Genotyping on circulating tumor DNA improves mutation detection rate in high-risk diffuse large B-cell lymphoma.
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ABSTRACT:
SUBMITTER: Xia Y
PROVIDER: S-EPMC10955196 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
Publications
Genotyping on circulating tumor DNA improves mutation detection rate in high-risk diffuse large B-cell lymphoma.
Xia Yi Y Wang Li L Liang Jinhua J Shen Haorui H Wu Jiazhu J Yin Hua H Li Yue Y Zhu Huayuan H Li Jianyong J Xu Wei W
Genes & diseases 20230920 4
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Project description:PURPOSE:Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. PATIENTS AND METHODS:We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. RESULTS:Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. CONCLUSION:Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.
| S-EPMC6161832 | biostudies-literature
Project description:Ten-eleven translocation-2 (TET2) mutation is frequently observed in myeloid malignancies, and loss-of-function of TET2 is essential for the initiation of malignant hematopoiesis. TET2 mutation presents across disease entities and was reported in lymphoid malignancies. We investigated TET2 mutations in 27 diffuse large B-cell lymphoma (DLBCL) patients and found a frameshift mutation in 1 case (3.7%). TET2 mutation occurred in some populations of DLBCL patients and was likely involved in the pathogenesis of their malignancies.
| S-EPMC6144178 | biostudies-literature
Project description:Background Characterization of gene mutation profiles can provide new treatment options for patients with diffuse large B-cell lymphoma (DLBCL). However, this method is challenged by the limited source of tissue specimens, especially those of DLBCL patients at advanced stages. Therefore, in the current study, we aimed to describe the gene mutation landscape of DLBCL using circulating tumor DNA (ctDNA) samples obtained from patients’ blood samples, as well as to explore the relationship between ctDNA mutations and the prognosis and treatment response of patients with newly diagnosed DLBCL. Methods A total of 169 newly diagnosed Chinese DLBCL patients were included in this study, among which 85 patients were divided into a training set and 84 were assigned into a validation set. The mutation profile of a 59-gene panel was analyzed by targeted next generation sequencing (NGS) of the patients’ ctDNA samples. Differences in clinical factors between patients with and without ctDNA mutations were analyzed. In addition, we also explored gene mutation frequencies between GCB and non-GCB subtypes, and the relationship between gene mutation status, clinical factors, mean VAF (variant allele frequencies) and the patients’ overall survival (OS) and progression-free survival (PFS). Results ctDNA mutations were detected in 64 (75.3%) patients of the training set and 67 (79.8%) patients of the validation set. The most commonly mutated genes in both sets were PCLO, PIM1, MYD88, TP53, KMT2D, CD79B, HIST1H1E and LRP1B, with mutation frequencies of >10%. Patients with detectable ctDNA mutations trended to present advanced Ann Arbor stages (III-IV), elevated LDH (lactate dehydrogenase) levels, shorter OS and PFS, and a lower complete response (CR) rate to the R-CHOP regimen compared with DLBCL patients without ctDNA mutations. In addition, mean VAF (≥4.94%) and PCLO mutations were associated with poor OS and PFS. Conclusion We investigated the ctDNA mutation landscape in Chinese patients with newly diagnosed DLBCL and found that ctDNA could reflect tumor burden and patients with detectable ctDNA mutations trended to have shorter OS and PFS and a lower CR rate.
| S-EPMC9713409 | biostudies-literature
Project description:Diffuse large B cell lymphomas (DLBCL) are the most common neoplasia of the lymphatic system. Circulating cell-free DNA released from tumor cells (ctDNA) has been studied in many tumor entities and successfully used to monitor treatment and follow up. Studies of ctDNA in DLBCL so far have mainly focused on tracking mutations in peripheral blood initially detected by next-generation sequencing (NGS) of tumor tissue from one lymphoma manifestation site. This approach, however, cannot capture the mutational heterogeneity of different tumor sites in its entirety. In this case report, we present repetitive targeted next-generation sequencing combined with digital PCR out of peripheral blood of a patient with DLBCL relapse. By combining both detection methods, we were able to detect a new dominant clone of ctDNA correlating with the development of secondary therapy-related acute myeloid leukemia (t-AML) during the course of observation. Conclusively, our case report reinforces the diagnostic importance of ctDNA in DLBCL as well as the importance of repeated ctDNA sequencing combined with focused digital PCR assays to display the dynamic mutational landscape during the clinical course.
| S-EPMC8946858 | biostudies-literature
Project description: Not available
| S-EPMC10983020 | biostudies-literature
Project description:Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have heterogeneous outcomes; durable remissions are infrequently observed with standard approaches. Circulating tumor DNA (ctDNA) assessment is a sensitive, potentially prognostic tool in this setting. We assessed baseline ctDNA to identify patients with R/R DLBCL at high risk of relapse after receiving polatuzumab vedotin and bendamustine plus rituximab (BR) or BR alone. Patients were transplant ineligible and had received ≥1 prior line of therapy. The ctDNA assay, based on a customized panel of recurrently mutated genes in DLBCL, measured mutant molecules per mL (MMPM) at baseline and end of treatment (EOT). Endpoints included progression-free survival (PFS) and overall survival (OS) in subgroups stratified by baseline ctDNA and log-fold change in ctDNA at EOT vs baseline. In biomarker-evaluable patients (n = 33), baseline ctDNA level correlated with serum lactate dehydrogenase (LDH) concentration, number of prior therapies, stage, and International Prognostic Index (IPI). After adjusting for number of prior therapies ≥2, IPI score ≥3, and LDH above the upper limit of normal, high (greater than median) baseline ctDNA MMPM was independently prognostic for shorter PFS (adjusted hazard ratio [HR], 0.18 [95% CI, 0.05-0.65]) and OS (adjusted HR, 0.20 [95% CI, 0.06-0.68]). In 23 patients with baseline and EOT samples, a significantly greater decrease in ctDNA MMPM was observed in patients with complete response (CR) (n = 13) than those without CR (n = 10); P = .0025. Baseline ctDNA assessment may identify patients at high risk of progression and should be further evaluated as a monitoring tool in R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT02257567.
| S-EPMC8941482 | biostudies-literature
Project description:Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79-382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.
| S-EPMC7973209 | biostudies-literature
Project description:IntroductionCirculating tumor DNA (ctDNA) can be obtained from cell-free DNA (cfDNA) andis a new technique for genotyping, response assessment and prognosis in lymphoma.MethodsEighteen patients with samples at diagnosis (ctDNA1), after treatment (ctDNA2) and extracted from diagnostic tissue (FFPE) were evaluated.ResultsIn all patients, at least one mutation in cfDNA was detected at diagnosis. CREBBP was the most frequent mutated gene (67 %). In 12 of the 15 patients with complete remission, the mutation attributed to the disease found at diagnosis cleared with treatment. A reduction in the ctDNA was observed after treatment in 14 patients, 12 of whom achieved complete remission. Correlations were found between the ctDNA at diagnosis and total metabolic tumor volume (r = 0.51; p-value = 0.014) and total lesion glycolysis 2.5 (r = 0.47; p-value = 0.024) by PET at diagnosis and between ctDNA at diagnosis and radiomic features of the lesions with the largest standardized uptake value. There was a strong inverse correlation between ΔctDNA1 and ΔSUVmax by PET/CT (r = -0.8788; p-value = 0.002).ConclusionAnalysis of ctDNA and PET/CT in large B-cell lymphoma are complementary data for evaluating tumor burden and tumor clearance after treatment. Analysis of radiomic data might help to identify tumor characteristics and their changes after treatment.
| S-EPMC11726095 | biostudies-literature
Project description: Not available
| S-EPMC8377611 | biostudies-literature
Project description:Background and aimsStudies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations. This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC.MethodsWe used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during 3 years follow up.ResultsIn tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, the CTNNB1 mutation rate was 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA suggested a possible clonal evolution of HCC or arising multicentric tumors with separate genetic profiles in individual patients.ConclusionCombining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.
| S-EPMC8028749 | biostudies-literature