Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis.

Carmen Ili,David Saavedra,Jaime López,Gavin Kelsey,Patricia García,Ismael Riquelme,Hannah Demond,Enrique Bellolio,Michel Abanto,Louise Zanella,Priscilla Brebi,Kurt Buchegger,Tamara Viscarra,Juan Castillo-Fernandez

doi:10.3390/cancers12092710

Abstract

Simple SummaryColorectal cancer is one of the most common neoplasia worldwide. Metastasis in lymph nodes and distant organs indicates poor prognosis; However, the influence of DNA methylation over colorectal metastasis is not well understood. We investigated the genome-wide DNA methylation profile of normal, primary tumour and lymph node metastasis of colon, finding a specific signature of early metastasis, present in primary tumour, that allowed a better understanding of colon cancer spread. In addition, the hypermethylation of FIGN, HTRA3, BDNF, HCN4 and STAC2 could be utilised in primary tumour as biomarkers of colorectal cancer prognosis.Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis. Genome-wide methylation sequencing of paired samples of colon (normal adjacent, primary tumour and lymph node metastasis) showed global hypomethylation and CpG island (CGI) hypermethylation of primary tumours compared to normal. In metastasis we observed high global and non-CGI regions methylation, but lower CGI methylation, compared to primary tumours. Gene ontology analysis showed shared biological processes between hypermethylated CGIs in metastasis and primary tumours. After complementary analysis with The Cancer Genome Atlas (TCGA) cohort, FIGN, HTRA3, BDNF, HCN4 and STAC2 genes were found associated with poor survival. We mapped the methylation landscape of colon normal tissues, primary tumours and lymph node metastasis, being capable of identified methylation changes throughout the genome. Furthermore, we found five genes with potential for methylation biomarkers of poor prognosis in colorectal cancer patients.

Highlights

Colorectal cancer (CRC) is a heterogeneous disease caused by both genetic and environmental factors [1]
We found low non-CpG island (CGI) methylation levels in colon cancer, which may be a consequence of the advanced CRC stage of the patients analysed, with at least one lymph node metastasis, which is associated with a poor survival
Our analysis found global hypomethylation and CGIs hypermethylation of colon primary tumour compared to normal tissues; which is in line with our general understanding of the cancer methylome

Summary

Introduction

Colorectal cancer (CRC) is a heterogeneous disease caused by both genetic and environmental factors [1]. It is the third most commonly diagnosed cancer worldwide (1.85 million cases per year) and is ranked second regarding the global number cancer deaths (880,792 deaths per year) [2]. Incidence rates are increasing in other regions, including Central and South. The majority of CRC occurrences are sporadic (70–80%) and related to risk factors such as age and lifestyle without an existent family history or genetic predisposition [4]. Reasons explaining the increased incidence of CRC in many parts of the world include an ageing population and a “Western”

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