Experimental Cancer Pathology

Prof. Manon van Engeland

The aim of the Epigenetics program of the Cancer Pathology Laboratory is to study the pathobiology of colorectal-, renal, breast- and skin cancer in order to identify novel tumor suppressor genes and biomarkers.

It is becoming increasingly clear that epigenetic alterations in cancer occur frequently and early in the process of carcinogenesis. Epigenetic alterations include DNA methylation, loss of imprinting, posttranslational histone modifications, nucleosome positioning, chromatin looping and small non-coding RNAs. The most extensively characterized epigenetic alteration in CRC is promoter hypermethylation, which occurs at CpG dinucleotide-dense regions, called CpG islands, present at the 5’ region of approximately 60% of genes. Most CpG islands lack methylation in normal tissue, independent of the transcriptional status of the gene. Hypermethylation of promoter CpG islands has been observed for numerous tumor suppressor- and DNA repair genes and functions equivalently to coding-region mutations or deletion, therefore considered the ‘’third hit’’  in the Knudson model for inactivation of tumor suppressor genes.

Promoter CpG island methylation for some genes is related to aging, but cancer-specific hypermethylation events are frequent as well and affect WNT-, RTK-, NOTCH-, TP53-, PI3K-, retinoic acid-, and IGF signaling as well as other pathways regulating cell cycle regulation, transcription regulation, DNA repair/stability, apoptosis, adhesion angiogenesis, invasion and metastasis. Thus, epigenetic alterations target many of the same pathways targeted for mutational events. Some genes are exclusively altered by epigenetic inactivation, others targeted by genetic events and a subgroup of genes have a combination of genetic and epigenetic inactivation. The reversible nature of these alterations, the high frequency at which they occur and the possibility of detection in cancer cells provide opportunities for use of this information in the clinic. In this research line we aim to identify novel tumor suppressorgenes through genome-wide methylation analysis. We focus on tumor suppressor genes that are candidate biomarkers for early detection and prediction of prognosis and response to therapy. These markers are being validated clinically (independent clinical studies) and experimentally (in vitro and in vivo validation of tumor suppressor function).