RNA m(6)A Methylation Regulators Subclassify Luminal Subtype in Breast Cancer

RNA N(6)-methyladenosine (m(6)A) methylation is the most prevalent epitranscriptomic modification in mammals, with a complex and fine-tuning regulatory system. Recent studies have illuminated the potential of m(6)A 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(6)A 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 m(6)A 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 m(6)A 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 m(6)A regulators may help to improve the accuracy of diagnosis and therapeutics of breast cancer.