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Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis

2022; Nature Portfolio; Linguagem: Inglês

10.1038/s43018-022-00491-x

2662-1347

Susana García‐Recio, Toshinori Hinoue, Gregory Wheeler, Benjamin Kelly, Ana C. Garrido-Castro, Tomás Pascual, Aguirre A. de Cubas, Youli Xia, Brooke Felsheim, Marni B. McClure, Andrei Rajkovic, Ezgi Karaesmen, Markia A. Smith, Huihui Fan, Paula I. González-Ericsson, Melinda E. Sanders, Chad J. Creighton, Jay Bowen, Kristen Leraas, Robyn Burns, Sara E. Coppens, Amy Wheless, Salma Rezk, Amy Garrett, Joel S. Parker, Kelly K. Foy, Hui Shen, Ben Ho Park, Ian E. Krop, Carey K. Anders, Julie M. Gastier‐Foster, Mothaffar F. Rimawi, Rita Nanda, Nancy U. Lin, Claudine Isaacs, P. Kelly Marcom, Anna Maria Storniolo, Fergus J. Couch, Uma Chandran, Michael A. Davis, Jonathan C. Silverstein, Alexander J. Ropelewski, Minetta C. Liu, Susan G. Hilsenbeck, Larry Norton, Andrea L. Richardson, W. Fraser Symmans, Antonio C. Wolff, Nancy E. Davidson, Lisa A. Carey, Adrian V. Lee, Justin M. Balko, Katherine A. Hoadley, Peter W. Laird, Elaine R. Mardis, Tari A. King, Aguirre A. de Cubas, Charles M. Perou,

Epigenetics and DNA Methylation

Abstract The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell–cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER + /luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.