High expression of JAM2 indicates better prognosis and immunotherapy response in breast cancer

In our study, multiple databases were used to explore the potential role and underlying mechanism of junctional adhesion molecule B (JAM2) in breast cancer (BRCA). The data of JAM2 were downloaded from The Cancer Cell Line Encyclopedia (CCLE), the Genotype-Tissue Expression (GTEx), The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases. Receiver operating characteristic (ROC) curve analysis was performed to analyze the area under the curve (AUC) of JAM2 expression correlated with normal breast tissue and breast cancer tissue. Gene set enrichment analysis (GSEA) was used to identify the potential biological mechanisms of the JAM2. The expression of JAM2 mRNA was downregulated in most tumors, including BRCA, which may be due to the hypermethylated status. The AUCs, which were 0.929 and 0.887 by the logistic regression and random forest algorithms, indicated that JAM2 mRNA expression has good diagnostic value in BRCA. Univariate and multivariate analyses indicated JAM2 as an independent prognostic factor for the overall survival of BRCA patients in both the TCGA cohort (HR = 0.62, P = 0.034) and METABRIC cohort (HR = 0.77, P = 0.001). GSEA showed that multiple tumor pathways were suppressed in the JAM2 high expression group. The expression of JAM2 was most positively related to the epithelial-mesenchymal transition (EMT) score (r = 0.38; P <0.01) by the reverse-phase protein array (RPPA) analysis. Patients with high JAM2 expression may be more sensitive to immunotherapy. 18 chemotherapy drugs that patients in the JAM2 low expression group were more sensitive to being identified. Our results demonstrated the diagnostic and prognostic value of JAM2. Analysis of the molecular mechanisms indicates the potential role of JAM2 as a tumor suppressor, and high JAM2 expression may predict a better immunotherapy response in BRCA.

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FBLN5 Is an Underlying Common Tumor Suppressor in Breast Cancer and Thyroid Cancer

10.21203/rs.3.rs-1162202/v1 ◽

2022 ◽

Author(s):

Zhao-min XIE ◽

Ying-sheng XIAO ◽

Chun-yan XU ◽

Qin XIE ◽

Wen-de WANG ◽

...

Keyword(s):

Breast Cancer ◽

Thyroid Cancer ◽

Tumor Suppressor ◽

Molecular Mechanisms ◽

Differential Expression Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Prognostic Gene ◽

Hormone Biosynthesis ◽

Key Genes

Abstract Background: Breast cancer (BC) patients have a greater risk of developing thyroid cancer (TC) than the general population. Similarly, TC patients are more likely to develop BC, suggesting an underlying common etiology. In this study, we sought to identify the potential cross-talking pathway and related molecular mechanisms conferring to the sequential development of BC and TC.Methods: We first used Multiple Primary-Standardized Incidence Ratios (MP-SIR) Program of SEER*Stat to calculate SIR to confirm the relationship between BC and TC. Then the RNA-seq was downloaded from The Cancer Genome Atlas (TCGA). And we built a co-expression network via Weighted Gene Co-expression Network Analysis (WGCNA) and obtained the most significant modules. The key genes were obtained by differential gene expression (DGE) analysis and WGCNA analysis. Furthermore, String database and Cytoscape software were used to construct protein-protein interactions (PPI), and defined the maximum Maximal Clique Centrality (MCC) value as hub gene.Then we performed prognosis analysis on the hub genes and obtained the prognostic genes of BC and TC. Finally, gene set enrichment analysis (GSEA) was used to investigate the molecular pathways associated with prognostic gene expressed both in BC and TC.Results: From the SEER database, we found that the risk of developing BC in TC patients was SIR 1.12, 95% CI [1.07, 1.18], and the risk of developing BC in TC patients was SIR 1.29, 95% CI [1.23, 1.26]. Fifty-nine key genes obtained by differential expression analysis and WGCNA identify that PI3K/AKT was the most enriched pathway in BC and TC. In addition, the Recombinant Fibulin 5 (FBLN5) was shown to be of significant prognostic value for both BC and TC and was down-regulated in BC and TC tissues. GSEA demonstrated that FBLN5 enrichment pathways associated with BC and TC mainly included: B cell receptor signaling pathway, steroid hormone biosynthesis, and pathways in cancer.Conclusions: The PI3K/AKT signaling is most co-enriched pathway in BC and TC. FBLN5 is the most relevant prognostic gene and an underlying common tumor suppressor in both BC and TC, with down-stream pathways involving immunity, hormone biosynthesis and carcinogenesis.

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Pannexin1 Is Associated with Enhanced Epithelial-To-Mesenchymal Transition in Human Patient Breast Cancer Tissues and in Breast Cancer Cell Lines

Cancers ◽

10.3390/cancers11121967 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1967 ◽

Cited By ~ 1

Author(s):

Nour Jalaleddine ◽

Layal El-Hajjar ◽

Hassan Dakik ◽

Abdullah Shaito ◽

Jessica Saliba ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Epithelial To Mesenchymal Transition ◽

Cell Communication ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition ◽

Genetic Ablation ◽

Functional Features

Loss of connexin-mediated cell-cell communication is a hallmark of breast cancer progression. Pannexin1 (PANX1), a glycoprotein that shares structural and functional features with connexins and engages in cell communication with its environment, is highly expressed in breast cancer metastatic foci; however, PANX1 contribution to metastatic progression is still obscure. Here we report elevated expression of PANX1 in different breast cancer (BRCA) subtypes using RNA-seq data from The Cancer Genome Atlas (TCGA). The elevated PANX1 expression correlated with poorer outcomes in TCGA BRCA patients. In addition, gene set enrichment analysis (GSEA) revealed that epithelial-to-mesenchymal transition (EMT) pathway genes correlated positively with PANX1 expression. Pharmacological inhibition of PANX1, in MDA-MB-231 and MCF-7 breast cancer cells, or genetic ablation of PANX1, in MDA-MB-231 cells, reverted the EMT phenotype, as evidenced by decreased expression of EMT markers. In addition, PANX1 inhibition or genetic ablation decreased the invasiveness of MDA-MB-231 cells. Our results suggest PANX1 overexpression in breast cancer is associated with a shift towards an EMT phenotype, in silico and in vitro, attributing to it a tumor-promoting effect, with poorer clinical outcomes in breast cancer patients. This association offers a novel target for breast cancer therapy.

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High Expression of miR-34a Associated with Less Aggressive Cancer Biology but Not with Survival in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21093045 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3045 ◽

Cited By ~ 13

Author(s):

Yoshihisa Tokumaru ◽

Eriko Katsuta ◽

Masanori Oshi ◽

Judith C. Sporn ◽

Li Yan ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Biology ◽

Epithelial Mesenchymal Transition ◽

Molecular Taxonomy ◽

The Cancer Genome Atlas ◽

P53 Pathway ◽

Mesenchymal Transition ◽

Gene Sets ◽

Aggressive Cancer

Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) cohorts were used to test our hypothesis that miR-34a high BCs translate to less aggressive cancer biology and better survival in large cohorts. There was no association between miR-34a expression levels and clinicopathological features of BC patients except for HER2 positivity. MiR-34a high expressing tumors were associated with lower Nottingham pathological grades and lower MKI67 expression. In agreement, high miR-34a tumors demonstrated lower GSVA scores of cell cycle and cell proliferation-related gene sets. High miR-34a tumors enriched the p53 pathway and apoptosis gene sets. Unexpectedly, high miR-34a tumors also associated with elevated EMT pathway score and ZEB1 and two expressions. MiR-34a expression did not associate with any distant metastasis. Further, high miR-34a tumors did not associate with better survival compared with miR-34a low tumors. In conclusion, the clinical relevance of miR-34a high expressing tumors was associated with suppressed cell proliferation, enhanced p53 pathway and apoptosis, but enhanced EMT and these findings did not reflect better survival outcomes in large BC patient cohorts.

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MUC1-C integrates activation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002115 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002115

Author(s):

Nami Yamashita ◽

Mark Long ◽

Atsushi Fushimi ◽

Masaaki Yamamoto ◽

Tsuyoshi Hata ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

T Cells ◽

Cd8 T Cells ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Molecular Taxonomy ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Ifn Γ

BackgroundImmune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness of TNBCs to ICIs is a lack of functional tumor-infiltrating lymphocytes (TILs) in ‘non-inflamed’ or ‘cold’ tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C in a mouse transgenic TNBC tumor model increases cytotoxic tumor-infiltrating CD8+ T cells (CTLs), supporting a role for MUC1-C in immune evasion. The basis for these findings and whether they extend to human TNBCs are not known.MethodsHuman TNBC cells silenced for MUC1-C using short hairpin RNAs (shRNAs) were analyzed for the effects of MUC1-C on global transcriptional profiles. Differential expression and rank order analysis was used for gene set enrichment analysis (GSEA). Gene expression was confirmed by quantitative reverse-transcription PCR and immunoblotting. The The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets were analyzed for effects of MUC1 on GSEA, cell-type enrichment, and tumor immune dysfunction and exclusion. Single-cell scRNA-seq datasets of TNBC samples were analyzed for normalized expression associations between MUC1 and selected genes within tumor cells.ResultsOur results demonstrate that MUC1-C is a master regulator of the TNBC transcriptome and that MUC1-C-induced gene expression is driven by STAT1 and IRF1. We found that MUC1-C activates the inflammatory interferon (IFN)-γ-driven JAK1→STAT1→IRF1 pathway and induces the IDO1 and COX2/PTGS2 effectors, which play key roles in immunosuppression. Involvement of MUC1-C in activating the immunosuppressive IFN-γ pathway was extended by analysis of human bulk and scRNA-seq datasets. We further demonstrate that MUC1 associates with the depletion and dysfunction of CD8+ T cells in the TNBC TIME.ConclusionsThese findings demonstrate that MUC1-C integrates activation of the immunosuppressive IFN-γ pathway with depletion of TILs in the TNBC TIME and provide support for MUC1-C as a potential target for improving TNBC treatment alone and in combination with ICIs. Of translational significance, MUC1-C is a druggable target with chimeric antigen receptor (CAR) T cells, antibody-drug conjugates (ADCs) and a functional inhibitor that are under clinical development.

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NKCC1 involvement in the epithelial-to-mesenchymal transition is a prognostic biomarker in gliomas

PeerJ ◽

10.7717/peerj.8787 ◽

2020 ◽

Vol 8 ◽

pp. e8787

Author(s):

Huaiyu Sun ◽

Shengrong Long ◽

Bingbing Wu ◽

Jia Liu ◽

Guangyu Li

Keyword(s):

Epithelial Mesenchymal Transition ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

High Expression ◽

Migration And Invasion ◽

Intracranial Tumors ◽

Transwell Assay ◽

Western Blots ◽

Mesenchymal Transition ◽

Expression Levels

Background Gliomas are the most prevalent type of intracranial tumors. NKCC1 is an important regulator in tumor cell volume. We noticed that abnormally high NKCC1 expression resulted in changes in the shape and adhesion of glioma cells. However, little is known about the role of NKCC1 in the epithelial-mesenchymal transition (EMT) of gliomas. This study aims to clarify the biological function of NKCC1 in glioblastoma multiforme (GBM) progression. Methods Using data from The Cancer Genome Atlas (TCGA), we performed a Kaplan–Meier analysis on NKCC1 expression levels to estimate the rate of survival of mesenchymal GBM patients. The correlation between NKCC1 and EMT-related proteins was analyzed from the Gene Expression Profiling Interactive Analysis (GEPIA) server. We conducted Gene Set Enrichment Analysis (GSEA) to verify molecular signatures and pathways. We then studied the expression of NKCC1 in grade I–IV glioma tissue samples collected from patients using immunohistochemistry (IHC). Finally, we evaluated the effects of NKCC1 migration and invasion on the cellular behaviors of U251 cells using the transwell assay and western blots. Results High NKCC1 expression was associated with poor prognoses in mesenchymal GBM. Our results suggest a correlation between NKCC1 and EMT-protein markers: CDH2 and VIM. GSEA showed that gliomas, TGF-beta signaling and EMT were enriched in the NKCC1 high expression phenotype. Higher expression levels of NKCC1 in gliomas correlate with higher glioma grades. Transwell assay and western blot results demonstrated that the knockdown of NKCC1 led to a reduction in migration and invasion, while also inhibiting MMP-2 and MMP-9 expression in U251. Conclusion These results suggest that high expression of NKCC1 regulates EMT in gliomas, providing a new therapeutic strategy for addressing the spread of gliomas by inhibiting the spread of intracranial tumors.

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APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1424869112 ◽

2015 ◽

Vol 112 (9) ◽

pp. 2841-2846 ◽

Cited By ~ 83

Author(s):

David W. Cescon ◽

Benjamin Haibe-Kains ◽

Tak W. Mak

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Immune Activation ◽

Cellular Proliferation ◽

Molecular Taxonomy ◽

Adverse Outcomes ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Breast Cancers ◽

Deletion Polymorphism

Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3Bdel), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3Bdel individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3Bdel breast cancers, which seems to be related to hypermutation arising in A3Bdel carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3Bdel require additional study, these findings nominate the A3Bdel polymorphism as a potential predictor for cancer immunotherapy.

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Up-regulation of L Antigen Family Member 3 Associates With Aggressive Progression of Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.553628 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xubin Dong ◽

Shihui Lv ◽

Dianna Gu ◽

Xiaohua Zhang ◽

Zhiqiang Ye

Keyword(s):

Breast Cancer ◽

Family Member ◽

Cell Lines ◽

Molecular Taxonomy ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Disease Stage ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Tnbc Cell

The role of L Antigen Family Member 3 (LAGE3) in breast cancer (BC) has not been sufficiently studied. In this study, we explored the clinical value and biological functions of LAGE3 in BC. Comprehensive analysis of LAGE3 was carried out on The Cancer Genome Atlas, Molecular Taxonomy of Breast Cancer International Consortium and Gene Expression Omnibus datasets. Results showed that LAGE3 expression was higher in BC tissues than in normal breast tissues of public datasets and our local cohort. Moreover, its expression was higher in BC patients with larger tumor size, significant lymph node metastasis, higher tumor grade, and more advanced disease stage. High expression of LAGE3 was correlated with poor prognosis, and LAGE3 could independently predict survival of BC patients. Functional enrichment analysis revealed a correlation between LAGE3 expression and biochemical metabolism and immune-related terms and cancer-related pathways. Analysis of tumor microenvironment indicated that LAGE3 expression was associated with the immune cell infiltration and anti-cancer immunity cycle. LAGE3 expression was higher in triple-negative breast cancer (TNBC) compared to hormone receptor-positive BC, but not HER2-positive subtype. Suppression of LAGE3 expression inhibited the proliferation and induced apoptosis of TNBC cell lines. Besides, the down-regulation of LAGE3 attenuated the migration and invasion but reduced the expression level of epithelial-mesenchymal-transition related proteins in TNBC cell lines. In conclusion, this study demonstrated for the first time that LAGE3 promotes the progression of BC. Therefore, it may be a potential diagnostic and prognostic biomarker, as well as a treatment target for BC.

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CIBERSORT analysis of TCGA and METABRIC identifies subgroups with better outcomes in triple negative breast cancer

Scientific Reports ◽

10.1038/s41598-021-83913-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kelly E. Craven ◽

Yesim Gökmen-Polar ◽

Sunil S. Badve

Keyword(s):

Breast Cancer ◽

T Cells ◽

Triple Negative Breast Cancer ◽

Molecular Mechanisms ◽

Triple Negative ◽

Immune Cell ◽

Molecular Taxonomy ◽

The Cancer Genome Atlas ◽

Activated T Cells ◽

Cancer Immunoediting

AbstractStudies have shown that the presence of tumor infiltrating lymphocytes (TILs) in Triple Negative Breast Cancer (TNBC) is associated with better prognosis. However, the molecular mechanisms underlying these immune cell differences are not well delineated. In this study, analysis of hematoxylin and eosin images from The Cancer Genome Atlas (TCGA) breast cancer cohort failed to show a prognostic benefit of TILs in TNBC, whereas CIBERSORT analysis, which quantifies the proportion of each immune cell type, demonstrated improved overall survival in TCGA TNBC samples with increased CD8 T cells or CD8 plus CD4 memory activated T cells and in Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) TNBC samples with increased gamma delta T cells. Twenty-five genes showed mutational frequency differences between the TCGA high and low T cell groups, and many play important roles in inflammation or immune evasion (ATG2B, HIST1H2BC, PKD1, PIKFYVE, TLR3, NOTCH3, GOLGB1, CREBBP). Identification of these mutations suggests novel mechanisms by which the cancer cells attract immune cells and by which they evade or dampen the immune system during the cancer immunoediting process. This study suggests that integration of mutations with CIBERSORT analysis could provide better prediction of outcomes and novel therapeutic targets in TNBC cases.

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High Expression of FGD3, a Putative Regulator of Cell Morphology and Motility, Is Prognostic of Favorable Outcome in Multiple Cancers

JCO Precision Oncology ◽

10.1200/po.17.00009 ◽

2017 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Scooter Willis ◽

Yuliang Sun ◽

Mark Abramovitz ◽

Teng Fei ◽

Brandon Young ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Mechanisms ◽

Meta Analysis ◽

Single Gene ◽

Molecular Taxonomy ◽

Prognostic Significance ◽

Favorable Outcome ◽

High Expression ◽

P Value ◽

Er Positive

Purpose Identification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers. Methods Exploratory analysis of 20,464 single-gene messenger RNAs (mRNAs) in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) discovery cohort indicates that low expression of FGD3 mRNA is prognostic for poor outcome. Prognostic significance of faciogenital dysplasia 3 (FGD3), SUSD3, and other single-gene proliferation markers was evaluated in breast cancer and The Cancer Genome Atlas (TCGA) cohorts. Results A meta-analysis of Cox regression of FGD3 mRNA as a continuous variable for overall survival of estrogen receptor (ER)–positive samples in METABRIC discovery, METABRIC validation, TCGA breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69 (95% CI, 0.63 to 0.75), indicating better outcome with high expression. In the ER-negative samples, the combined meta-analysis HR was 0.72 (95% CI, 0.63 to 0.82), suggesting that FGD3 is prognostic regardless of ER status. The potential of FGD3 as a biomarker for freedom from recurrence was evaluated in the Breast International Group 1-98 (BIG 1-98; Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer) study (HR, 0.85; 95% CI, 0.76 to 0.93) for breast cancer–free interval. In the Hungarian Academy of Science (HAS) breast cancer cohort, splitting on the median had an HR of 0.49 (95% CI, 0.42 to 0.58) for recurrence-free survival. A comparison of the Stouffer P value in five ER-positive cohorts showed that FGD3 ( P = 3.8E-14) outperformed MKI67 ( P = 1.06E-8) and AURKA ( P = 2.61E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 ( P = 3.88E-5) outperformed MKI67 ( P = .477) and AURKA ( P = .820). Conclusion FGD3 was previously shown to inhibit cell migration. FGD3 mRNA is regulated by ESR1 and is associated with favorable outcome in six distinct breast cancer cohorts and four TCGA cancer cohorts. This suggests that FGD3 is an important clinical biomarker.

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Analysis of m6A-Related Signatures in the Tumor Immune Microenvironment and Identification of Clinical Prognostic Regulators in Adrenocortical Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.637933 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yi Jin ◽

Zhanwang Wang ◽

Dong He ◽

Yuxing Zhu ◽

Xueying Hu ◽

...

Keyword(s):

Adrenocortical Carcinoma ◽

Molecular Mechanisms ◽

Potential Role ◽

Cox Regression ◽

Risk Group ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high rate of mortality and recurrence. N6-methyladenosine methylation (m6A) is the most common modification to affect cancer development, but to date, the potential role of m6A regulators in ACC prognosis is not well understood. In this study, we systematically analyzed 21 m6A regulators in ACC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. We identified three m6A modification patterns with different clinical outcomes and discovered a significant relationship between diverse m6A clusters and the tumor immune microenvironment (immune cell types and ESTIMATE algorithm). Additionally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that the m6A clusters were strongly associated with immune infiltration in the ACC. Next, to further explore the m6A prognostic signatures in ACC, we implemented Lasso (Least Absolute Shrinkage and Selection Operator) Cox regression to establish an eight-m6A-regulator prognostic model in the TCGA dataset, and the results showed that the model-based high-risk group was closely correlated with poor overall survival (OS) compared with the low-risk group. Subsequently, we validated the key modifications in the GEO datasets and found that high HNRNPA2B1 expression resulted in poor OS and event-free survival (EFS) in ACC. Moreover, to further decipher the molecular mechanisms, we constructed a competing endogenous RNA (ceRNA) network based on HNRNPA2B1, which consists of 12 long noncoding RNAs (lncRNAs) and 1 microRNA (miRNA). In conclusion, our findings indicate the potential role of m6A modification in ACC, providing novel insights into ACC prognosis and guiding effective immunotherapy.

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