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VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma
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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.

Cytogenetic and Genome Research
|December 10, 2023
PubMed
Summary

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.

Keywords:
BiomarkersNon-respondingRefractory/relapsed diffuse large B-cell lymphoma

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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.