The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways

A comprehensive constellation of somatic nonsilent mutations and copy-number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors, we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of TNFAIP3 (26%) were among the most common aberrations. Candidate cancer driver genes cluster in the B-cell receptor (BCR), NF-κB, NOTCH, and NFAT signaling pathways. One of the most commonly altered genes is CABIN1, a calcineurin inhibitor acting as a negative regulator of the NFAT and MEF2B transcriptional activity. CABIN1 deletions enhance BCR-stimulated NFAT and MEF2B transcriptional activity, while CABIN1 mutations enhance only MEF2B transcriptional activity by impairing binding of mSin3a to CABIN1. Our data provide an unbiased identification of genetically altered genes that may play a role in the molecular pathogenesis of OAMZL and serve as therapeutic targets. Significance: We report systematic application of whole-exome sequencing and CN variations in OAMZL, revealing common alterations in regulation of NFAT signaling pathway that may facilitate identification of new therapies.

[1]  M. Seifert,et al.  Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing , 2020, Cancers.

[2]  A. Tzankov,et al.  High throughput sequencing reveals high specificity of TNFAIP3 mutations in ocular adnexal marginal zone B‐cell lymphomas , 2020, Hematological oncology.

[3]  C. Lengerke,et al.  Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma. , 2019, Blood.

[4]  R. Gascoyne,et al.  Novel insights into the genetics and epigenetics of MALT lymphoma unveiled by next generation sequencing analyses , 2019, Haematologica.

[5]  I. Lossos,et al.  LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL. , 2019, Cancer cell.

[6]  B. Guillen-Guio,et al.  Whole-Exome Sequencing Identifies Somatic Mutations Associated With Mortality in Metastatic Clear Cell Kidney Carcinoma , 2019, Front. Genet..

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

[8]  T. Owa,et al.  Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. , 2018, The Lancet. Oncology.

[9]  Stefano Monti,et al.  Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes , 2018, Nature Medicine.

[10]  G. Vassiliou,et al.  Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites , 2018, Haematologica.

[11]  Roland Schmitz,et al.  Genetics and Pathogenesis of Diffuse Large B‐Cell Lymphoma , 2018, The New England journal of medicine.

[12]  D. Rossi,et al.  Recent advances in understanding the biology of marginal zone lymphoma , 2018, F1000Research.

[13]  D. Dunson,et al.  Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma , 2017, Cell.

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

[15]  B. Berman,et al.  Identification of distinct mutational patterns and new driver genes in oesophageal squamous cell carcinomas and adenocarcinomas , 2017, Gut.

[16]  C. Dearden,et al.  Epidemiology and environmental aspects of marginal zone lymphomas. , 2017, Best practice & research. Clinical haematology.

[17]  J. Choi,et al.  The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP , 2017, Oncotarget.

[18]  R. Tibshirani,et al.  Long-term course of patients with primary ocular adnexal MALT lymphoma: a large single-institution cohort study. , 2017, Blood.

[19]  S. Bicciato,et al.  A comparative transcriptomic analysis of astrocytes differentiation from human neural progenitor cells , 2016, The European journal of neuroscience.

[20]  L. Pasqualucci,et al.  The genetics of nodal marginal zone lymphoma. , 2016, Blood.

[21]  W. Klapper,et al.  Recurrent mutations in NF-κB pathway components, KMT2D, and NOTCH1/2 in ocular adnexal MALT-type marginal zone lymphomas , 2016, Oncotarget.

[22]  S. Tomlins,et al.  Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies , 2016, Modern Pathology.

[23]  Roland Schmitz,et al.  Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma , 2015, Nature Medicine.

[24]  I. Lossos,et al.  Chlamydophila psittaci-negative ocular adnexal marginal zone lymphomas express self polyreactive B-cell receptors , 2015, Leukemia.

[25]  Wyeth W Wasserman,et al.  FLAGS, frequently mutated genes in public exomes , 2014, BMC Medical Genomics.

[26]  M. Calaminici,et al.  Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma , 2013, Nature Genetics.

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

[28]  B. Giusti,et al.  EXCAVATOR: detecting copy number variants from whole-exome sequencing data , 2013, Genome Biology.

[29]  Sander R. Dubovy,et al.  Molecular and genomic aberrations in Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas , 2013, American journal of hematology.

[30]  Steven J. M. Jones,et al.  Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. , 2013, Blood.

[31]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[32]  F. Vega,et al.  Transcriptional Regulation of Serine/Threonine Protein Kinase (AKT) Genes by Glioma-associated Oncogene Homolog 1* , 2013, The Journal of Biological Chemistry.

[33]  M. Du,et al.  Distinct involvement of NF‐κB regulators by somatic mutation in ocular adnexal malt lymphoma , 2013, British journal of haematology.

[34]  A. Sivachenko,et al.  Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples , 2013, Nature Biotechnology.

[35]  Irene Puga,et al.  Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes , 2013, Nature Reviews Immunology.

[36]  K. Elenitoba-Johnson,et al.  Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma , 2012, The Journal of experimental medicine.

[37]  S. Pileri,et al.  The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development , 2012, The Journal of experimental medicine.

[38]  Murat Sincan,et al.  Detecting false‐positive signals in exome sequencing , 2012, Human mutation.

[39]  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.

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

[41]  S. Hoehme,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2001 .

[42]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[43]  S. Falkow,et al.  Gastric MALT lymphoma B cells express polyreactive, somatically mutated immunoglobulins. , 2010, Blood.

[44]  I. Lossos,et al.  Extranodal marginal zone lymphoma of the ocular adnexa. , 2009, Blood.

[45]  J. Weill,et al.  Human marginal zone B cells. , 2009, Annual review of immunology.

[46]  Jun O. Liu.  Calmodulin‐dependent phosphatase, kinases, and transcriptional corepressors involved in T‐cell activation , 2009, Immunological reviews.

[47]  J. Viola,et al.  Dual Roles for NFAT Transcription Factor Genes as Oncogenes and Tumor Suppressors , 2008, Molecular and Cellular Biology.

[48]  Jan Delabie,et al.  Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma , 2008, Science.

[49]  L. Pham,et al.  Constitutive NF-κB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas , 2006 .

[50]  L. Pham,et al.  Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. , 2005, Blood.

[51]  Sander R. Dubovy,et al.  Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci. , 2005, Blood.

[52]  Y. Natkunam,et al.  The NFATc1 transcription factor is widely expressed in white cells and translocates from the cytoplasm to the nucleus in a subset of human lymphomas , 2005, British journal of haematology.

[53]  Michael Loran Dustin,et al.  LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation. , 2004, Immunity.

[54]  M. Boiocchi,et al.  Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. , 2004, Journal of the National Cancer Institute.

[55]  P. Isaacson,et al.  Bacterial infection and MALT lymphoma. , 2004, The New England journal of medicine.

[56]  M Hummel,et al.  Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936 , 2003, Leukemia.

[57]  Lin Chen,et al.  Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2 , 2003, Nature.

[58]  T. Honjo,et al.  Notch–RBP-J signaling is involved in cell fate determination of marginal zone B cells , 2002, Nature Immunology.

[59]  Jun O. Liu,et al.  Deletion of Calcineurin and Myocyte Enhancer Factor 2 (MEF2) Binding Domain of Cabin1 Results in Enhanced Cytokine Gene Expression in T Cells , 2001, The Journal of experimental medicine.

[60]  Anjana Rao,et al.  Gene regulation mediated by calcium signals in T lymphocytes , 2001, Nature Immunology.

[61]  H. Youn,et al.  Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2. , 2000, Immunity.

[62]  H. Youn,et al.  Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. , 1999, Science.

[63]  S. Akira,et al.  Interleukin-10 Receptor Signaling through the JAK-STAT Pathway , 1999, The Journal of Biological Chemistry.

[64]  H. Youn,et al.  Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. , 1998, Immunity.

[65]  M. Stolte,et al.  Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection , 1995, The Lancet.

[66]  P. Isaacson,et al.  Primary B cell lymphoma of the thyroid and its relationship to Hashimoto's thyroiditis. , 1988, Human pathology.

[67]  K. Stamatopoulos,et al.  Immunoglobulin gene repertoire in ocular adnexal lymphomas: hints on the nature of the antigenic stimulation , 2012, Leukemia.

[68]  L. Pham,et al.  Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. , 2006, Blood.

[69]  Claude-Alain H. Roten,et al.  Theoretical and practical advances in genome halving , 2004 .

[70]  K. Lennert,et al.  Development of malignant lymphoma in myoepithelial sialadenitis (Sjögren's syndrome) , 2004, Virchows Archiv A.