Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance

SIMPLE SUMMARY: Many patients with the aggressive cancer diffuse large B-cell lymphoma (DLBCL) still respond poorly to treatment and suffer from relapsed or refractory disease. The identification of gene mutations that are responsible for the outgrowth of the relapsed tumor is crucial to understand the underlying mechanisms of therapy resistance. In this review, we provide a comprehensive overview of the affected genes and their biological functions in the context of therapy resistance. Furthermore, we discuss novel therapeutic strategies to treat patients with relapsed disease. We expect that the identification of these gene alterations in routine diagnostics holds great potential in guiding future therapy strategies in DLBCL. ABSTRACT: The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be treated successfully with a combination of chemotherapy and the monoclonal anti-CD20 antibody rituximab. Nonetheless, approximately one-third of the patients with DLBCL still experience relapse or refractory (R/R) disease after first-line immunochemotherapy. Whole-exome sequencing on large cohorts of primary DLBCL has revealed the mutational landscape of DLBCL, which has provided a framework to define novel prognostic subtypes in DLBCL. Several studies have investigated the genetic alterations specifically associated with R/R DLBCL, thereby uncovering molecular pathways linked to therapy resistance. Here, we summarize the current state of knowledge regarding the genetic alterations that are enriched in R/R DLBCL, and the corresponding pathways affected by these gene mutations. Furthermore, we elaborate on their potential role in mediating therapy resistance, also in connection with findings in other B-cell malignancies, and discuss alternative treatment options. Hence, this review provides a comprehensive overview on the gene lesions and molecular mechanisms underlying R/R DLBCL, which are considered valuable parameters to guide treatment.