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Updated: Jul 10, 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
Massive parallel sequencing unveils homologous recombination deficiency in follicular dendritic cell sarcoma
Luisa Lorenzi1, Torsten Haferlach2, Luigi Mori3
1Pathology Unit, ASST Spedali Civili di Brescia, Department of Molecular and Translational Medicine, University of Brescia, Brescia. luisa.lorenzi@unibs.it.
Abstract:
Standardized treatment options are lacking for patients with unresectable or multifocal follicular dendritic cell sarcoma (FDCS) and disease-related mortality is as high as 20%. Applying whole-genome sequencing (WGS) in one case and whole-exome sequencing (WES) in additional twelve cases, this study adds information on the molecular landscape of FDCS, expanding knowledge on pathobiological mechanisms and identifying novel markers of potential theragnostic significance. Massive parallel sequencing showed high frequency of mutations on oncosuppressor genes, particularly in RB1, CARS and BRCA2 and unveiled alterations on homologous recombination DNA damage repair-related genes in 70% (9/13) of cases. This indicates that patients with high-stage FDCS may be eligible for poly ADP ribose polymerase inhibition protocols. Low tumor mutational burden was confirmed in this study despite common PDL1 expression in FDCS arguing on the efficacy of immune checkpoint inhibitors. CDKN2A deletion, detected by WGS and confirmed by fluorescence in situ hybridization in 41% of cases (9/22) indicates that impairment of cell cycle regulation may sustain oncogenesis in FDCS. Absence of mutations in the RAS/RAF/MAPK pathway and lack of clonal hematopoiesis-related mutations in FDCS sanction its differences from dendritic cell-derived neoplasms of hematopoietic derivation. WGS and WES in FDCS provides additional information on the molecular landscape of this rare tumor, proposing novel candidate genes for innovative therapeutical approaches to improve survival of patients with multifocal disease.
Insights
Follicular dendritic cell sarcoma (FDCS) molecular landscape revealed frequent mutations in tumor suppressor genes. This rare cancer may benefit from poly ADP ribose polymerase inhibitors, not immune checkpoint inhibitors.
Area of Science:
- Genomics
- Oncology
- Rare Cancers
Background:
- Follicular dendritic cell sarcoma (FDCS) lacks standardized treatments, with high mortality.
- Understanding FDCS molecular mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the molecular landscape of unresectable or multifocal FDCS.
- To identify novel theragnostic markers for improved patient outcomes.
Main Methods:
- Whole-genome sequencing (WGS) on one case.
- Whole-exome sequencing (WES) on twelve additional cases.
- Fluorescence in situ hybridization (FISH) for CDKN2A deletion confirmation.
Main Results:
- High frequency of mutations in oncosuppressor genes (RB1, CARS, BRCA2).
- Alterations in homologous recombination DNA damage repair genes found in 70% of cases.
- CDKN2A deletion identified in 41% of cases, suggesting cell cycle dysregulation.
- Low tumor mutational burden and common PDL1 expression indicate limited efficacy of immune checkpoint inhibitors.
- Absence of RAS/RAF/MAPK pathway mutations differentiates FDCS from hematopoietic neoplasms.
Conclusions:
- WGS and WES provide insights into FDCS pathobiology.
- FDCS patients may be candidates for poly ADP ribose polymerase (PARP) inhibitors.
- Novel therapeutic targets identified to improve survival in multifocal FDCS.
