Surveying the Genomic Landscape of Mantle Cell Lymphoma Indicates the Importance of Multimodal Genomic and Transcriptomic Exploration

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by heterogeneous clinical courses despite a common pathobiological initiating event. In this work we explore the genomic variants that characterize MCL and integrate transcriptomic data to comprehensively describe MCL biology. We performed whole exome sequencing (WES) on 28 tumor-normal pairs (lymph node and skin, respectively), as well as whole genome sequencing (WGS) and RNA sequencing on subsets of samples. We used established DNA and RNA analysis pipelines to detect single-nucleotide variants (SNV) and indels, structural variants, copy-number alterations, and RNA fusions. The canonical t(11;14)(q13;q32) CCND1::IGH translocation was detected in 8 of 10 WGS samples. Structural variant analysis additionally identified recurrent rearrangements involving KMT2A and PAFAH1B2. SNV and indel analyses revealed frequent mutations in ATM, TP53, CCND1, IGH, and NOTCH1. ATM exhibited diverse variant classes, including missense mutations, frameshift mutations, deletions, and duplications, while all detected NOTCH1 mutations were predicted loss-of-function frameshift variants. Copy-number analysis identified recurrent losses affecting DNA damage response genes, including TP53 and ATM, and recurrent gains involving transcriptional regulators and oncogenic signaling genes. Integrated pathway analysis demonstrated enrichment of transcriptional misregulation, DNA repair, PI3K/AKT signaling, and interleukin signaling pathways. We also identified recurrent alterations in candidate genes, including ASXL1, suggesting additional mechanisms of epigenetic dysregulation in MCL. Together, these findings provide a comprehensive description of somatic alterations in MCL and demonstrate that diverse genomic lesions converge on common pathways involved in genomic instability, transcriptional regulation, and tumor survival.