Dataset Information

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

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.

SUBMITTER: Garcia-Recio S

PROVIDER: S-EPMC9886551 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Garcia-Recio Susana S Hinoue Toshinori T Wheeler Gregory L GL Kelly Benjamin J BJ Garrido-Castro Ana C AC Pascual Tomas T De Cubas Aguirre A AA Xia Youli Y Felsheim Brooke M BM McClure Marni B MB Rajkovic Andrei A Karaesmen Ezgi E Smith Markia A MA Fan Cheng C Ericsson Paula I Gonzalez PIG Sanders Melinda E ME Creighton Chad J CJ Bowen Jay J Leraas Kristen K Burns Robyn T RT Coppens Sara S Wheless Amy A Rezk Salma S Garrett Amy L AL Parker Joel S JS Foy Kelly K KK Shen Hui H Park Ben H BH Krop Ian I Anders Carey C Gastier-Foster Julie J Rimawi Mothaffar F MF Nanda Rita R Lin Nancy U NU Isaacs Claudine C Marcom P Kelly PK Storniolo Anna Maria AM Couch Fergus J FJ Chandran Uma U Davis Michael M Silverstein Jonathan J Ropelewski Alexander A Liu Minetta C MC Hilsenbeck Susan G SG Norton Larry L Richardson Andrea L AL Symmans W Fraser WF Wolff Antonio C AC Davidson Nancy E NE Carey Lisa A LA Lee Adrian V AV Balko Justin M JM Hoadley Katherine A KA Laird Peter W PW Mardis Elaine R ER King Tari A TA Perou Charles M CM

Nature cancer 20221230 1

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 rece ...[more]

PMID: 36585450

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Project description:The goal of this dataset is to compare the gene expression patterns between primary and metastatic tumors Metastatic cancer patients typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is likely due to many factors, including increased clonal heterogeneity, multiple drug resistance mechanisms, and the role of the tumor microenvironment. The AURORA US Metastasis Project was established to collect and molecularly characterize specimens from 55 breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtype. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in adaptive immunity. In 17% of metastatic tumors, we identified DNA methylation and/or focal DNA deletions near HLA-A that were associated with its significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some MBC patients.

Project description:Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of the most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. In contrast, we found remarkable conservation of cancer-associated DNA hypermethylation profiles within primary tumor-metastasis pairs. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC

Dataset Information

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

Publications

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

Similar Datasets

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