Genomic Complexity Linked With Poor Outcomes in DLBCL

A new analysis of patients with diffuse large B-cell lymphoma (DLBCL) suggests genomic complexity is associated with a poor prognosis and poor response to standard immunochemotherapy.

The report, published in the journal Oncoimmunology, gives new context to the different treatment responses seen in DLBCL, the most common type of non-Hodgkin lymphoma.

Corresponding author Hua You, PhD, of Guangzhou Medical University, in China, and Duke University, in the United States, and colleagues, explained that tumor mutational burden (TMB) has increasingly become an important biomarker in understanding treatment responses, but hematological malignancies tend to have lower TMBs compared to solid tumors. DLBCL has relatively high TMB for a hematological malignancy, and it also has low response rates to immune checkpoint inhibitors.

You and colleagues sought to better understand the clinical implications of TMB in this cancer type, and so they conducted an analysis of 275 genes that are commonly mutated in patients with hematologic cancers.

The authors recruited 424 patients with DLBCL who had undergone standard immunochemotherapy. Patients with primary cutaneous DLBCL, primary mediastinal large B-cell lymphoma, and primary central nervous system lymphoma were excluded.

Patient samples underwent fluorescent multiplex immunohistochemistry and next-generation sequencing targeted toward the commonly mutated set of genes.

The analysis elucidated a number of patterns. They found that patients with nonsynonymous mutations in KMT2D and TP53 were more likely to have higher levels of nonsynonymous mutations.

The authors further showed that in patients with germinal center B-cell-like (GCB) DLBCL who had wild-type TP53, a high mutation number correlated with significantly poorer clinical outcomes.

“In correlating NGS mutation numbers to clinical outcome, we found that only in patients with wild-type (WT) TP53, and more particularly in the GCB subtype with WT-TP53, significantly poorer survival was associated with high numbers of nonsynonymous mutations (with all cutoffs ranged from >4 to >23) and [mutated] genes (with all cutoffs ranged from >4 to >18),” You and colleagues wrote.

More broadly, the investigators said a high number of mutations was linked with lower PD-1 expression in T cells and PD-L1 expression in macrophages, “suggesting a positive role” of high mutation numbers in immune responses.

To validate their data, the authors used a publicly available data set of 304 patients with DLBCL who had undergone whole-exome sequencing as part of research at Harvard University. That analysis confirmed that KMT2D mutations were associated with high genomic complexity, which in turn was associated with poorer survival rates.

“Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy,” they said.

The findings could help pave the way for more precise therapeutic decisions for patients with DLBCL, though the investigators said further research is needed for that to become a reality. “Further studies elucidating the oncogenic and neoantigen roles of DLBCL mutations in DLBCL patients are needed, as well as the therapeutic implications of genetic and immune biomarkers,” the authors said.

Reference

You H, Xu-Monette ZY, Wei L, et al. Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma. Oncoimmunology. 2021;10(1):1928365. Published online July 20, 2021. doi:10.1080/2162402X.2021.1928365