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

Abstract

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