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

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.

Keywords: BCL2/IGH rearrangement; GCB; HGBL; NOS; TMB-High; TREX1; whole-exome sequencing.

Figure 1

Patient’s baseline 18F-fluorodeoxyglucose (FDG)—positron emission tomography (PET) with computed tomography (CT), February 2020. Computed tomography (CT) provides detailed visualization of the soft tissue mass surrounding the left shoulder, which is outlined with a red line. PET images demonstrate multiple lesions, including involvement of the articular process of the left scapula, a mass in the 5th intercostal space with vertebral bone destruction and extension into the spinal canal, multiple cervical lymph node lesions, and widespread bone metastases.

Figure 2

FISH analysis using BCL2 Break Apart probe (MetaSystems, Germany) (3′ BCL2 region: red; 5′ BCL2 region: green). For the analysis, a tissue section from a formalin-fixed, paraffin-embedded (FFPE) tumor biopsy sample was used.