Abstract
Triple-negative breast cancers (TNBC) lack estrogen and progesterone receptors and HER2 amplification, and are resistant to therapies that target these receptors. Tumors from TNBC patients are heterogeneous based on genetic variations, tumor histology, and clinical outcomes. We used high throughput genomic data for TNBC patients (n = 137) from TCGA to characterize inter-tumor heterogeneity. Similarity network fusion (SNF)-based integrative clustering combining gene expression, miRNA expression, and copy number variation, revealed three distinct patient clusters. Integrating multiple types of data resulted in more distinct clusters than analyses with a single datatype. Whereas most TNBCs are classified by PAM50 as basal subtype, one of the clusters was enriched in the non-basal PAM50 subtypes, exhibited more aggressive clinical features and had a distinctive signature of oncogenic mutations, miRNAs and expressed genes. Our analyses provide a new classification scheme for TNBC based on multiple omics datasets and provide insight into molecular features that underlie TNBC heterogeneity.
Highlights
Breast cancer is heterogeneous in nature, as breast tumors can arise from different cells of origin, and can present with distinct mutational signatures, biological and clinical phenotypes, and survival outcomes[1,2,3]
Out of 1098 breast invasive carcinomas in the The Cancer Genome Atlas (TCGA) database, 180 have been classified as triple-negative by Lehmann et al based on low expression levels of ER, PR, and HER221
Gene expression-based PAM50 intrinsic classification of breast cancer[5] includes basal-like and luminal A/B subtypes, and two models have been proposed to explain the cellular origin of these tumor subtypes[50]
Summary
Breast cancer is heterogeneous in nature, as breast tumors can arise from different cells of origin, and can present with distinct mutational signatures, biological and clinical phenotypes, and survival outcomes[1,2,3]. New breast tumors can be assigned to one of these classes based on the expression pattern of 50 informative genes termed PAM50 (ref.[5]) These breast cancer subtypes have different molecular characteristics and clinical outcomes[6]. Basal-like tumors highly express cytokeratins that are usually present in the basal cells of normal breast, and cell proliferation genes. Another intrinsic subtype called claudin-low was subsequently identified[7]. The survival outcome of patients with the BL1 subtype was found to be significantly better than the survival for patients from the other three subtypes combined
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