Гены метилирования ДНК при множественной миеломе: что мы уже знаем и как это можно использовать?

BACKGROUND. The last 20 years have seen a substantial evolution of diagnostic methods and innovation approaches to analyzing genome and transcriptome of tumor cells. Underresearched, however, is the value of aberrant patterns of DNA methylation or methylation-modifying genes in the pathogenesis of multiple myeloma (MM) development and in the mechanisms of tumor progression. Mutation detection by next-generation sequencing (NGS) in disease relapse- and/or drug resistance-associated genes provides the basis for identifying novel targets for drug therapy. AIM. To analyze the molecular genetic landscape and prognostic value of NGS detected mutations in the genes of MM patients. MATERIALS & METHODS. This prospective study enrolls 45 MM patients treated at the Russian Research Institute of Hematology and Transfusiology (Saint Petersburg) from 2011 to the present. The median age of patients was 60 years (range 38–81 years). All patients received mutation screening using a NGS panel with 118 genes. The cells of bone marrow aspirate were subjected to the analysis. A comprehensive study of genetic status included also the standard karyotyping and FISH analysis. RESULTS. Somatic mutations in DNA methylation regulatory genes DNMT3A and TET2 had no significant impact either on objective response or long-term survival rates. However, in case of somatic mutations detected in gene NOTCH1 or ATM, the 3-year progression-free survival was 27.3 % (95% confidence interval [95% CI] 8.0–83.5 %) vs. 59.0 % (95% CI 42.3–82.9 %) without these mutations, the 3-year overall survival was 64 % (95% CI 42.7–96.4 %) and 95% (95% CI 87–100 %), respectively. CONCLUSION. Mutation status of DNA methylation genes has no significant impact either on antitumor response or on long-term survival rates in MM patients. However, genuine potential of of DNA methylation patterns and DNA methylation-modifying genes has not yet been evaluated. Further studies need to be conducted in this field to stratify the risks and to improve the treatment strategy. DNA methylation-modulating agents may eventually join the arsenal of therapeutic options for MM.