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

Project description:Age and physiological status like menopause are key factors in mammary development and are associated with breast cancer risk. Less clear is what factors influence breast cancer intrinsic subtypes that are associated with prognosis. Here, we investigated the age of the host in a mammary chimera model. The mammary glands of wildtype BALB/c mice were cleared of endogenous epithelium at 3 weeks of age and subsequently transplanted during puberty (5 weeks) or upon maturation (10 weeks) with syngeneic Trp53null mammary fragments. The Trp53null mammary epithelium undergoes a high rate of neoplastic transformation, such that carcinomas arise over the course of a year. Tumors arose more rapidly (p=0.003, log-rank test) when transplanted to adult hosts (AH, n=89) compared to tumors arising following transplantation into juvenile hosts (JH, n=55). However, JH tumors grew several times faster than AH tumors, were more perfused as indicated by 2-fold larger blood vessels (p=0.015), and exhibited a 2-fold higher mitotic index (p=0.009). Transplantation into juvenile hosts (JH) gave rise to 80% ER positive tumors compared to 60% in adult hosts. However, tumor cells were significantly more ER immunoreactive (p=0.0001) in JH tumors compared to those in AH tumors and were more highly positive for insulin like growth factor receptor phosphorylation (p=0.026). Expression profiles of JH (n=15) and AH (n=12) tumors identified 243 differentially expressed genes. The main biological processes enriched in JH tumors were organ morphology, proliferation, and lipid metabolism. An expression profile of juvenile versus adult (JVA) tumors revealed a luminal transcriptional program, characterized by expression of Foxa1, Igf2, Ccnd1 and Fgfr2. The human homologs of JVA genes (JVAh) were used to create two centroids (AHh or JHh) to classify human breast cancers from archival microarray datasets in two-dimensional space. Luminal human breast cancers were more like JH tumors compared to basal-like cancers, whereas luminal A tumors were more like JH tumors than luminal B tumors. Consistent with this, JVAh genes segregated human luminal A from luminal B breast cancers via hierarchical clustering. The distinct biology of tumors arising from tissue undergoing morphogenesis in the context of puberty suggests that young age at neoplastic transformation promotes a luminal tumor phenotype and supports the contention that the tumor intrinsic subtype is influenced by physiological status at the time of putative initiation.

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Multi-omics analysis identifies intrinsic Trp53 driven metastatic breast cancer subtypes [RNA-seq]

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