Key Points

  • The primary CCND1 rearrangement is mediated by the same mechanisms in cMCL and nnMCL but they differ in the (epi)genetic and driver makeup.

  • Genomic complexity and DNA methylation changes related to proliferative cell history stratify patients with distinct clinical outcomes.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm initially driven by CCND1 rearrangement with two molecular subtypes, conventional (cMCL) and leukemic non-nodal (nnMCL), that differ in their clinicobiological behavior. To identify the genetic/epigenetic alterations determining this diversity, we used whole-genome (n=61) and exome (n=21) sequencing (74% cMCL, 26% nnMCL) combined with transcriptome and DNA methylation profiles in the context of five MCL reference epigenomes. We identified that open and active chromatin at the major translocation cluster locus might facilitate the t(11;14)(q13;32), which modifies the 3-dimensional structure of the involved regions. This translocation is mainly acquired in precursor B cells mediated by RAG in both MCL subtypes, while in 8% of cases occurs in mature B cells mediated by AID. We identified novel recurrent MCL drivers, including CDKN1B, SAMHD1, BCOR, SYNE1, HNRNPH1, SMARCB1, and DAZAP1. Complex structural alterations emerge as a relevant early oncogenic mechanism in MCL targeting key driver genes. Breakage-fusion bridge cycles and translocations activated oncogenes (BMI1, MIR17HG, TERT, MYC, and MYCN), generating gene amplifications and remodeling regulatory regions. cMCL carried significant higher numbers of structural variants, copy number alterations, and driver changes than nnMCL, with exclusive alterations of ATM in cMCL, whereas TP53 and TERT alterations were slightly enriched in nnMCL. Several drivers had prognostic impact, but only TP53 and MYC aberrations added value independently of genomic complexity. An increasing genomic complexity together with the presence of breakage-fusion bridge cycles and high DNA methylation changes related to the proliferative cell history discriminate patients with different clinical evolution.

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