can also be used to determine positive and negative prognoses and provide the possibility to identify relatively indolent or aggressive tumors. This may help in decision making regarding the selection of more aggressive or less aggressive treatment and monitoring of the case …”