Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma

Abstract

Purpose MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of DLBCL patients, and to evaluate the clinical significance of MYC mutations in DLBCL patients treated with R-CHOP immunochemotherapy. Experimental Design We identified MYC mutations in 750 DLBCL patients using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients. Results The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions), and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3´ untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline single nucleotide polymorphism encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts. Conclusions Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis.

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

“…47 The prevalence and pattern of MYC mutations in BL (50% to 70%) and DLBCL (5% to 33%) are different. [47][48][49] The gain-offunction MYC mutants (eg, T58 or F138) that are common in BL, occur in ,1% of DLBCL patients. 47 T58 mutations protect MYC mRNA from degradation, leading to higher levels of MYC protein.…”

“…[47][48][49] The gain-offunction MYC mutants (eg, T58 or F138) that are common in BL, occur in ,1% of DLBCL patients. 47 T58 mutations protect MYC mRNA from degradation, leading to higher levels of MYC protein. 50,51 Furthermore, T58 mutants both accelerate cellular proliferation and inhibit apoptosis by decreasing the induction of BIM.…”

“…27 In contrast, most of the non-T58 or F138 MYC variants, including the polymorphism N11S, decrease MYC protein expression in DLBCL. 47 Compared with MYC wild-type, they do not induce cellular proliferation but can still inhibit apoptosis in situations of metabolic stress. 47 The MYC gene can also undergo amplification in 8% to 20% of DLBCLs.…”

“…47 Compared with MYC wild-type, they do not induce cellular proliferation but can still inhibit apoptosis in situations of metabolic stress. 47 The MYC gene can also undergo amplification in 8% to 20% of DLBCLs. 52,53 However, this has not been consistently shown to be associated with increased MYC protein expression or an inferior clinical outcome.…”

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

“…6,7 Patients with MYC mutations may experience either a better or poorer outcome, depending on the type of mutation. 8 This may explain the contradictory reports found in the literature. Patients with MYC overexpression, particularly the Myc-N11S variant, have a better outcome than patients with other MYC mutations.…”