MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and <i>TP53</i>/p53 – a Nordic Lymphoma Group study
Joana M. Rodrigues,
Peter Hollander,
Lina Schmidt,
Eirinaios Gkika,
Masoud Razmara,
Darshan Kumar,
Christian Geisler,
Kirsten Grønbæk,
Christian W. Eskelund,
Riikka Räty,
Arne Kolstad,
Christer Sundström,
Ingrid Glimelius,
Anna Porwit,
Mats Jerkeman,
Sara Ek
Affiliations
Joana M. Rodrigues
Department of Immunotechnology, Lund University
Peter Hollander
Cancer Immunotherapy, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala
Lina Schmidt
Department of Immunotechnology, Lund University
Eirinaios Gkika
Department of Immunotechnology, Lund University
Masoud Razmara
Department of Clinical Pathology, Akademiska University Hospital, Uppsala
Darshan Kumar
Aiforia Technologies Plc, Helsinki
Christian Geisler
Department of Hematology, Rigshospitalet, Copenhagen
Kirsten Grønbæk
Department of Hematology, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen
Christian W. Eskelund
Department of Hematology, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen
Riikka Räty
Department of Hematology, Helsinki University Hospital, Helsinki
Arne Kolstad
Department of Oncology, Innlandet Hospital Trust, Division Gjøvik-Lillehammer
Christer Sundström
Department of Immunology, Genetics and Pathology, Cancer Precision Medicine, Uppsala University, Uppsala
Ingrid Glimelius
Department of Immunology, Genetics and Pathology, Cancer Precision Medicine, Uppsala University, Uppsala
Anna Porwit
Division of Oncology, Department of Clinical Sciences, Lund University, Lund
Mats Jerkeman
Division of Oncology, Department of Clinical Sciences, Lund University, Lund
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. We performed an investigation of the expression of MYC protein in a cohort of 251 MCL patients complemented by analyses of structural aberrations and mRNA, in a sub-cohort of patients. Fourteen percent (n=35) of patients showed high MYC protein expression with >20% positive cells (MYChigh), among whom 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 ten 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 MYChigh tumor had both an independent inferior overall survival and an inferior progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% 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 MYChigh tumors also tended to have additional high-risk features and to be older at diagnosis. A subgroup of 13 patients had concomitant MYChigh expression and TP53/p53 alterations and 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 overall survival of only 0.9 years. In summary, we found that at diagnosis a subset of MCL patients (14%) overexpressed MYC protein, and had a poor prognosis but that MYC rearrangements were rare. Tumors with concurrent MYC overexpression and TP53/p53 alterations pinpointed MCL patients with a dismal prognosis with a median overall survival of less than 3 years. We propose that MYC needs to be assessed beyond the current high-risk factors in MCL in order to identify cases in need of alternative treatment.
