Integrative analysis of DNA copy number, DNA methylation and gene expression in multiple myeloma reveals alterations related to relapse.
Multiple myeloma (MM) remains incurable despite the introduction of novel agents, and a relapsing course is observed in most patients. Although the development of genomic technologies has greatly improved our understanding of MM pathogenesis, the mechanisms underlying relapse have been less thoroughly investigated. In this study, an integrative analysis of DNA copy number, DNA methylation and gene expression was conducted in matched diagnosis and relapse samples from MM patients. Overall, the acquisition of abnormalities at relapse was much more frequent than the loss of lesions present at diagnosis, and DNA losses were significantly more frequent in relapse than in diagnosis samples. Interestingly, copy number abnormalities involving more than 100 Mb of DNA at relapse significantly affect the gene expression of these samples, provoking a particular deregulation of the IL-8 pathway. On the other hand, no significant modifications of gene expression were observed in those samples with less than 100 Mb affected by chromosomal changes. Although several statistical approaches were used to identify genes whose abnormal expression at relapse was regulated by methylation, only two genes that were significantly deregulated in relapse samples (SORL1 and GLT1D1) showed a negative correlation between methylation and expression. Further analysis revealed that DNA methylation was involved in regulating SORL1 expression in MM. Finally, relevant changes in gene expression observed in relapse samples, such us downregulation of CD27 and P2RY8, were most likely not preceded by alterations in the corresponding DNA. Taken together, these results suggest that the genomic heterogeneity described at diagnosis remains at relapse.
Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.|Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Patryk
P
Krzeminski
Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.
Luis A
LA
Corchete
Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Juan L
JL
García
Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.|Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Lucía
L
López-Corral
Unidad de Genómica y Proteómica, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Encarna
E
Fermiñán
Unidad de Genómica y Proteómica, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Eva M
EM
García
Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.
Ana A
AA
Martín
Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.|Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Jesús M
JM
Hernández-Rivas
Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.|Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Ramón
R
García-Sanz
Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas (CIMA), Pamplona, Spain.
Jesús F
JF
San Miguel
Departamento de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.|Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.
Norma C
NC
Gutiérrez
D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D030541:Databases, Genetic; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D016695:Glycosyltransferases / Q000235:genetics; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D058470:Receptors, Purinergic P2Y / Q000235:genetics; D012008:Recurrence; D012307:Risk Factors; D018511:Systems Integration; D013997:Time Factors; D016896:Treatment Outcome; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics
D014408:Biomarkers, Tumor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C578279:P2RY8 protein, human; D058470:Receptors, Purinergic P2Y; C102582:SORL1 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016695:Glycosyltransferases
DNA methylation; SNP; SORL1; microarrays; multiple myeloma