Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors

Sadegh Saghafinia; Marco Mina; Nicolo Riggi; Douglas Hanahan; Giovanni Ciriello

doi:10.1016/j.celrep.2018.09.082

Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors

Cell Rep. 2018 Oct 23;25(4):1066-1080.e8. doi: 10.1016/j.celrep.2018.09.082.

Authors

Sadegh Saghafinia¹, Marco Mina², Nicolo Riggi³, Douglas Hanahan⁴, Giovanni Ciriello⁵

Affiliations

¹ Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
² Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), University of Lausanne (UNIL), Lausanne, Switzerland.
³ Department of Experimental Pathology, University of Lausanne (UNIL), Lausanne, Switzerland.
⁴ Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
⁵ Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), University of Lausanne (UNIL), Lausanne, Switzerland. Electronic address: giovanni.ciriello@unil.ch.

PMID: 30355485
DOI: 10.1016/j.celrep.2018.09.082

Abstract

The discovery of cancer-associated alterations has primarily focused on genetic variants. Nonetheless, altered epigenomes contribute to deregulate transcription and promote oncogenic pathways. Here, we designed an algorithmic approach (RESET) to identify aberrant DNA methylation and associated cis-transcriptional changes across >6,000 human tumors. Tumors exhibiting mutations of chromatin remodeling factors and Wnt signaling displayed DNA methylation instability, characterized by numerous hyper- and hypo-methylated loci. Most silenced and enhanced genes coalesced in specific pathways including apoptosis, DNA repair, and cell metabolism. Cancer-germline antigens (CG) were frequently epigenomically enhanced and their expression correlated with response to anti-PD-1, but not anti-CTLA4, in skin melanoma. Finally, we demonstrated the potential of our approach to explore DNA methylation changes in pediatric tumors, which frequently lack genetic drivers and exhibit epigenomic modifications. Our results provide a pan-cancer map of aberrant DNA methylation to inform functional and therapeutic studies.

Keywords: DNA methylation instability; TCGA pan-cancer cohort; aberrant DNA methylation; cancer epigenetics; pediatric cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Child
DNA Methylation / genetics*
Epigenesis, Genetic
Gene Silencing
Humans
Neoplasms / genetics*