RESUMO
Clinical and molecular prognostic factors in gliomas include age, IDH mutation, the glioma CpG island methylator phenotype (G-CIMP+) and promoter methylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) gene. Among these markers, a predictive value was reported in glioblastomas (GBM) for MGMT promoter methylation, in particular in elderly GBM patients. In this study, methylation data from 46 glioma samples with the Illumina 450K platform were obtained and extended using external data to include a total of 247 glioma samples. Methylation analysis of the whole MGMT gene with this platform revealed two strongly survival-associated CpG regions within the promoter and the gene body, which were confirmed in a reported dataset of high grade-gliomas. Methylation at the promoter (CpG 25, cg12981137 and the prognostic model MGMT-STP27) and at the gene body CpG 165 (cg07933035), were significantly associated with better overall survival, and strongly correlated with G-CIMP+ status. In this series, the prognostic value of MGMT methylation at the promoter was not observed in G-CIMP- cases, although around 50 % of them were MGMT-methylated. These results were also obtained in an homogeneously-treated series of chemoradiated G-CIMP- GBMs analyzed by MSP and qMSP, and confirmed in a reported pyrosequencing-analyzed series of gliomas. Interestingly, in contrast to the MGMT promoter, gene body methylation was of prognostic value in G-CIMP-patients older than 65 years. Our study highlights the relevance of the prognostic value of the different regions of methylation throughout the MGMT gene that could be affected by specific G-CIMP profiles and age groups.
Assuntos
Neoplasias Encefálicas/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Proteínas Supressoras de Tumor/genética , Adulto , Fatores Etários , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Feminino , Perfilação da Expressão Gênica , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Análise de Componente Principal , Prognóstico , Regiões Promotoras Genéticas/genética , Análise de Sobrevida , Adulto JovemRESUMO
We propose a novel biomarker that can identify patients at high risk of early progression after chimeric antigen receptor (CAR) T cell therapy. Calculation of cell-free DNA (cfDNA) with a pre-apheresis (PA) and pre-lymphodepletion (PL) sample allows monitoring of tumor dynamics (∆cfDNA). In the present study, ∆cfDNA and other biomarkers and clinical variables were evaluated in 58 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL). ∆cfDNA (>11 ng/mL plasma; P =.003), C-reactive protein (CRP) PL (>1.06 mg/dL; P = .004), lactate dehydrogenase (LDH) PL (>304; P = .006), disease status PL (progressive disease; P = .035) and sex (male; P = .016) were highly correlated with 1 month progression. After adjusting for ∆cfDNA, CRP PL, and LDH PL, disease status PL, and sex, ∆cfDNA remained associated with 1-month progression after CAR T cell infusion.
Assuntos
Ácidos Nucleicos Livres , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Masculino , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Ácidos Nucleicos Livres/uso terapêutico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Imunoterapia Adotiva/efeitos adversos , Biomarcadores , Terapia Baseada em Transplante de Células e TecidosRESUMO
Although next-generation sequencing (NGS) data on lymphomas require further validation before being implemented in daily practice, the clinical application of NGS can be considered right around the corner. The aim of our study was to validate an NGS lymphoid panel for tissue and liquid biopsy with the most common types of non-Hodgkin's lymphoma [follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)]. In this series, 372 somatic alterations were detected in 93.6% (44/47) of the patients through tissue biopsy. In FL, we identified 93 somatic alterations, with a median of 7.4 mutations per sample. In DLBCL, we detected 279 somatic variants with a median of 8.6 mutations (range 0-35). In 92% (24/26) of the cases, we were able to detect some variant in the circulating tumor DNA. We detected a total of 386 variants; 63.7% were detected in both types of samples, 13.2% were detected only in the circulating tumor DNA, and 23% were detected only in the tissue biopsy. We found a correlation between the number of circulating tumor DNA mutations, advanced stage, and bulky disease. The genetic alterations detected in this panel were consistent with those previously described at diagnosis. The liquid biopsy sample is therefore a complementary tool that can provide new genetic information, even in cases where a solid biopsy cannot be performed or an insufficient sample was obtained. In summary, we describe and analyze in this study the findings and difficulties encountered when incorporating liquid biopsy into clinical practice in non-Hodgkin's lymphoma at diagnosis.
Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Mutação , Humanos , Biópsia Líquida , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
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