# High Tumor Mutation Burden (TMB) and a Novel Somatic Mutation in the TREX1 Gene in a Patient with Aggressive and Refractory High-Grade B-Cell Lymphoma: A Case Report

## TL;DR

A patient with aggressive high-grade B-cell lymphoma had a novel TREX1 gene mutation and high tumor mutation burden, contributing to treatment resistance and poor outcome.

## Contribution

The discovery of a novel TREX1 somatic mutation and high tumor mutation burden in a high-grade B-cell lymphoma case.

## Key findings

- The patient had a novel TREX1 p.T49fs somatic mutation not previously reported in non-Hodgkin lymphomas.
- High tumor mutation burden and genomic instability were identified as potential drivers of aggressive disease progression.
- Multiple somatic mutations and chromosomal abnormalities were detected, including TP53, B2M, and del(17p).

## Abstract

High-grade B-cell lymphoma (HGBL), not otherwise specified (NOS), is a rare entity within the spectrum of B-cell lymphomas. HGBL, NOS remains a diagnosis of exclusion with limited data available on the optimal clinical approach. We report a case of a 67-year-old man with HGBL, NOS with a germinal center B-cell (GCB) immunophenotype. The disease was characterized by an aggressive clinical course, refractory to multiple lines of cytotoxic chemotherapy, immunotargeted treatment, therapy with a PD-1 inhibitor, and haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Ultimately, the disease progression led to the patient’s death nine months post-diagnosis. A FISH assay identified a sole genetic rearrangement: BCL2/IGH. Whole-exome sequencing revealed a number of significant somatic mutations, such as TP53 p.C238G, B2M p.L12R, STAT6 p.D419G, STAT3 p.S614R, TREX1 p.T49fs, and CREBBP p.C367Ter, as well as a high focal amplification of the MUC3A gene and the deletion of the short arm of chromosome 17 (del(17p)). An inactivating somatic mutation in the TREX1 gene (p.T49fs) has not been previously described in patients with non-Hodgkin lymphomas. Additionally, our analysis uncovered a key cancer hallmark: tumor genomic instability, manifested as a high tumor mutational burden, which likely contributed to the aggressive disease course.