Identification and Validation of m6A-Related lncRNA Signature as Potential Predictive Biomarkers in Breast Cancer

Abstract

The metastasis and poor prognosis are still regarded as the main challenge in the clinical treatment of breast cancer (BC). Both N6-methyladenosine (m6A) modification and lncRNAs play vital roles in the carcinogenesis and evolvement of BC. Considering the unknown association of m6A and lncRNAs in BC, this study therefore aims to discern m6A-related lncRNAs and explore their prognostic value in BC patients. Firstly, a total of 6 m6A-related lncRNAs were screened from TCGA database and accordingly constructed a prognostic-predicting model. The BC patients were then divided into high-risk and low-risk groups dependent on the median cutoff of risk score based on this model. Then, the predictive value of this model was validated by the analyses of cox regression, Kaplan-Meier curve, ROC curve, and the biological differences in the two groups were validated by PCA, KEGG, GSEA, immune status as well as in vitro assay. Finally, we accordingly constructed a risk prognostic model based on the 6 identified m6A-related lncRNAs, including Z68871.1, AL122010.1, OTUD6B-AS1, AC090948.3, AL138724.1, EGOT. Interestingly, the BC patients were divided into the low-risk and high-risk groups with different prognoses according to the risk score. Notably, the risk score of the model was an excellent independent prognostic factor. In the clinical sample validation, m6A regulatory proteins were differentially expressed in patients with different risks, and the markers of tumor-associated macrophages and m6A regulators were co-localized in high-risk BC tissues. This well-validated risk assessment tool based on the repertoire of these m6A-related genes and m6A-related lncRNAs, is of highly prognosis-predicting ability, and might provide a supplemental screening method for precisely judging BC prognosis.

Definition of a Novel Cuproptosis-Relevant lncRNA Signature for Uncovering Distinct Survival, Genomic Alterations, and Treatment Implications in Lung Adenocarcinoma

“…AL035587.1 is potentially modulated by m6A, m5C, and m1A RNA modifications in head and neck squamous cell carcinoma [ 39 ]. AL122010.1 is an immune- [ 40 ], stemness- [ 41 ], autophagy- [ 42 ], and m6A-relevant lncRNA [ 43 ] that enables to predict survival outcomes breast cancer. AC099850.3 is upregulated in LUAD and correlated to advanced stage, undesirable prognostic outcomes together with immune infiltration [ 44 ].…”

The emerging roles and mechanism of m6a in breast cancer progression

“…Moreover, the established models based on both m6A and other factors are attracting more and more attention. For instance, we previously constructed a risk signature based on 6 screened m6A-related lncRNAs, including Z68871.1, AL122010.1, OTUD6B-AS1, AC090948.3, AL138724.1, EGOT ( Lv et al, 2021 ). This model could identify the prognosis and immune state in BC.…”

The Key Role of RNA Modification in Breast Cancer

“…Ten m 6 A-modified lncRNAs-LINC00571, ANKRD10- IT1, LINC00593, miR-205HG, CIRBP- AS1, BLACAT1, SUCLG2- AS1, SAMD12- AS1, BVES-AS1, a18SrRNA nd HOXB-AS1 were used to construct a prognostic score model, and may be potential predictors of survival in patients with TNBC ( Wu et al, 2021 ). A prognostic risk model comprised of six m 6 A-regulated lncRNAs-Z68871.1, AL122010.1, AL138724.1,OTUD6B-AS1, AC090948.3 and eosinophil granule ontogeny transcript (EGOT) for high-risk patients with tumor-infiltrating immune cells, indicated that m 6 A-regulated lncRNAs may modulate the immune microenvironment in breast cancer ( Lv et al, 2021b ). High expression of the m 6 A regulator hnRNPC, and low expression of hsa-miR-944, are associated with advanced stage breast cancer and poor prognosis ( Lv et al, 2021a ).…”

“…These studies indicated that METTL3, METTL14, WTAP, FTO, ALKBH5, and other N6-methyladenosine-related lncRNAs were associated with progression of breast cancer, and may be prognostic indicators. Changes in expression and activity of m 6 A modulators may promote breast cancer progression ( Chen and Du, 2019 ; Lv et al, 2021b ; Zhang et al, 2021 ) ( Table 1 ). Few studies have mentioned m 5 C modifications and breast cancer, and most have focused on NSUN2.…”