Combination of Immune-Related Network and Molecular Typing Analysis Defines a Three-Gene Signature for Predicting Prognosis of Triple-Negative Breast Cancer

Abstract

Recent breakthroughs in immune checkpoint inhibitors (ICIs) have shown promise in triple-negative breast cancer (TNBC). Due to the intrinsic heterogeneity among TNBC, clinical response to ICIs varies greatly among individuals. Thus, discovering rational biomarkers to select susceptible patients for ICIs treatment is warranted. A total of 422 TNBC patients derived from The Cancer Genome Atlas (TCGA) database and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were included in this study. High immunogenic gene modules were identified using weighted gene co-expression network analysis (WGCNA). Immune-related genes (IRGs) expression patterns were generated by consensus clustering. We developed a three-gene signature named immune-related gene panel (IRGP) by Cox regression method. Afterward, the associations of IRGP with survival outcomes, infiltration of immune cells, drug sensitivity, and the response to ICIs therapy were further explored. We found five high immunogenic gene modules. Two distinct IRGclusters and IRG-related genomic clusters were identified. The IRGP was constructed based on TAPBPL, FBP1, and GPRC5C genes. TNBC patients were then subdivided into high- and low-IRGriskscore subgroups. TNBC patients with low IRGriskscore had a better survival outcome, higher infiltration of immune cells, lower TP53 mutation rate, and more benefit from ICIs treatment than high IRGriskscore patients. These findings offer novel insights into molecular subtype of TNBC and provided potential indicators for guiding ICIs treatment.

An engineered niche delineates metastatic potential of breast cancer

“…Diagnostic signatures focus on the extremes (healthy vs. cancer, stage I vs. stage IV) to increase efficacy 12–15 . Prognostic signatures are developed across the disease spectrum and are often as correlated with the stage of disease as they are with gene expression 70–75 . In fact, most breast cancer signatures that claim to have clinical value do not outperform random gene sets and are rather artifacts of increased proliferation in cancer 51,52 .…”

“… 12 , 13 , 14 , 15 Prognostic signatures are developed across the disease spectrum and are often as correlated with the stage of disease as they are with gene expression. 70 , 71 , 72 , 73 , 74 , 75 In fact, most breast cancer signatures that claim to have clinical value do not outperform random gene sets and are rather artifacts of increased proliferation in cancer. 51 , 52 When a selection of human gene signatures was applied to lungs in our system, each failed to match the ability of our signature to delineate metastatic potential against random gene sets (Figure S10 ).…”

“… 51 , 52 When a selection of human gene signatures was applied to lungs in our system, each failed to match the ability of our signature to delineate metastatic potential against random gene sets (Figure S10 ). 70 , 71 , 73 , 74 , 75 , 76 We generated a 9‐gene signature that separates metastatic breast cancer from healthy, noninvasive, and invasive nonmetastatic counterparts (Figure 4 ). Our signature outperforms random gene sets, applies across the entire disease spectrum, is effective in independent mouse studies (Figure 5 ), and each gene is differentially expressed in human lung cancer (Figure 6 ).…”

CDK1-SRC Interaction-Dependent Transcriptional Activation of HSP90AB1 Promotes Antitumor Immunity in Hepatocellular Carcinoma

“…Gene expression and clinicopathological features of patients in the HCC-related TCGA data set were integrated and analyzed for clinical correlation using the R software package "ComplexHeatmap", followed by delineation of a heat map. 25…”

Construction of a prognostic model for triple‐negative breast cancer based on immune‐related genes, and associations between the tumor immune microenvironment and immunological therapy

“…[11][12][13] In addition, immune molecules in the TIME have great potential as prognostic biomarkers. [14][15][16] Zhang et al 17 reported that as well as having prognostic significance, a set of immune-related genes in TNBC had important predictive value with respect to immune invasion and the effects of immunotherapy. However, studies to date have not fully elucidated the role of immune genes in TNBC.…”