Genomic and epigenomic insights into the origin, pathogenesis and clinical behavior of mantle cell lymphoma subtypes.

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.

[1]  E. Campo,et al.  Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation , 2019, Nature Communications.

[2]  Ryan D. Morin,et al.  IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms , 2020, Nature Communications.

[3]  E. Giné,et al.  The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome , 2019, Nature Cancer.

[4]  Ryan D. Morin,et al.  --The double hit signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to FISH. , 2019, Blood.

[5]  D. Rossi,et al.  KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study , 2019, Haematologica.

[6]  J. Manley,et al.  TCF3 mutually exclusive alternative splicing is controlled by long-range cooperative actions between hnRNPH1 and PTBP1 , 2019, RNA.

[7]  Romina Royo,et al.  A practical guide for mutational signature analysis in hematological malignancies , 2019, Nature Communications.

[8]  J. Pearson,et al.  Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers. , 2019 .

[9]  S. Pinder,et al.  Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years , 2019, Breast Cancer Research.

[10]  D. Torrents,et al.  CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1- mantle cell lymphoma. , 2019, Blood.

[11]  Ville Mustonen,et al.  The repertoire of mutational signatures in human cancer , 2018, Nature.

[12]  S. Dawson,et al.  Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma , 2018, Nature Medicine.

[13]  Feng Liu,et al.  Palimpsest: an R package for studying mutational and structural variant signatures along clonal evolution in cancer , 2018, Bioinform..

[14]  Howard Y. Chang,et al.  Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element , 2018, Cell.

[15]  E. Campo,et al.  Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. , 2018, Blood.

[16]  B. Stillman,et al.  The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592 , 2018, Cell cycle.

[17]  Hui Shen,et al.  DNA methylation loss in late-replicating domains is linked to mitotic cell division , 2018, Nature Genetics.

[18]  A. Rosenwald,et al.  Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL Network. , 2018, Blood.

[19]  E. Giné,et al.  A new molecular assay and genomic complexity predict outcome in conventional and leukemic non-nodal mantle cell lymphoma , 2018 .

[20]  J. W. Hansen,et al.  TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. , 2017, Blood.

[21]  S. Swerdlow.  WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues , 2017 .

[22]  S. Gabriel,et al.  Rare Germline Variants in ATM Are Associated with Chronic Lymphocytic Leukemia , 2017, Leukemia.

[23]  R. Wilson,et al.  CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression , 2017, Cell.

[24]  C. Porter.  Germ line mutations associated with leukemias. , 2016, Hematology. American Society of Hematology. Education Program.

[25]  Steven J. M. Jones,et al.  The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery , 2016, Cell.

[26]  E. Giné,et al.  Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage. , 2016, Cancer cell.

[27]  Shijie C. Zheng,et al.  Correlation of an epigenetic mitotic clock with cancer risk , 2016, Genome Biology.

[28]  L. Wessels,et al.  Defining chromosomal translocation risks in cancer , 2016, Proceedings of the National Academy of Sciences.

[29]  M. Lieber.  Mechanisms of human lymphoid chromosomal translocations , 2016, Nature Reviews Cancer.

[30]  Ryan D. Morin,et al.  Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations , 2016, Oncotarget.

[31]  R. Advani,et al.  The World Health Organization Classification of Lymphoid Neoplasms , 2013 .

[32]  Martin A. Nowak,et al.  Mutations driving CLL and their evolution in progression and relapse , 2015, Nature.

[33]  W. Klapper,et al.  High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. , 2015, Blood.

[34]  A. Valencia,et al.  Non-coding recurrent mutations in chronic lymphocytic leukaemia , 2015, Nature.

[35]  Carolina E. Pardo,et al.  Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin , 2015, Molecular and Cellular Biology.

[36]  E. Campo,et al.  Mantle cell lymphoma: evolving management strategies. , 2015, Blood.

[37]  Modesto Orozco,et al.  Comprehensive characterization of complex structural variations in cancer by directly comparing genome sequence reads , 2014, Nature Biotechnology.

[38]  Dereje D. Jima,et al.  The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. , 2014, Blood.

[39]  E. Campo,et al.  Assessment of SOX11 Expression in Routine Lymphoma Tissue Sections: Characterization of New Monoclonal Antibodies for Diagnosis of Mantle Cell Lymphoma , 2014, The American journal of surgical pathology.

[40]  Manel Juan,et al.  Landscape of somatic mutations and clonal evolution in mantle cell lymphoma , 2013, Proceedings of the National Academy of Sciences.

[41]  A. Nussenzweig,et al.  The AID-induced DNA damage response in chromatin. , 2013, Molecular cell.

[42]  G. Morgan,et al.  Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. , 2013, Blood.

[43]  Richard A. Moore,et al.  The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma. , 2013, Blood.

[44]  Zachary D. Smith,et al.  Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. , 2013, Cell stem cell.

[45]  Ryan M. Layer,et al.  LUMPY: a probabilistic framework for structural variant discovery , 2012, Genome Biology.

[46]  Zohar Mukamel,et al.  Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues , 2012, Nature Genetics.

[47]  M. Lieber,et al.  IgH partner breakpoint sequences provide evidence that AID initiates t(11;14) and t(8;14) chromosomal breaks in mantle cell and Burkitt lymphomas. , 2012, Blood.

[48]  E. Campo,et al.  Molecular pathogenesis of mantle cell lymphoma. , 2012, The Journal of clinical investigation.

[49]  A. Børresen-Dale,et al.  The Life History of 21 Breast Cancers , 2012, Cell.

[50]  E. Giné,et al.  Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease , 2012, Leukemia.

[51]  Ryan D. Morin,et al.  Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. , 2012, Blood.

[52]  R. Lai,et al.  Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis , 2011, Haematologica.

[53]  J. Leonard,et al.  Is there a role for "watch and wait" in patients with mantle cell lymphoma? , 2011, Seminars in hematology.

[54]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[55]  D. Aran,et al.  Replication timing-related and gene body-specific methylation of active human genes. , 2011, Human molecular genetics.

[56]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[57]  R. Gascoyne,et al.  Deregulation of the telomerase reverse transcriptase (TERT) gene by chromosomal translocations in B-cell malignancies. , 2010, Blood.

[58]  A. Rosenwald,et al.  Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. , 2010, Cancer research.

[59]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[60]  Paul Marjoram,et al.  Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers , 2009, Proceedings of the National Academy of Sciences.

[61]  J. Leonard,et al.  Outcome of deferred initial therapy in mantle-cell lymphoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  H. Pospíšilová,et al.  Translocations targeting CCND2, CCND3, and MYCN do occur in t(11;14)-negative mantle cell lymphomas. , 2008, Blood.

[63]  J. Herman,et al.  CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin lymphomas. , 2002, Blood.

[64]  Riccardo Dalla-Favera,et al.  Mechanisms of chromosomal translocations in B cell lymphomas , 2001, Oncogene.

[65]  E. Campo,et al.  BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. , 2001, Cancer research.

[66]  B. Nadel,et al.  Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma. , 2001, Cancer research.