The prognosis of MYC translocation positive diffuse large B‐cell lymphoma depends on the second hit

Abstract

A proportion of MYC translocation positive diffuse large B‐cell lymphomas (DLBCL) harbour a BCL2 and/or BCL6 translocation, known as double‐hit DLBCL, and are clinically aggressive. It is unknown whether there are other genetic abnormalities that cooperate with MYC translocation and form double‐hit DLBCL, and whether there is a difference in clinical outcome between the double‐hit DLBCL and those with an isolated MYC translocation. We investigated TP53 gene mutations along with BCL2 and BCL6 translocations in a total of 234 cases of DLBCL, including 81 with MYC translocation. TP53 mutations were investigated by PCR and sequencing, while BCL2 and BCL6 translocation was studied by interphase fluorescence in situ hybridization. The majority of MYC translocation positive DLBCLs (60/81 = 74%) had at least one additional genetic hit. In MYC translocation positive DLBCL treated by R‐CHOP (n = 67), TP53 mutation and BCL2, but not BCL6 translocation had an adverse effect on patient overall survival. In comparison with DLBCL with an isolated MYC translocation, cases with MYC/TP53 double‐hits had the worst overall survival, followed by those with MYC/BCL2 double‐hits. In MYC translocation negative DLBCL treated by R‐CHOP (n = 101), TP53 mutation, BCL2 and BCL6 translocation had no impact on patient survival. The prognosis of MYC translocation positive DLBCL critically depends on the second hit, with TP53 mutations and BCL2 translocation contributing to an adverse prognosis. It is pivotal to investigate both TP53 mutations and BCL2 translocations in MYC translocation positive DLBCL, and to distinguish double‐hit DLBCLs from those with an isolated MYC translocation.

MYC/BCL2/BCL6 triple hit lymphoma: a study of 40 patients with a comparison to MYC/BCL2 and MYC/BCL6 double hit lymphomas

“…Studies have shown that TP53 mutation is associated with P53 overexpression and both are associated with an inferior prognosis in patients with diffuse large B-cell lymphoma [37][38][39]. Previous studies have shown that P53 expression can enhance the negative effect of MYC translocation and expression [40,41]. In earlier studies, P53 overexpression was shown to augment the negative prognostic effect of MYC/BCL2 double hit lymphoma and MYC/BCL2 double expression lymphoma [28,30]; in other words, P53 expression is a poor prognostic factor in MYC/BCL2 double hit lymphoma.…”

Double hit and double expressors in lymphoma: Definition and treatment

“…The authors postulate that in this setting, TP53 mutations may be synergistic with BCL2 translocations through inhibition of apoptosis, and furthermore, the combination may confer a competitive advantage in clonal evolution. Interestingly, Clipson et al 49 noted that patients with DLBCL with MYC rearrangements and TP53 mutations demonstrated worse survival than patients with MYC/BCL2 DHL, and this suggested the need to evaluate for TP53 mutations in cases of MYC-rearranged DLBCL. Wang et al 11 also evaluated the impact of p53 expression in MYC-rearranged DLBCL, MYC-overexpressed DLBCL, MYC/BCL2 DHL, and DEL.…”

High Incidence and Clinical Significance of MYC Rearrangements in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

“…(5)(6)(7)(8) In over half of the cases, MYC rearrangements occur in combination with a second hit in the BCL2 and/or BCL6 genes and these patients demonstrate an even worse outcome with a median overall survival (OS) reported between 0.2 and 1.5 years. (5,(8)(9)(10)(11)(12) In the 2017 revision of the WHO c double hit lymphomas (or triple hit lymphomas ) are classified as a separate disease entity with a very aggressive behavior. (13) In addition, 19 to 34% of the DLBCL patients have double protein expression of MYC and BCL2 (DE), but lack genetic rearrangements in these genes, demonstrating an intermediate survival between DLBCL with single or no expression of MYC and BCL2, and DLBCL with double or triple hits.…”