{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T21:04:40Z","timestamp":1782939880842,"version":"3.54.5"},"reference-count":49,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple myeloma (MM) is a disease characterized by spatiotemporal heterogeneity of tumor clones. Different genetic aberrations can be observed simultaneously in tumor cells from different loci, and as the disease progresses, new subclones may appear. The role of liquid biopsy, which is based on the analysis of tumor DNA circulating in the blood plasma, continues to be explored in MM. Here, we present an analysis of the STR profiles and mutation status of the KRAS, NRAS, and BRAF genes, evaluated in plasma free circulating tumor DNA (ctDNA), CD138+ bone marrow cells, and plasmacytomas. The prospective single-center study included 97 patients, with a median age of 55 years. Of these, 94 had newly diagnosed symptomatic MM, and three had primary plasma cell leukemia. It should be noted that if mutations were detected only in ctDNA, \u201cnon-classical\u201d codons were more often affected. A variety of adverse laboratory and clinical factors have been associated with the detection of rare KRAS or NRAS gene mutations in bone marrow or ctDNA, suggesting that these mutations may be factors of an unfavorable prognosis for MM. Liquid biopsy studies provide undeniable fundamental information about tumor heterogeneity and clonal evolution in MM. Moreover, we focus on using liquid biopsy to identify new high-risk factors for MM.<\/jats:p>","DOI":"10.3390\/ijms25179426","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T09:39:32Z","timestamp":1725010772000},"page":"9426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Loss of Heterozygosity and Mutations in the RAS-ERK Pathway Genes in Tumor Cells of Various Loci in Multiple Myeloma"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4142-171X","authenticated-orcid":false,"given":"Maiia","family":"Soloveva","sequence":"first","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7944-6202","authenticated-orcid":false,"given":"Maksim","family":"Solovev","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2957-1619","authenticated-orcid":false,"given":"Natalya","family":"Risinskaya","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Nikulina","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Yakutik","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bella","family":"Biderman","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Obukhova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8044-598X","authenticated-orcid":false,"given":"Yulia","family":"Chabaeva","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergej","family":"Kulikov","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9463-9187","authenticated-orcid":false,"given":"Andrey","family":"Sudarikov","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Mendeleeva","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1038\/ncomms3997","article-title":"Heterogeneity of genomic evolution and mutational profiles in multiple myeloma","volume":"5","author":"Bolli","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1182\/blood.V126.23.371.371","article-title":"Spatiotemporal Analysis of Intraclonal Heterogeneity in Multiple Myeloma: Unravelling the Impact of Treatment and the Propagating Capacity of Subclones Using Whole Exome Sequencing","volume":"126","author":"Melchor","year":"2015","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41467-017-00296-y","article-title":"Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing","volume":"8","author":"Rasche","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Soloveva, M., Solovev, M., Nikulina, E., Risinskaya, N., Biderman, B., Yakutik, I., Obukhova, T., and Mendeleeva, L. (2023). Loss of Heterozygosity in the Circulating Tumor DNA and CD138+ Bone Marrow Cells in Multiple Myeloma. Genes, 14.","DOI":"10.3390\/genes14020351"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.clml.2019.03.017","article-title":"Future of Personalized Therapy Targeting Aberrant Signaling Pathways in Multiple Myeloma","volume":"19","author":"Anwer","year":"2019","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e257","DOI":"10.1038\/bcj.2014.77","article-title":"Efficacy and safety of long-term treatment with lenalidomide and dexamethasone in patients with relapsed\/refractory multiple myeloma","volume":"4","author":"Swern","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1056\/NEJMoa043445","article-title":"Bortezomib or high-dose dexamethasone for relapsed multiple myeloma","volume":"352","author":"Richardson","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/leu.2011.196","article-title":"Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study","volume":"26","author":"Kumar","year":"2012","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pasca, S., Tomuleasa, C., Teodorescu, P., Ghiaur, G., Dima, D., Moisoiu, V., Berce, C., Stefan, C., Ciechanover, A., and Einsele, H. (2019). KRAS\/NRAS\/BRAF Mutations as Potential Targets in Multiple Myeloma. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01137"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/hon.2353","article-title":"Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation","volume":"35","author":"Mey","year":"2017","journal-title":"Hematol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.18.00070","article-title":"Vemurafenib in Patients With Relapsed Refractory Multiple Myeloma Harboring BRAFV600 Mutations: A Cohort of the Histology-Independent VE-BASKET Study","volume":"2","author":"Raje","year":"2018","journal-title":"JCO Precis. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1182\/blood.2022017789","article-title":"A phase 2 clinical trial of combined BRAF\/MEK inhibition for BRAFV600E-mutated multiple myeloma","volume":"141","author":"Giesen","year":"2023","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6432","DOI":"10.1158\/1078-0432.CCR-21-2040","article-title":"Single-Cell Profiling Reveals Metabolic Reprogramming as a Resistance Mechanism inBRAF-Mutated Multiple Myeloma","volume":"27","author":"Waldschmidt","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1182\/blood-2018-03-840132","article-title":"Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma","volume":"132","author":"Walker","year":"2018","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cca.2019.12.026","article-title":"Emerging biomarkers in Multiple Myeloma: A review","volume":"503","author":"Gupta","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1182\/bloodadvances.2018025197","article-title":"Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow","volume":"2","author":"Mazzotti","year":"2018","journal-title":"Blood Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15086","DOI":"10.1038\/ncomms15086","article-title":"Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates","volume":"8","author":"Kis","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1038\/leu.2016.366","article-title":"Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma","volume":"31","author":"Mithraprabhu","year":"2016","journal-title":"Leukemia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e538","DOI":"10.1016\/S1470-2045(14)70442-5","article-title":"International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma","volume":"15","author":"Rajkumar","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.3324\/haematol.2012.065698","article-title":"Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents","volume":"97","author":"Usmani","year":"2012","journal-title":"Haematologica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1093\/annonc\/mdp329","article-title":"Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: A longitudinal study on 1003 consecutive patients","volume":"21","author":"Varettoni","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1200\/JCO.2011.34.9290","article-title":"Soft-Tissue Plasmacytomas in Multiple Myeloma: Incidence, Mechanisms of Extramedullary Spread, and Treatment Approach","volume":"29","author":"Cibeira","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.3109\/10428194.2012.740562","article-title":"Extramedullary multiple myeloma","volume":"54","author":"Weinstock","year":"2012","journal-title":"Leuk. Lymphoma"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00277-012-1414-5","article-title":"Features of extramedullary myeloma relapse: High proliferation, minimal marrow involvement, adverse cytogenetics: A retrospective single-center study of 24 cases","volume":"91","author":"Rasche","year":"2012","journal-title":"Ann. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/bjh.17338","article-title":"Expert review on soft-tissue plasmacytomas in multiple myeloma: Definition, disease assessment and treatment considerations","volume":"194","author":"Beksac","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"McAvera, R., Quinn, J., Murphy, P., and Glavey, S. (2023). Genetic Abnormalities in Extramedullary Multiple Myeloma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411259"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1046\/j.1365-2141.2002.03258.x","article-title":"Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma","volume":"116","author":"Dahl","year":"2002","journal-title":"Br. J. Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1186\/s12885-020-06870-w","article-title":"Plasmacytoma in patients with multiple myeloma: Morphology and immunohistochemistry","volume":"20","author":"Firsova","year":"2020","journal-title":"BMC Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1097\/PAS.0000000000001459","article-title":"Genetic Basis of Extramedullary Plasmablastic Transformation of Multiple Myeloma","volume":"44","author":"Liu","year":"2020","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1111\/bjh.13383","article-title":"Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation","volume":"169","author":"Weinstock","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.17650\/1818-8346-2022-17-4-67-80","article-title":"Multiple myeloma with extramedullary plasmacytoma: Pathogenesis and clinical case","volume":"17","author":"Firsova","year":"2022","journal-title":"Oncohematology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Risinskaya, N., Kozhevnikova, Y., Gavrilina, O., Chabaeva, J., Kotova, E., Yushkova, A., Isinova, G., Zarubina, K., Obukhova, T., and Kulikov, S. (2022). Loss of Heterozygosity in the Tumor DNA of De Novo Diagnosed Patients Is Associated with Poor Outcome for B-ALL but Not for T-ALL. Genes, 13.","DOI":"10.3390\/genes13030398"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3449","DOI":"10.3390\/curroncol29050278","article-title":"STR Profiling Reveals Tumor Genome Instability in Primary Mediastinal B-Cell Lymphoma","volume":"29","author":"Risinskaya","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1111\/bjh.16440","article-title":"The utility of non-invasive liquid biopsy for mutational analysis and minimal residual disease assessment in extramedullary multiple myeloma","volume":"189","author":"Long","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.1200\/JCO.2014.59.1503","article-title":"Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma","volume":"33","author":"Walker","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","article-title":"Improved survival with vemurafenib in melanoma with BRAF V600E mutation","volume":"364","author":"Chapman","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.cell.2009.12.040","article-title":"Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF","volume":"140","author":"Heidorn","year":"2010","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1038\/s41467-018-04001-5","article-title":"Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma","volume":"9","author":"Manier","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/2041-2223-3-14","article-title":"Comparison of STR profiling from low template DNA extracts with and without the consensus profiling method","volume":"3","author":"Grisedale","year":"2012","journal-title":"Investig. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.clml.2013.09.013","article-title":"Deep Sequencing Reveals Myeloma Cells in Peripheral Blood in Majority of Multiple Myeloma Patients","volume":"14","author":"Vij","year":"2014","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_41","first-page":"271","article-title":"Liquid biopsy and blood-based minimal residual disease evaluation in multiple myeloma","volume":"31","author":"Gozzetti","year":"2023","journal-title":"Oncol. Res. Featur. Preclin. Clin. Cancer Ther."},{"key":"ref_42","first-page":"22","article-title":"The detection of minimal residual disease in patients with chronic B-cell lymphatic leukemia using patient-specified polymerase chain reaction","volume":"12","author":"Sidorova","year":"2011","journal-title":"Klin. Lab. Diagn."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1600-0625.2011.01375.x","article-title":"A simple and efficient method for DNA extraction from skin and paraffin-embedded tissues applicable to T-cell clonality assays","volume":"21","author":"Sidorova","year":"2011","journal-title":"Exp. Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows\u2013Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1093\/nar\/gkw227","article-title":"VarDict: A novel and versatile variant caller for next-generation sequencing in cancer research","volume":"44","author":"Lai","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_49","first-page":"16","article-title":"Detection of BRAF V600E mutation in patients with hairy cell leukemia by allele-specific RT-PCR","volume":"59","author":"Yakutik","year":"2014","journal-title":"Hematol. Transfusiology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9426\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:45:35Z","timestamp":1760111135000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,30]]},"references-count":49,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25179426"],"URL":"https:\/\/doi.org\/10.3390\/ijms25179426","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,30]]}}}