Caracterização genômica de pacientes portadores de mieloma múltiplo por hibridização genômica comparativa em matriz (aCGH)

Abstract

Multiple Myeloma (MM) is a hematologic neoplasm characterized by uncontrolled clonal proliferation of differentiated B lymphocytes in the bone marrow, leading to excessive production of monoclonal immunoglobulins. Bone marrow involvement and excess immunoglobulins in the body are the main causes of clinical symptoms. Currently, the number of MM cases has increased, predominantly affecting men, with a higher incidence in individuals over 60 years of age. Diagnosis is based on clinical evaluation, bone marrow examinations, immunoglobulin levels, and imaging tests for bone assessment. In this context, this study aimed to characterize the genomic and epidemiological profile of patients with MM in the state of Ceará. For this purpose, 95 patients were analyzed, stratified according to the International Staging System (ISS), considering age, gender, region, laboratory parameters, and occupation. The results indicated significant associations between risk stratification and variables such as Hb (p=0.003), B2M (p<0.001), albumin (p=0.048), platelets (p=0.023) and renal failure (p=0.002). The aCGH analysis in 16 patients revealed a total of 323 CNVs, 172 gains, 117 losses and 32 regions of loss of heterozygosity (LOH), with sizes ranging from 3Kb to 110,779Kb. Among the gains, driver genes such as HERC2, not yet correlated with MM, MSR1, also not reported in MM and with a strong association with the tumor microenvironment, and DMBT1, a tumor suppressor gene for brain and epithelial cancer, but not yet correlated with MM, stood out. Specific gains in the JAK-STAT pathway were observed in the ISS1 group, with emphasis on the driver genes JAK2 and JAK3, in addition to the RIG-I-like receptor pathway that was also present in the ISS3 group, implying the activation of the NF-κB pathway. Gains in the olfactory pathways were identified in all groups and have been associated with cancer. In the ISS1 and ISS2 groups, losses in DNA replication, nucleotide excision repair and chemical carcinogenesis pathways suggest involvement with characteristics such as genomic instability, apoptosis evasion, cell proliferation, angiogenesis and metastasis. The ISS2 group presented a higher number of LOH and a lower number of gains, possibly unique characteristics. MM, therefore, presents the JAK-STAT and RIG-I-like receptor signaling pathways strongly associated with the disease. HERC2 and MSR1 genes emerge as probable biomarkers for the ISS 1 group, as does the OCLN gene for the ISS 2 group, which also presented a higher number of LOH and a lower number of gains. These findings contribute to elucidating the pathogenesis of MM and directing therapeutic strategies.