DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation

Rajbir Nath Batra, Aviezer Lifshitz, Ana Tufegdzic Vidakovic, Suet-Feung Chin, Ankita Sati-Batra, Stephen-John Sammut, Elena Provenzano, H. Raza Ali, Ali Dariush, Alejandra Bruna, Leigh Murphy, Arnie Purushotham, Ian Ellis, Andrew Green, Francine E. Garrett-Bakelman, Chris Mason, Ari Melnick, Samuel A. J. R. Aparicio, Oscar M. Rueda, Amos Tanay () and Carlos Caldas ()
Additional contact information
Rajbir Nath Batra: University of Cambridge
Aviezer Lifshitz: Weizmann Institute of Science
Ana Tufegdzic Vidakovic: The Francis Crick Institute
Suet-Feung Chin: University of Cambridge
Ankita Sati-Batra: University of Cambridge
Stephen-John Sammut: University of Cambridge
Elena Provenzano: Cancer Research UK Cambridge Centre
H. Raza Ali: University of Cambridge
Ali Dariush: University of Cambridge
Alejandra Bruna: University of Cambridge
Leigh Murphy: Research Institute in Oncology and Hematology
Arnie Purushotham: King’s College London
Ian Ellis: University of Nottingham and Nottingham University Hospital NHS Trust
Andrew Green: University of Nottingham and Nottingham University Hospital NHS Trust
Francine E. Garrett-Bakelman: Weill Cornell Medicine
Chris Mason: Weill Cornell Medicine
Ari Melnick: Weill Cornell Medicine
Samuel A. J. R. Aparicio: Department of Molecular Oncology, British Columbia Cancer Research Centre
Oscar M. Rueda: University of Cambridge
Amos Tanay: Weizmann Institute of Science
Carlos Caldas: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

Date: 2021
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DOI: 10.1038/s41467-021-25661-w

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