Contributions
Abstract: PB2148
Type: Publication Only
Background
Multiple myeloma (MM) is characterized by pronounced genomic heterogeneity due to a complex combination of numerical and structural changes in chromosomes that play a key role in oncogenesis. In studies of malignant plasma cells using fluorescence in situ hybridization (FISH) and flow cytometry, karyotype abnormalities are detected in more than 90% of MM patients, frequency and severity of which correlates with the stage of the disease, the prognosis and response to therapy. Genetic mutations also play an important role in the pathogenesis of MM.
Aims
To study the relationship between the mutational status of a number of immune response genes and cytogenetic aberrations in MM patients.
Methods
39 patients with MM aged from 33 to 75 years (median - 57 years) in the onset of the disease were evaluated, 14 men (35.9%), 25 women (64.1%). FISH-method of the bone marrow cells interphase nuclei is performed with Kreatech FISH Probe DNA probes. Genotyping of 20 polymorphic locus of the 13 immune response genes of genomic DNA from peripheral blood leukocytes was carried out by polymerase chain reaction with allele-specific primers (single nucleotide polymorphism - SNP).
Results
The patients were divided into two groups. The first group included 24 (61.5%) patients with MM who had no chromosomal abnormalities in the FISH analysis. The second group consisted of 15 (38.5%) patients with different cytogenetic aberrations in the form of monosomy 13, trisomy 4, 11, 13, 14, 17, 20 chromosomes, amplification of 1q21, del DLEU1 (13q14), del IGH (14q32), del TP53 (q13;q32), t(4;14) (p16;q32) and t(14;16) (q32;q23). When comparing the obtained cytogenetic data with the results of SNP genotyping, it was found that the presence of the mutant allele G in the haplotypes (CG+GG) of the interleukin-6 (IL6) gene at the locus-174 by four times (p=0.04), and the presence of the «wild» type G allele in the homozygous state at the mutation point -915 of the transforming growth factor-β (TGF-β) gene, it reduces the detection rate of cytogenetic aberrations in MM by 33 times (p=0.02). The conducted studies confirmed the generally recognized molecular heterogeneity of MM. The genes IL6 and TGF-β are localized in 7 and 19 chromosomes, respectively. Aberrations in these chromosomes are detected in MM with hyperdiploid karyotype, which has a favorable prognosis. Proteins synthesized by these genes play a particular role in MM. IL-6 is one of the growth and survival factors of malignant plasma cells, inhibiting their apoptosis. In addition, IL-6 is able to interact with other factors involved in the pathogenesis of MM, such as adhesion molecules, tumor suppressor genes and oncogenes. The transforming growth factor-β (TGF-β) refers to a transcription factors family that are involved in cell proliferation, differentiation, and apoptosis. In MM, TGF-β can act as a suppressor and a tumor growth promoter.
Conclusion
Cytogenetic studies in MM are used to predict the course of the disease. The detection of genetic characteristics of malignant disorders creates prerequisites for the development of targeted therapy. Given the important role of IL-6 and TGF-β in this disease, it is advisable to use the mutation status of the IL6 and TGF-β genes to predict the course of MM and personalized treatment. Thus, the complex determination of chromosomal changes, the spectrum of mutations and the evolution of subclones in MM requires further research in this direction.
Session topic: 13. Myeloma and other monoclonal gammopathies – Biology & Translational Research
Keyword(s): Cytogenetic abnormalities, Gene polymorphism, Multiple Myeloma, prognosis
Abstract: PB2148
Type: Publication Only
Background
Multiple myeloma (MM) is characterized by pronounced genomic heterogeneity due to a complex combination of numerical and structural changes in chromosomes that play a key role in oncogenesis. In studies of malignant plasma cells using fluorescence in situ hybridization (FISH) and flow cytometry, karyotype abnormalities are detected in more than 90% of MM patients, frequency and severity of which correlates with the stage of the disease, the prognosis and response to therapy. Genetic mutations also play an important role in the pathogenesis of MM.
Aims
To study the relationship between the mutational status of a number of immune response genes and cytogenetic aberrations in MM patients.
Methods
39 patients with MM aged from 33 to 75 years (median - 57 years) in the onset of the disease were evaluated, 14 men (35.9%), 25 women (64.1%). FISH-method of the bone marrow cells interphase nuclei is performed with Kreatech FISH Probe DNA probes. Genotyping of 20 polymorphic locus of the 13 immune response genes of genomic DNA from peripheral blood leukocytes was carried out by polymerase chain reaction with allele-specific primers (single nucleotide polymorphism - SNP).
Results
The patients were divided into two groups. The first group included 24 (61.5%) patients with MM who had no chromosomal abnormalities in the FISH analysis. The second group consisted of 15 (38.5%) patients with different cytogenetic aberrations in the form of monosomy 13, trisomy 4, 11, 13, 14, 17, 20 chromosomes, amplification of 1q21, del DLEU1 (13q14), del IGH (14q32), del TP53 (q13;q32), t(4;14) (p16;q32) and t(14;16) (q32;q23). When comparing the obtained cytogenetic data with the results of SNP genotyping, it was found that the presence of the mutant allele G in the haplotypes (CG+GG) of the interleukin-6 (IL6) gene at the locus-174 by four times (p=0.04), and the presence of the «wild» type G allele in the homozygous state at the mutation point -915 of the transforming growth factor-β (TGF-β) gene, it reduces the detection rate of cytogenetic aberrations in MM by 33 times (p=0.02). The conducted studies confirmed the generally recognized molecular heterogeneity of MM. The genes IL6 and TGF-β are localized in 7 and 19 chromosomes, respectively. Aberrations in these chromosomes are detected in MM with hyperdiploid karyotype, which has a favorable prognosis. Proteins synthesized by these genes play a particular role in MM. IL-6 is one of the growth and survival factors of malignant plasma cells, inhibiting their apoptosis. In addition, IL-6 is able to interact with other factors involved in the pathogenesis of MM, such as adhesion molecules, tumor suppressor genes and oncogenes. The transforming growth factor-β (TGF-β) refers to a transcription factors family that are involved in cell proliferation, differentiation, and apoptosis. In MM, TGF-β can act as a suppressor and a tumor growth promoter.
Conclusion
Cytogenetic studies in MM are used to predict the course of the disease. The detection of genetic characteristics of malignant disorders creates prerequisites for the development of targeted therapy. Given the important role of IL-6 and TGF-β in this disease, it is advisable to use the mutation status of the IL6 and TGF-β genes to predict the course of MM and personalized treatment. Thus, the complex determination of chromosomal changes, the spectrum of mutations and the evolution of subclones in MM requires further research in this direction.
Session topic: 13. Myeloma and other monoclonal gammopathies – Biology & Translational Research
Keyword(s): Cytogenetic abnormalities, Gene polymorphism, Multiple Myeloma, prognosis