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.
Highlights
Breast cancer is the most ubiquitous cancer in women worldwide
Six types of breast cancer datasets (Table S1) originated from the Cancer Genome Atlas (TCGA) database [36] were downloaded from UCSC xena platform [37]: the gene expression profiles obtained were originally generated from the Illunima HiSeq 2000 platform and transformed into log2(RSEM+1) format; somatic mutation data was compiled in Mutation Annotation Format (MAF); gene-level copy number variations (CNVs) were measured experimentally using the Affymetrix Genome-Wide Human SNP Array 6.0 platform and preprocessed with GISTIC2 method [38]; DNA methylation levels estimated by beta values m6A Regulators in Breast Cancer were measured based on the GPL13534 platform (Illumina Infinium HumanMehytlation450 Bead-Chip array)
According to the DNA methylation status of 11 probes located on basalfeatured m6A regulators, luminal subtypes were subclassified into two clusters with significantly different prognosis
Summary
Breast cancer is the most ubiquitous cancer in women worldwide It is a heterogeneous disease and has been classified into different subtypes according to the gene expression profile. These subtypes are termed as human epidermal growth factor 2 (HER2)-enriched, basal-like, and luminal subtypes [1, 2]. Luminal subtype, accounting for 70% of breast cancers, has positive response to endocrine therapies and the best prognosis [6]. Basal-like cancers were further classified into 6 [12] or 4 [13] subgroups based on their genomic and transcriptomic profiling. Despite the extensive investigations on breast cancer, genetic variance still brings about different responses to standard treatment protocol within the same subtype. It is important to comprehensively understand the regulatory mechanism of gene alterations in pathological status
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