MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 – a Nordic Lymphoma Group study

Abstract

The transcription factor MYC is a well-described oncogene with an important role in lymphomagenesis, but its significance for clinical outcome in mantle cell lymphoma (MCL) remains to be determined. Here, we perform an investigation of the protein expression of MYC in a cohort of 251 MCL patients complemented with analyses of structural aberrations and mRNA, in a sub-cohort of patients. 14% (n=35) of patients showed high MYC protein expression with >20% positive cells (MYC^high), among which only one translocation was identified and 86% (n=216) of patients showed low MYC protein expression. Low copy number gains of MYC were detected in 10 patients, but with no correlation to MYC protein levels. However, MYC mRNA levels correlated significantly to MYC protein levels with a R² value of 0.76. Patients with a MYC^high tumor had both an independent inferior overall survival (OS) and progression-free survival (PFS) (Hazard ratio (HR)=2.03, 95% Confidence interval (CI) 1.2–3.4 and HR=2.2, 95%CI 1.04–4.6, respectively) when adjusted for additional high-risk features. Patients with MYC^high tumors also tended to have additional high-risk features and to be older at diagnosis. A subgroup of 13 patients had concomitant MYC^high expression and TP53/p53 alterations and had a substantially increased risk of progression (HR=16.9, 95%CI 7.4–38.3) and death (HR=7.8, 95%CI 4.4–14.1) with an average OS of only 0.9 years. In summary, we show that a subset of diagnostic MCL patients (14%) overexpress MYC protein, and has a poor prognosis but that MYC rearrangements are rare. Tumors with concurrent MYC overexpression and TP53/p53 alterations pinpoint MCL patients with a dismal prognosis below three years of median OS. We propose that MYC needs to be assessed beyond the current high-risk factors in MCL to identify cases in need of alternative treatment.