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Targeted RNA-seq signature of Breast Cancer Circulating Tumor Cells correlates with occurrence of bone-only metastases

ABSTRACT: Bone is the most frequent site of metastases from breast cancer (BC), although no biomarkers are yet available to predict the risk of skeletal dissemination. Here, we attempted to identify a gene signature correlated with bone metastasis (BM) onset in circulating tumor cells (CTCs) isolated from 40 metastatic BC patients, grouped according to their metastasis sites at the time of enrollment, namely “BM” (bone-only), “ES” (extra-skeletal) or “BM+ES” (bone and extra-skeletal). A 134-gene panel, derived from an extensive literature review, was validated on sub-clones of the MDA-MB-231 BC cell line with variable organotropism and then applied to CTC groups for targeted RNA sequencing. No correlation was found between CTC number and clinico-pathologic variables, whereas 31 differentially expressed genes emerged from “BM” and “ES” CTC comparison. The putative prognostic meaning of the “top-10” most deregulated genes was finally explored and pointed out by employing an external BC dataset.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160314 | GEO | 2020/10/29

REPOSITORIES: GEO

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Project description:Introduction: The incidence of brain metastases in cancer patients is increasing, with lung and breast cancer being the most common sources. Despite advancements in targeted therapies, the prognosis remains poor, highlighting the importance to investigate the underlying mechanisms in brain metastases. The aim of this study was to investigate the differences in the molecular mechanisms involved in brain metastasis of breast and lung cancers. In addition, we aimed to identify cancer lineage-specific druggable targets in the brain metastasis. Methods: To that aim, a cohort of 44 FFPE tissue samples, including 22 breast cancer and 22 lung adenocarcinoma (LUAD) and their matched-paired brain metastases were collected. Targeted gene expression profiles of primary tumors were compared to their matched-paired brain metastases samples using nCounter PanCancer IO 360™ Panel of NanoString technologies. Pathway analysis was performed using gene set analysis (GSA) and gene set enrichment analysis (GSEA). The validation was performed by using Immunohistochemistry (IHC) to confirm the expression of immune checkpoint inhibitors. Results: Our results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. p ≤ 0.05). We found that upregulated differentially expressed genes in breast cancer brain metastasis (BM-BC) and brain metastasis from lung adenocarcinoma (BM-LUAD) were associated with the metabolic stress pathway, particularly related to the glycolysis. Additionally, we found that the upregulated genes in BM-BC and BM-LUAD played roles in immune response regulation, tumor growth, and proliferation. Importantly, we identified high expression of the immune checkpoint VTCN1 in BM-BC, and VISTA, IDO1, NT5E, and HDAC3 in BM-LUAD. Validation using immunohistochemistry further supported these findings. Conclusion: In conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.

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Targeted RNA-seq signature of Breast Cancer Circulating Tumor Cells correlates with occurrence of bone-only metastases

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