TY - JOUR
T1 - Robust prediction of gene regulation in colorectal cancer tissues from DNA methylation profiles
AU - Klett, Hagen
AU - Balavarca, Yesilda
AU - Toth, Reka
AU - Gigic, Biljana
AU - Habermann, Nina
AU - Scherer, Dominique
AU - Schrotz-King, Petra
AU - Ulrich, Alexis
AU - Schirmacher, Peter
AU - Herpel, Esther
AU - Brenner, Hermann
AU - Ulrich, Cornelia M.
AU - Michels, Karin B.
AU - Busch, Hauke
AU - Boerries, Melanie
PY - 2018/4/3
Y1 - 2018/4/3
N2 - DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene-specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo-methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92<AUC<0.97) as well as in individual patient data (average AUC = 0.82), suggesting a robust interplay between methylation and gene regulation. Validation analysis in other cancerous tissues resulted in lower prediction performances (0.69<AUC<0.90); however, it identified genes that share robust dependencies across cancerous tissues. In conclusion, we present a robust classification approach that predicts the gene-specific regulation through DNA methylation in CRC tissues with possible transition to different cancer entities. Furthermore, we present HMGA1 as consistently associated with methylation across cancers, suggesting a potential candidate for DNA methylation targeting cancer therapy.
AB - DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene-specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo-methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92<AUC<0.97) as well as in individual patient data (average AUC = 0.82), suggesting a robust interplay between methylation and gene regulation. Validation analysis in other cancerous tissues resulted in lower prediction performances (0.69<AUC<0.90); however, it identified genes that share robust dependencies across cancerous tissues. In conclusion, we present a robust classification approach that predicts the gene-specific regulation through DNA methylation in CRC tissues with possible transition to different cancer entities. Furthermore, we present HMGA1 as consistently associated with methylation across cancers, suggesting a potential candidate for DNA methylation targeting cancer therapy.
UR - http://www.scopus.com/inward/record.url?scp=85046459244&partnerID=8YFLogxK
U2 - 10.1080/15592294.2018.1460034
DO - 10.1080/15592294.2018.1460034
M3 - Journal articles
AN - SCOPUS:85046459244
VL - 13
SP - 386
EP - 397
JO - Epigenetics
JF - Epigenetics
SN - 1559-2294
IS - 4
ER -