Multi-omics Profiling of Younger Asian Breast Cancers Reveals Distinctive Molecular Signatures
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113184 | GEO | 2018/04/17
REPOSITORIES: GEO
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Project description:Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-? signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs.
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Project description:Background: Unlike estrogen receptor (ER) negative breast cancer, ER-positive breast cancer outcomes are less influenced by lymphocyte content, indicating a need for investigation of checkpoint targets and immune tolerance mechanisms that may be specific to this disease subset. Methods: A supervised analysis of microarray data from the Alliance/ACOSOG Z1031 trial was conducted to identify upregulated genes in Luminal B breast cancers that exhibited persistent tumor proliferation despite aromatase inhibitor therapy (33 cases Ki67 >10%) versus Luminal B breast cancers that were more sensitive (33 cases Ki67 <10%). Results: This study identified thirty genes (Pearson’s r>0.4 with Ki67 as a continuous variable). These genes were enriched for immune tolerance processes (p<0.005) and three targetable immune checkpoint components were upregulated in resistant cases: IDO1, LAG3, and PD1. High IDO1 mRNA associated with poor prognosis in ER+ disease across two independent cohorts (METABRIC and TCGA). Furthermore, analysis indicated IDO1 was tightly associated with IFN-γ/STAT1 signaling. As a composite immune tolerance signature, expression of these pathway components associated with higher baseline Ki67 and lower ER, PgR levels and poor disease specific survival. In tissue microarray analysis, IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in Luminal B cases. Further mRNA and tissue microarray analyses associated IDO1 expression with the presence of macrophages (M1 by CIBERSORT) and regulatory T cells. Conclusion: Targetable immune-checkpoint components are upregulated in majority of neoadjuvant endocrine therapy resistant Luminal B cases. Our findings suggests potential for immune checkpoint inhibitors in poor outcome ER+ breast cancer.
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Project description:Multi-omics Profiling of Younger Asian Breast Cancers Reveals Distinctive Molecular Signatures
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Project description:Despite proven therapy options for estrogen receptor (ER)-positive tumors, a significant number of patients with these cancers exhibit relapse with associated metastasis. Studies have shown that the loss of expression of RasGAPs leads to aggressive phenotypes and poor outcomes in several cancers including breast cancer. In our study, mining TCGA gene expression profiles of ER-positive breast tumors, we found that low expression of the RasGAP, DAB2IP is associated with a significant decrease in relapse-free survival in patients with Luminal A breast tumors. Immunostaining found that DAB2IP loss occurs in grade 2 tumors and higher. Consistent with this, genes upregulated in low DAB2IP Luminal A tumors are shared with more aggressive tumor subtypes, and are associated with proliferation, metastasis, and enhanced ER-signaling. In addition, cell-based studies reveal that low DAB2IP expression in ER-positive breast cancer cells is associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the NF-B signaling pathway. Further, integrating cell-based ChIP-seq with motif analysis and TCGA RNA-seq data, we identify a candidate set of NF-B target genes that are upregulated with loss of DAB2IP and are proposed to regulate several oncogenic phenotypes, including altered RNA processing. This study provides new insight into mechanisms associated with aggressiveness and recurrence within a subset of Luminal A breast cancers that are otherwise typically less aggressive.
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Project description:Despite proven therapy options for estrogen receptor (ER)-positive tumors, a significant number of patients with these cancers exhibit relapse with associated metastasis. Studies have shown that the loss of expression of RasGAPs leads to aggressive phenotypes and poor outcomes in several cancers including breast cancer. In our study, mining TCGA gene expression profiles of ER-positive breast tumors, we found that low expression of the RasGAP, DAB2IP is associated with a significant decrease in relapse-free survival in patients with Luminal A breast tumors. Immunostaining found that DAB2IP loss occurs in grade 2 tumors and higher. Consistent with this, genes upregulated in low DAB2IP Luminal A tumors are shared with more aggressive tumor subtypes, and are associated with proliferation, metastasis, and enhanced ER-signaling. In addition, cell-based studies reveal that low DAB2IP expression in ER-positive breast cancer cells is associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the NF-B signaling pathway. Further, integrating cell-based ChIP-seq with motif analysis and TCGA RNA-seq data, we identify a candidate set of NF-B target genes that are upregulated with loss of DAB2IP and are proposed to regulate several oncogenic phenotypes, including altered RNA processing. This study provides new insight into mechanisms associated with aggressiveness and recurrence within a subset of Luminal A breast cancers that are otherwise typically less aggressive. Gene expression profiling by RNA-sequencing of DAB2IP knockdown and control MCF10A cells.
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