ABSTRACT
MOTIVATION: Patient and sample diversity is one of the main challenges when dealing with clinical cohorts in biomedical genomics studies. During last decade, several methods have been developed to identify biomarkers assigned to specific individuals or subtypes of samples. However, current methods still fail to discover markers in complex scenarios where heterogeneity or hidden phenotypical factors are present. Here, we propose a method to analyze and understand heterogeneous data avoiding classical normalization approaches of reducing or removing variation. RESULTS: DEcomposing heterogeneous Cohorts using Omic data profiling (DECO) is a method to find significant association among biological features (biomarkers) and samples (individuals) analyzing large-scale omic data. The method identifies and categorizes biomarkers of specific phenotypic conditions based on a recurrent differential analysis integrated with a non-symmetrical correspondence analysis. DECO integrates both omic data dispersion and predictor-response relationship from non-symmetrical correspondence analysis in a unique statistic (called h-statistic), allowing the identification of closely related sample categories within complex cohorts. The performance is demonstrated using simulated data and five experimental transcriptomic datasets, and comparing to seven other methods. We show DECO greatly enhances the discovery and subtle identification of biomarkers, making it especially suited for deep and accurate patient stratification. AVAILABILITY AND IMPLEMENTATION: DECO is freely available as an R package (including a practical vignette) at Bioconductor repository (http://bioconductor.org/packages/deco/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Genomics , Software , Biomarkers , HumansABSTRACT
BACKGROUND: The presence of genetic changes is a hallmark of chronic lymphocytic leukemia (CLL). The most common cytogenetic abnormalities with independent prognostic significance in CLL are 13q14, ATM and TP53 deletions and trisomy 12. However, CLL displays a great genetic and biological heterogeneity. The aim of this study was to analyze the genomic imbalances in CLL cytogenetic subsets from both genomic and gene expression perspectives to identify new recurrent alterations. PATIENTS AND METHODS: The genomic imbalances and expression levels of 67 patients were analyzed. The novel recurrent abnormalities detected with bacterial artificial chromosome array were confirmed by FISH and oligonucleotide microarrays. In all cases, gene expression profiling was assessed. RESULTS: Copy number alterations were identified in 75% of cases. Overall, the results confirmed FISH studies for the regions frequently involved in CLL and also defined a new recurrent gain on chromosome 20q13.12, in 19% (13/67) of the CLL patients. Oligonucleotide expression correlated with the regions of loss or gain of genomic material, suggesting that the changes in gene expression are related to alterations in copy number. CONCLUSION: Our study demonstrates the presence of a recurrent gain in 20q13.12 associated with overexpression of the genes located in this region, in CLL cytogenetic subgroups.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 20 , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Comparative Genomic Hybridization , Gene Dosage , Gene Expression Profiling , Genomic Instability , Humans , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/bloodABSTRACT
Specific microRNA (miRNA) signatures have been associated with different cytogenetic subtypes in acute leukemias. This finding prompted us to investigate potential associations between genetic abnormalities in multiple myeloma (MM) and singular miRNA expression profiles. Moreover, global gene expression profiling was also analyzed to find correlated miRNA gene expression and select miRNA target genes that show such correlation. For this purpose, we analyzed the expression level of 365 miRNAs and the gene expression profiling in 60 newly diagnosed MM patients, selected to represent the most relevant recurrent genetic abnormalities. Supervised analysis showed significantly deregulated miRNAs in the different cytogenetic subtypes as compared with normal PC. It is interesting to note that miR-1 and miR-133a clustered on the same chromosomal loci, were specifically overexpressed in the cases with t(14;16). The analysis of the relationship between miRNA expression and their respective target genes showed a conserved inverse correlation between several miRNAs deregulated in MM cells and CCND2 expression level. These results illustrate, for the first time, that miRNA expression pattern in MM is associated with genetic abnormalities, and that the correlation of the expression profile of miRNA and their putative mRNA targets is useful to find statistically significant protein-coding genes in MM pathogenesis associated with changes in specific miRNAs.
Subject(s)
Gene Expression Profiling , MicroRNAs/analysis , Multiple Myeloma/genetics , Basic-Leucine Zipper Transcription Factors/genetics , CD47 Antigen/genetics , Chromosome Aberrations , Cyclin D2/genetics , Humans , Multiple Myeloma/etiologyABSTRACT
BACKGROUND: Colorectal cancer relapses or metastasizes in 30% of cases. Cytokeratin 20 is present in 95% of colorectal tumors and their metastases and could be used as a marker to detect tumor cells. AIM: To assess the usefulness and prognostic value of peripheral blood and bone marrow cytokeratin 20 determinations in patients with colorectal cancer. MATERIAL AND METHODS: Blood and bone marrow samples were obtained from 56 patients with colorectal cancer aged 26 to 77 years (31 females) before surgical procedure. They were followed for a mean of 22 months (range 2.9 to 72 months) after surgery. Blood and bone marrow from 45 patients without cancer and 35 healthy subjects were used as negative controls. Messenger RNA expression of cytokeratin 20 was studied by real time and nested polymerase chain reaction. RESULTS: Cytokeratin 20 was detected in 6% of controls and 41% of patients. There was no relation between cytokeratin 20 expression and age, gender, overall survival, tumor relapse, progression, localization or stage. CONCLUSIONS: Cytokeratin 20 determination is not useful as a marker of tumor progression or dissemination in patients with colorectal cancer.
Subject(s)
Biomarkers, Tumor/blood , Colorectal Neoplasms , Keratin-20/blood , Neoplasm Recurrence, Local/blood , Adult , Aged , Bone Marrow/chemistry , Bone Marrow/pathology , Case-Control Studies , Colorectal Neoplasms/blood , Colorectal Neoplasms/pathology , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Neoplastic Cells, Circulating , Prognosis , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity , Time FactorsABSTRACT
Background: Colorectal cancer relapses or metastasizes in 30 percent of cases. Cytokeratin 20 is present in 95 percent of colorectal tumors and their metastases and could be used as a marker to detect tumor cells. Aim: To assess the usefulness and prognostic value of peripheral blood and bone marrow cytokeratin 20 determinations in patients with colorectal cancer. Material and methods: Blood and bone marrow samples were obtained from 56 patients with colorectal cancer aged 26 to 77 years (31 females) before surgical procedure. They were followed for a mean of 22 months (range 2.9 to 72 months) after surgery. Blood and bone marrow from 45 patients without cancer and 35 healthy subjects were used as negative controls. Messenger RNA expression of cytokeratin 20 was studied by real time and nested polymerase chain reaction. Results: Cytokeratin 20 was detected in 6 percent of controls and 41 percent of patients. There was no relation between cytokeratin 20 expression and age, gender, overall survival, tumor relapse, progression, localization or stage. Conclusions: Cytokeratin 20 determination is not useful as a marker of tumor progression or dissemination in patients with colorectal cancer.
