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Updated: Jul 8, 2025
VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma
Published on: December 28, 2015
Recurrent Mutations in Refractory/Relapsed Diffuse Large B-Cell Lymphoma by Targeted Gene Sequencing
Aditi Sharma1, Ashim Das1, Amanjit Bal1
1Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Introduction:
Whole-genome sequencing of diffuse large B-cell lymphoma (DLBCL) has identified recurrent mutations involved in pathogenesis and potentially affecting response to therapy. In this pilot study, a targeted gene panel was created to identify mutations associated with relapse/refractoriness.
Material And Methods:
A 14-gene targeted panel was designed to sequence thirteen patients who were in remission and 8 cases that had relapsed/refractory to treatment. A paired diagnostic biopsy and a relapse biopsy were sequenced to find genes repeatedly altered in relapse.
Results:
A total of 751 nonsynonymous and truncating mutations were identified. Truncated mutations in NOTCH1, TNFAIP3, and CD58 were associated with poor treatment outcomes. In cases that did not respond to treatment, a high number of mutations were found in the EZH2 gene, followed by the DNA-binding domain of TP53 and MYD88. Termination mutations in the intracellular domain of NOTCH were found in 75% of non-responsive cases. Co-occurrence of loss of function mutations of TNFAIP3 and missense mutations in MYD88 was associated with a non-responsive cohort.
Discussion:
The study highlights mutations associated with chemotherapeutic response in DLBCL with implications for initial diagnostic biopsy response prediction.
Insights
Identifying mutations in diffuse large B-cell lymphoma (DLBCL) can predict treatment outcomes. Specific gene mutations, like NOTCH1 and TNFAIP3, are linked to poor response and relapse in DLBCL patients.
Area of Science:
- Oncology
- Genetics
- Hematology
Background:
- Diffuse large B-cell lymphoma (DLBCL) pathogenesis involves recurrent mutations.
- Whole-genome sequencing has identified mutations affecting DLBCL therapy response.
- A targeted gene panel was developed to investigate relapse and refractoriness in DLBCL.
Purpose of the Study:
- To identify specific gene mutations associated with relapse and refractoriness in DLBCL.
- To explore the correlation between genetic alterations and chemotherapeutic response in DLBCL patients.
- To assess the potential of mutations in predicting treatment outcomes from initial diagnostic biopsies.
Main Methods:
- A 14-gene targeted panel was utilized for sequencing.
- Paired diagnostic and relapse biopsies from 21 DLBCL patients (13 remission, 8 relapsed/refractory) were analyzed.
- Mutations were identified and analyzed for their association with treatment response.
Main Results:
- A total of 751 nonsynonymous and truncating mutations were detected.
- Truncated mutations in NOTCH1, TNFAIP3, and CD58 correlated with poor treatment outcomes.
- High mutation frequencies in EZH2, TP53 (DNA-binding domain), and MYD88 were observed in non-responsive cases, with NOTCH intracellular domain termination mutations in 75% of these patients. Loss-of-function TNFAIP3 and missense MYD88 mutations co-occurred in non-responsive patients.
Conclusions:
- Specific mutations in DLBCL are associated with chemotherapeutic response.
- The identified mutations have implications for predicting treatment response using initial diagnostic biopsies.
- Targeted sequencing can aid in understanding DLBCL relapse and refractoriness.
