The MIR142 gene in lymphomas: a comprehensive analysis of data from cBioPortal for Cancer Genomics and our own findings

Abstract

Introduction. MicroRNA miR-142 is involved at multiple levels in the pathogenesis of diffuse large B-cell lymphoma (DLBCL): mature chains are oncosuppressive and target a number of pro-oncogenes that are essential for lymphomagenesis. Aim. To perform a comparative analysis of the frequency and spectrum of aberrations (mutations, methylation status, and copy number alterations) in the MIR142 gene in the tumor tissue of patients with systemic DLBCL and primary central nervous system lymphoma (PCNSL), and to analyze their clinical significance. Materials and methods. Biopsies from 137 patients with systemic DLBCL, 35 patients with PCNSL, and 11 patients with reactive lymphadenopathy (controls) were examined. Mutations and methylation of the MIR142 gene were analyzed. To verify changes in the copy number of the MIR142 gene locus, the results of profiling, using Affymetrix SNP 6.0 microarrays, of tumor samples from 364 patients with systemic DLBCL and 43 patients with PCNSL, presented in the cBioPortal for Cancer Genomics database, were analyzed. Results. A higher frequency of mutations in the MIR142 gene (p = 0,010) and a different spectrum of their location in PCNSL compared to systemic DLBCL were demonstrated. In PCNSL, the subgroup of patients with MIR142 mutations was characterized by a significantly higher proliferative potential of the tumor substrate (p = 0,021). In systemic DLBCL, the MIR142 mutation status was associated with an earlier disease onset (p = 0,025), as well as a higher frequency of non-lymphatic organ tumor involvement (p = 0,046). Comparative analysis revealed the greatest heterogeneity in the representation of the methylated allele of the MIR142 gene in the tumor lymphoid tissue of patients with systemic DLBCL. Complete demethylation of the analyzed gene was found in 43,6% of systemic DLBCL and 30,0% of PCNSL patients, which was not observed in the control group (p = 0,007 and p = 0,040, respectively). A higher methylation level of the analyzed gene was noted in patients over 60 years of age in both PCNSL (p = 0,042) and systemic DLBCL (p = 0,077). The results obtained indicate that the main mechanism of alterations in MIR142 copy number is the occurrence of microdeletion/microduplication events, which are more frequent in PCNSL. A decrease in the gene copy number had a favorable effect on overall survival in the patients with lymphomas studied. Thus, the 5-year overall survival rates of patients with PCNSL were 71,4% in the group with deletions, 56,3% – in the group with duplications, and 25% – in the absence of changes. Conclusion. Our study is the first to compare the frequency and spectrum of aberrations (mutations, methylation status, and copy number alterations) in the MIR142 gene in tumor tissue from patients with systemic DLBCL and PCNSL, as well as to analyze their association with the clinical course of these diseases. In general, the obtained data on long-term treatment outcomes for both systemic DLBCL and PCNSL are indirectly consistent with the results of previous studies showing an association between high miR-142 expression and decreased survival in lymphoma patients.