title: Clustering of Expression Data in Chronic Lymphocytic Leukemia Reveals New Molecular Subdivisions.
abstract: Although the identification of inherent structure in chronic lymphocytic leukemia (CLL) gene expression data using class discovery approaches has not been extensively explored, the natural clustering of patient samples can reveal molecular subdivisions that have biological and clinical implications. To explore this, we preprocessed raw gene expression data from two published studies, combined the data to increase the statistical power, and performed unsupervised clustering analysis. The clustering analysis was replicated in 4 independent cohorts. To assess the biological significance of the resultant clusters, we evaluated their prognostic value and identified cluster-specific markers. The clustering analysis revealed two robust and stable subgroups of CLL patients in the pooled dataset. The subgroups were confirmed by different methodological approaches (non-negative matrix factorization NMF clustering and hierarchical clustering) and validated in different cohorts. The subdivisions were related with differential clinical outcomes and markers associated with the microenvironment and the MAPK and BCR signaling pathways. It was also found that the cluster markers were independent of the immunoglobulin heavy chain variable (IGVH) genes mutational status. These findings suggest that the microenvironment can influence the clinical behavior of CLL, contributing to prognostic differences. The workflow followed here provides a new perspective on differences in prognosis and highlights new markers that should be explored in this context.
authors.affiliation: Facultad de Ciencias, Departamento de Ciencias Biológicas, Universidad de los Andes, Bogotá D.C., Colombia.
authors.forename: Sally
authors.initials: S
authors.lastname: Yepes
authors.affiliation: Facultad de Ciencias, Departamento de Ciencias Biológicas, Universidad de los Andes, Bogotá D.C., Colombia.
authors.forename: Maria Mercedes
authors.initials: MM
authors.lastname: Torres
authors.affiliation: Facultad de Medicina, Universidad de los Andes, Departamento de Patología, Hospital Universitario, Fundación Santa Fe de Bogotá, Bogotá D.C., Colombia.
authors.forename: Rafael E
authors.initials: RE
authors.lastname: Andrade
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D016000:Cluster Analysis; D015331:Cohort Studies; D015973:Gene Expression Regulation, Leukemic; D052138:Genes, Neoplasm; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification* / Q000235:genetics*; D016019:Survival Analysis; D014158:Transcription, Genetic; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region