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RNA m⁶A Methylation Regulators Subclassify Luminal Subtype in Breast Cancer.

ABSTRACT: RNA N⁶-methyladenosine (m⁶A) methylation is the most prevalent epitranscriptomic modification in mammals, with a complex and fine-tuning regulatory system. Recent studies have illuminated the potential of m⁶A regulators in clinical applications including diagnosis, therapeutics, and prognosis. Based on six datasets of breast cancer in The Cancer Genome Atlas (TCGA) database and two additional proteomic datasets, we provide a comprehensive view of all the known m⁶A regulators in their gene expression, copy number variations (CNVs), DNA methylation status, and protein levels in breast tumors and their association with prognosis. Among four breast cancer subtypes, basal-like subtype exhibits distinct expression and genomic alteration in m⁶A regulators from other subtypes. Accordingly, four representative regulators (IGF2BP2, IGF2BP3, YTHDC2, and RBM15) are identified as basal-like subtype-featured genes. Notably, luminal A/B samples are subclassified into two clusters based on the methylation status of those four genes. In line with its similarity to basal-like subtype, cluster1 shows upregulation in immune-related genes and cell adhesion molecules, as well as an increased number of tumor-infiltrating lymphocytes. Besides, cluster1 has worse disease-free and progression-free survival, especially among patients diagnosed with stage II and luminal B subtype. Together, this study highlights the potential functions of m⁶A regulators in the occurrence and malignancy progression of breast cancer. Given the heterogeneity within luminal subtype and high risk of recurrence and metastasis in a portion of patients, the prognostic stratification of luminal A/B subtypes utilizing basal-featured m⁶A regulators may help to improve the accuracy of diagnosis and therapeutics of breast cancer.

SUBMITTER: Yang L

PROVIDER: S-EPMC7878528 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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RNA m6A Methylation Regulators Subclassify Luminal Subtype in Breast Cancer.

Yang Lin L Wu Shuangling S Ma Chunhui C Song Shuhui S Jin Feng F Niu Yamei Y Tong Wei-Min WM

Frontiers in oncology 20210129

RNA N6-methyladenosine (m6A) methylation is the most prevalent epitranscriptomic modification in mammals, with a complex and fine-tuning regulatory system. Recent studies have illuminated the potential of m6A regulators in clinical applications including diagnosis, therapeutics, and prognosis. Based on six datasets of breast cancer in The Cancer Genome Atlas (TCGA) database and two additional proteomic datasets, we provide a comprehensive view of all the known m< ...[more]

PMID: 33585234

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Project description:PurposeN6-methyladenosine (m6A) is the most prevalent modification in mRNA methylation which has a wide effect on biological functions. This study aims to figure out the efficacy of m6A RNA methylation regulator-based biomarkers with prognostic significance in breast cancer.Patients and methodsThe 23 RNA methylation regulators were firstly analyzed through ONCOMINE, then relative RNA-seq transcriptome and clinical data of 1,096 breast cancer samples and 112 normal tissue samples were acquired from The Cancer Gene Atlas (TCGA) database. The expressive distinction was also showed by the Gene Expression Omnibus (GEO) database. The gene expression data of m6A RNA regulators in human tissues were acquired from the Genotype-Tissue Expression (GTEx) database. The R v3.5.1 and other online tools such as STRING, bc-GeneExminer v4.5, Kaplan-Meier Plotter were applied for bioinformatics analysis.ResultsResults from ONCOMINE, TCGA, and GEO databases showed distinctive expression and clinical correlations of m6A RNA methylation regulators in breast cancer patients. The high expression of YTHDF3, ZC3H13, LRPPRC, and METTL16 indicated poor survival rate in patients with breast cancer, while high expression of RBM15B pointed to a better survival rate. Both univariate and multivariate Cox regression analyses revealed that age and risk scores were related to overall survival (OS). Univariate analysis also delineated that stage, tumor (T) status, lymph node (N) status, and metastasis (M) status were associated with OS. From another perspective, Kaplan-Meier Plotter platform showed that the relatively high expression of YTHDF3 and LRPPRC and the relatively low expression of RBM15B, ZC3H13, and METTL16 in breast cancer patients had worse Relapse-Free Survival (RFS). Breast Cancer Gene-Expression Miner v4.5 showed that LRPPRC level was negatively associated with ER and PR expression, while METTL16, RBM15B, ZC3H13 level was positively linked with ER and PR expression. In HER-2 (+) breast cancer patients, the expression of LRPPRC, METTL16, RBM15B, and ZC3H13 were all lower than the HER-2 (-) group.ConclusionThe significant difference in expression levels and prognostic value of m6A RNA methylation regulators were analyzed and validated in this study. This signature revealed the potential therapeutic value of m6A RNA methylation regulators in breast cancer.

Project description:PurposeNeoadjuvant chemotherapy (NAC) is less effective for luminal breast cancer because luminal breast cancer has a lower rate of pathological complete response (pCR) after NAC than human epidermal growth factor receptor 2 (HER2)-type and triple-negative breast cancer (TNBC). We investigated the efficacy of NAC and the predictive factors of a better response in luminal breast cancer.MethodsBetween 2010 and 2016, we retrieved data of 244 patients with clinically node-positive breast cancer who were treated with NAC followed by surgery from a prospectively collected database. We classified breast cancer into luminal HER2- and non-luminal HER2- breast cancer (luminal HER2+, HER2+, and TNBC types). We analyzed each subtype with respect to surgical outcomes, response to NAC, and determined variables associated with surgical outcomes and response in patients with luminal HER2- breast cancer.ResultsThe total, breast, and axillary pCR rates were significantly lower in 114 patients with luminal HER2- breast cancer than in those with other subtypes (7.9%, 12.3%, and 22.8%, respectively). However, breast-conserving surgery (BCS) conversion and tumor response rates did not significantly differ between patients with luminal HER2- and those with non-luminal HER2- breast cancer (p = 0.836 and p = 0.180, respectively). In the multivariate analysis, high tumor response rate (? 46.4%) was significantly associated with an increased BCS conversion rate. In the subgroup analysis of luminal HER2- breast cancer, the multivariate analysis showed that higher Ki67 expression and axilla pCR and BCS conversion rates were significantly associated with tumor response to NAC.ConclusionDespite the low pCR rate, the tumor response and BCS conversion rates after NAC of luminal HER2- breast cancer were similar to those of other subtypes. NAC has the potential benefit of reducing the size of breast cancer, thereby increasing the BCS conversion rate in luminal HER2- breast cancer.

Project description:The significance of N6-methyladenosine (m6A) RNA modifications in the progression of breast cancer (BC) has been recognised. However, their potential role and mechanism of action in the tumour microenvironment (TME) and immune response has not been demonstrated. Thus, the role of m6A regulators and their downstream target gene components in BC remain to be explored. In this study, we used a series of bioinformatics methods and experiments to conduct exploratory research on the possible role of m6A regulators in BC. First, two regulatory modes of immune activation and inactivation were determined by tumour classification. The TME, immune cell infiltration, and gene set variation analysis results confirmed the reliability of this pattern. The prognostic model of the m6A regulator was established by the least absolute shrinkage and selection operator and univariate and multivariate Cox analyses, with the two regulators most closely related to survival verified by real-time quantitative reverse transcription polymerase chain reaction. Next, the prognostic m6A regulator identified in the model was crossed with the differential copy number of variant genes in invasive BC (IBC), and it was determined that YTHDF1 was a hub regulator. Subsequently, single-cell analysis revealed the expression patterns of m6A regulators in different IBC cell populations and found that YTHDF1 had significantly higher expression in immune-related IBC cells. Therefore, we selected the intersection of the BC differential expression gene set and the differential expression gene set of a cell line with knocked-down YTHDF1 in literature to identify downstream target genes of YTHDF1, in which we found IFI6, EIR, and SPTBN1. A polymerase chain reaction was conducted to verify the results. Finally, we confirmed the role of YTHDF1 as a potential prognostic biomarker through pan-cancer analysis. Furthermore, our findings revealed that YTHDF1 can serve as a new molecular marker for BC immunotherapy.

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RNA m⁶A Methylation Regulators Subclassify Luminal Subtype in Breast Cancer.

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RNA m<sup>6</sup>A Methylation Regulators Subclassify Luminal Subtype in Breast Cancer.

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