title: Extensive Transcriptomic and Genomic Analysis Provides New Insights about Luminal Breast Cancers.
abstract: Despite constituting approximately two thirds of all breast cancers, the luminal A and B tumours are poorly classified at both clinical and molecular levels. There are contradictory reports on the nature of these subtypes: some define them as intrinsic entities, others as a continuum. With the aim of addressing these uncertainties and identifying molecular signatures of patients at risk, we conducted a comprehensive transcriptomic and genomic analysis of 2,425 luminal breast cancer samples. Our results indicate that the separation between the molecular luminal A and B subtypes-per definition-is not associated with intrinsic characteristics evident in the differentiation between other subtypes. Moreover, t-SNE and MST-kNN clustering approaches based on 10,000 probes, associated with luminal tumour initiation and/or development, revealed the close connections between luminal A and B tumours, with no evidence of a clear boundary between them. Thus, we considered all luminal tumours as a single heterogeneous group for analysis purposes. We first stratified luminal tumours into two distinct groups by their HER2 gene cluster co-expression: HER2-amplified luminal and ordinary-luminal. The former group is associated with distinct transcriptomic and genomic profiles, and poor prognosis; it comprises approximately 8% of all luminal cases. For the remaining ordinary-luminal tumours we further identified the molecular signature correlated with disease outcomes, exhibiting an approximately continuous gene expression range from low to high risk. Thus, we employed four virtual quantiles to segregate the groups of patients. The clinico-pathological characteristics and ratios of genomic aberrations are concordant with the variations in gene expression profiles, hinting at a progressive staging. The comparison with the current separation into luminal A and B subtypes revealed a substantially improved survival stratification. Concluding, we suggest a review of the definition of luminal A and B subtypes. A proposition for a revisited delineation is provided in this study.
authors.affiliation: Information-based Medicine Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.|School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Inna
authors.initials: I
authors.lastname: Tishchenko
authors.affiliation: Information-based Medicine Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.|School of Environmental and Life Science, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Heloisa Helena
authors.initials: HH
authors.lastname: Milioli
authors.affiliation: CReDITSS Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Riveros
authors.affiliation: Information-based Medicine Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.|School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Pablo
authors.initials: P
authors.lastname: Moscato
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D023281:Genomics / Q000379:methods; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D016019:Survival Analysis; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor