title: Integrated analysis of tumor samples sheds light on tumor heterogeneity.
abstract: The heterogeneity of tumor samples is a major challenge in the analysis of high-throughput profiling of tumor biopsies and cell lines. The measured aggregate signals of multigenerational progenies often represent an average of several tumor subclones with varying genomic aberrations and different gene expression levels. The goal of the present study was to integrate copy number analyses from SNP-arrays and karyotyping, gene expression profiling, and pathway analyses to detect heterogeneity, identify driver mutations, and explore possible mechanisms of tumor evolution. We showed the heterogeneity of the studied samples, characterized the global copy number alteration profiles, and identified genes whose copy number status and expression levels were aberrant. In particular, we identified a recurrent association between two BRAF(V600E) and BRAF(V600K) mutations and changes in DKK1 gene expression levels, which might indicate an association between the BRAF and WNT pathways. These findings show that the integrated approaches used in the present study can robustly address the challenging issue of tumor heterogeneity in high-throughput profiling.
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Parisi
authors.forename: Mariann
authors.initials: M
authors.lastname: Micsinai
authors.forename: Francesco
authors.initials: F
authors.lastname: Strino
authors.forename: Stephan
authors.initials: S
authors.lastname: Ariyan
authors.forename: Deepak
authors.initials: D
authors.lastname: Narayan
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.forename: Elaine
authors.initials: E
authors.lastname: Cheng
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Peining
authors.initials: P
authors.lastname: Li
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
mesh_terms: D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics; D056915:DNA Copy Number Variations; D019143:Evolution, Molecular; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007621:Karyotyping; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf