DUGiDocsPolimorfismos de los genes moduladores de la respuesta inmune como predictores de recaída en los pacientes con mieloma múltiple
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Multiple myeloma (MM) remains an incurable disease despite the incorporation of new therapies. The natural history of disease is of the relapse following treatments due to the re-emergence of the tumour from residual disease that cannot be eradicated, significantly reducing the life expectancy of these patients. Cellular and humoral immune impairment is a feature of MM evolution, allowing neoplastic plasma cells to escape from natural immune surveillance.
The immune system is a powerful defense mechanism against cancer; it can recognize and attack premalignant cells before tumours develop (immune surveillance). The adaptive immune response is regulated by multiple co-stimulatory and co-inhibitory signaling pathways. The balance between co-stimulatory and co-inhibitory signals, immune checkpoints, determines the functionally of T cells during immunity and tolerance.
However, few data are available concerning the role of immune surveillance in preventing o controlling myeloma relapse in patients with MM. In this direction, we explored the polymorphisms (SNPs) of genes that encode co-stimulatory/inhibitory molecules of the immune response and evaluated their impact on overall survival (OS) and progression free survival (PFS).
In the first study, we retrospectively analysed polymorphisms of CTLA4 (rs231775 and rs733618), BTLA (rs9288953), CD28 (rs3116496), PD-1 (rs36084323 and rs11568821) y LAG-3 (rs870849) genes in 239 patients with newly diagnosed MM. Patients with a CTLA4 rs231775 AA/AG genotype showed a median PFS significantly lower than those with GG genotype, this negative effect was especially evident in patients who have received an autologous transplant. Our results suggest that the CTLA4 genotype may identify patients with earlier progression of MM. This polymorphism could potentially be used as a prognostic biomarker.
In the second study, we focused on the analysis of genetic variants of CD200. Several studies have shown that overexpression of CD200 in MM cells is associated with worse survival, however there are not data concerning the correlation between genetic variants of CD200 and survival in patients with MM. We retrospectively analysed the clinical impact of the of CD200 genotype (rs1131199 and rs2272022) in 291 patients with newly diagnosed MM. We did not find any significant difference of expression of CD200 in the MM cells between the different genotypes for each polymorphism studied. Patients with a CD200 rs1131199 GG genotype showed a median OS significantly lower than those with CC+CG genotype. This effect was specially detected in patients not receiving an auto-TPH. In these patients, the rs1131199 GG genotype negatively influenced in the mortality not related with the progression of MM mainly due to infections events. This polymorphism could potentially identify patients at high risk of mortality associated with infections
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