Transcriptome-Based Network Analysis Unveils Eight Immune-Related Genes as Molecular Signatures in the Immunomodulatory Subtype of Triple-Negative Breast Cancer

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Abstract

Objective: Triple-negative breast cancer (TNBC) is a high heterogeneity cancer. The identification of genomic aberrations that drive each of the TNBC subtypes may predict the prognosis of patients with TNBC and provide novel therapeutic strategies in clinical practice. This study focuses on the transcriptome-based gene expression of TNBC and aims to generate comprehensive gene co-expression networks correlated with the immune-related subtype of TNBC.

Methods: The transcriptome profiles of 107 female patients with TNBC were analyzed. Weighted gene co-expression network analysis (WGCNA) was applied to construct related networks and to sort hub-genes associated with the survival of TNBC patients. The data of the transcriptional expression, genomic alteration, survival status, and tumor immune microenvironment, which associated with hub-genes, were extracted, retrieved, and analyzed from Oncomine, UALCAN, TCGA, starBase, Kaplan–Meier Plotter, cBioPortal, and TIMER databases.

Results: Immune-related hub-genes, including BIRC3, BTN3A1, CSF2RB, GIMAP7, GZMB, HCLS1, LCP2, and SELL, were found to be associated with clinical features of TNBC evaluated by WGCNA. These hub-genes belonged to the immunomodulatory subtype of TNBC and were upregulated in the TNBC cells. The protein expression of eight immune-related hub-genes was further confirmed to be upregulated in TNBC/CD8+ tissues detected by immunohistochemical staining. Survival analysis revealed that overexpression of eight immune-related hub-genes was in favor of the survival of patients with TNBC. Moreover, a positive correlation between eight immune-related hub-genes and immune cell infiltration was observed in TNBC patients. Furthermore, checkpoint inhibitor genes such as PD-L1, PD-1, and CTLA4 were more enrichment in the immunomodulatory subtype of TNBC and the expression of PD-L1, PD-1, and CTLA4 was positively correlated with eight immune-related hub-genes in the breast cancer dataset of TCGA.

Conclusions: Eight immune-related hub-genes were identified to be molecular signatures in the immunomodulatory subtype of TNBC, which may provide therapeutic targets for the treatment of patients with breast cancer.

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Most cited references 48

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The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

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Stromal gene expression predicts clinical outcome in breast cancer.

Greg Finak, Nicholas Bertos, François Pépin … (2008)

Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

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Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.

Sylvia Adams, Robert J Gray, Sandra Demaria … (2014)

Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

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Author and article information

Contributors

Jinguo Zhang: URI : http://loop.frontiersin.org/people/973635/overview

Guoxiong Xu: URI : http://loop.frontiersin.org/people/853628/overview

Journal

Journal ID (nlm-ta): Front Oncol

Journal ID (publisher-id): Front. Oncol.

Title: Frontiers in Oncology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2234-943X

Publication date (Electronic): 18 September 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 1787

Affiliations

[1] ¹Research Center for Clinical Medicine, Jinshan Hospital, Fudan University , Shanghai, China

[2] ²Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China

[3] ³Department of Pathology, Jinshan Hospital, Fudan University , Shanghai, China

[4] ⁴Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University , Shanghai, China

Author notes

Edited by: Zhi Sheng, Virginia Tech, United States

Reviewed by: Marco A. Velasco-Velazquez, National Autonomous University of Mexico, Mexico; Massimo Fantini, Precision Biologics, Inc., United States

*Correspondence: Guoxiong Xu guoxiong.xu@ 123456fudan.edu.cn

This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology

†ORCID: Guoxiong Xu orcid.org/0000-0002-9074-8754

Article

DOI: 10.3389/fonc.2020.01787

PMC ID: 7530237

PubMed ID: 33042828

SO-VID: dcb0bbd3-7735-457f-b46a-3f16c9478578

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 06 May 2020

Date accepted : 11 August 2020

Page count

Figures: 10, Tables: 2, Equations: 0, References: 78, Pages: 19, Words: 10733

Funding

Funded by: National Natural Science Foundation of China 10.13039/501100001809

Funded by: Natural Science Foundation of Shanghai 10.13039/100007219

Funded by: Shanghai Municipal Health and Family Planning Commission 10.13039/501100014175

Transcriptome-Based Network Analysis Unveils Eight Immune-Related Genes as Molecular Signatures in the Immunomodulatory Subtype of Triple-Negative Breast Cancer

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Karger: Oncology

Most cited references 48

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

Stromal gene expression predicts clinical outcome in breast cancer.

Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.

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