Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials

Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet, comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay. The IGH::CCND1 fusion was identified in 94% of patients, clonal IGH-V-(D)-J rearrangements in all, while 79% had ≥ 1 somatic gene mutation. The top mutated genes were ATM, TP53, KMT2D, SAMHD1, BIRC3 and NFKBIE. Copy number variations (CNVs) were detected in 83% of patients with RB1, ATM, CDKN2A/B and TP53 being the most deleted and KLF2, CXCR4, CCND1, MAP2K1 and MYC the top amplified genes. CNVs and mutations were more frequently observed in older patients with adverse impact on prognosis. TP53^mut, NOTCH1^mut, FAT1^mut TRAF2^del, CDKN2A/B^del and MAP2K1^amp associated with inferior failure-free and overall survival (OS), while TRAF2^mut, EGR2^del and BCL2^amp associated with inferior OS only. Genetic complexity (≥ 3 CNVs) observed in 51% of analysed patients associated significantly with impaired FFS and OS. We demonstrate that targeted sequencing from peripheral blood and bone marrow detects diagnostically and prognostically important genetic factors of MCL in patients treated in prospective trials, facilitating genetic characterization in clinical routine.