TY - JOUR
T1 - Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis
AU - AURORA US Network
AU - Garcia-Recio, Susana
AU - Hinoue, Toshinori
AU - Wheeler, Gregory L.
AU - Kelly, Benjamin J.
AU - Garrido-Castro, Ana C.
AU - Pascual, Tomas
AU - De Cubas, Aguirre A.
AU - Xia, Youli
AU - Felsheim, Brooke M.
AU - McClure, Marni B.
AU - Rajkovic, Andrei
AU - Karaesmen, Ezgi
AU - Smith, Markia A.
AU - Fan, Cheng
AU - Ericsson, Paula I.Gonzalez
AU - Sanders, Melinda E.
AU - Creighton, Chad J.
AU - Bowen, Jay
AU - Leraas, Kristen
AU - Burns, Robyn T.
AU - Coppens, Sara
AU - Wheless, Amy
AU - Rezk, Salma
AU - Garrett, Amy L.
AU - Parker, Joel S.
AU - Foy, Kelly K.
AU - Shen, Hui
AU - Park, Ben H.
AU - Krop, Ian
AU - Anders, Carey
AU - Gastier-Foster, Julie
AU - Rimawi, Mothaffar F.
AU - Nanda, Rita
AU - Lin, Nancy U.
AU - Isaacs, Claudine
AU - Marcom, P. Kelly
AU - Storniolo, Anna Maria
AU - Couch, Fergus J.
AU - Chandran, Uma
AU - Davis, Michael
AU - Silverstein, Jonathan
AU - Ropelewski, Alexander
AU - Liu, Minetta C.
AU - Hilsenbeck, Susan G.
AU - Norton, Larry
AU - Richardson, Andrea L.
AU - Symmans, W. Fraser
AU - Wolff, Antonio C.
AU - Davidson, Nancy E.
AU - Carey, Lisa A.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85145201110&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85145201110&partnerID=8YFLogxK
U2 - 10.1038/s43018-022-00491-x
DO - 10.1038/s43018-022-00491-x
M3 - Article
C2 - 36585450
AN - SCOPUS:85145201110
SN - 2662-1347
VL - 4
SP - 128
EP - 147
JO - Nature Cancer
JF - Nature Cancer
IS - 1
ER -