LYMPHOID NEOPLASIA| JULY 30, 2020
Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencingPrasath Pararajalingam, Krysta M. Coyle, Sarah E. Arthur, Nicole Thomas, Miguel Alcaide, Barbara Meissner, Merrill Boyle, Quratulain Qureshi, Bruno M. Grande, Christopher Rushton, Graham W. Slack, Andrew J. Mungall, Constantine S. Tam, Rishu Agarwal, Sarah-Jane Dawson, Georg Lenz, Sriram Balasubramanian, Randy D. Gascoyne, Christian Steidl, Joseph Connors, Diego Villa, Timothy E. Audas, Marco A. Marra, Nathalie A. Johnson, David W. Scott, Ryan D. Morin
Blood (2020) 136 (5): 572–584.
https://doi.org/10.1182/blood.2019002385
Key PointsRNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL.
Most somatic HNRNPH1 mutations are intronic and disrupt regulation of HNRNPH1 through alternative splicing.
AbstractMantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.
Subjects:
Lymphoid Neoplasia
Topics:
exome, follow-up, mantle-cell lymphoma, mutation, protein p53, rna splicing, rna, messenger, tp53 gene, genes, neoplasms
REFERENCES1.Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2017;92(8):806-813.
2.Chen D, Viswanatha DS, Zent CS, et al. Indolent Mantle Cell Lymphoma: A Distinct Subgroup Characterized by Leukemic Phase Disease without Lymphadenopathy [abstract]. Blood. 2009;114(22). Abstract 3937.
3.Abrisqueta P, Scott DW, Slack GW, et al. Observation as the initial management strategy in patients with mantle cell lymphoma. Ann Oncol. 2017;28(10):2489-2495.
4.Lim SY, Horsman JM, Hancock BW. The Mantle Cell Lymphoma International Prognostic Index: Does it work in routine practice? Oncol Lett. 2010;1(1):187-188.
5.Maddocks K. Update on mantle cell lymphoma. Blood. 2018;132(16):1647-1656.
6.Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol. 2016;34(11):1256-1269.
7.Mohanty A, Sandoval N, Das M, et al. CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma. Oncotarget. 2016;7(45):73558-73572.
8.Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood. 2007;109(11):4599-4606.
9.Beà S, Valdés-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA. 2013;110(45):18250-18255.
10.Zhang J, Jima D, Moffitt AB, et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123(19):2988-2996.
11.Wu C, de Miranda NF, Chen L, et al. Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations. Oncotarget. 2016;7(25):38180-38190.
12.Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012;119(9):1963-1971.
13.Halldórsdóttir AM, Lundin A, Murray F, et al. Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia. 2011;25(12):1904-1908.
14.Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3(2):185-197.
15.Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med. 2018;378(13):1211-1223.
16.Espinet B, Salaverria I, Bea S, et al. Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma. Genes Chromosome Canc. 49(5):439-451.
17.Agarwal R, Chan Y-C, Tam CS, et al. Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat Med. 2019;25(1):119-129.
18.Scott DW, Abrisqueta P, Wright GW, et al; Lymphoma/Leukemia Molecular Profiling Project. New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies. J Clin Oncol. 2017;35(15):1668-1677.
19.Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv. 2013;1303.3997.
20.Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15-21. doi:10.1093/bioinformatics/bts635
21.Saunders CT, Wong WSW, Swamy S, Becq J, Murray LJ, Cheetham RK. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics. 2012;28(14):1811-1817.
22.Kim S, Scheffler K, Halpern AL, et al. Strelka2: fast and accurate calling of germline and somatic variants. Nat Methods. 2018;15(8):591-594.
23.McLaren W, Gil L, Hunt SE, et al. The Ensembl Variant Effect Predictor. Genome Biol. 2016;17(1):122.
24.Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-218.
25.Gonzalez-Perez A, Lopez-Bigas N. Functional impact bias reveals cancer drivers. Nucleic Acids Res. 2012;40(21):e169.
26.Mularoni L, Sabarinathan R, Deu-Pons J, Gonzalez-Perez A, López-Bigas N. OncodriveFML: a general framework to identify coding and non-coding regions with cancer driver mutations. Genome Biol. 2016;17(1):128.
27.Tamborero D, Gonzalez-Perez A, Lopez-Bigas N. OncodriveCLUST: exploiting the positional clustering of somatic mutations to identify cancer genes. Bioinformatics. 2013;29(18):2238-2244.
28.Mansouri L, Noerenberg D, Young E, et al. Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood. 2016;128(23):2666-2670.
29.Arthur SE, Jiang A, Grande BM, et al. Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nat Commun. 2018;9(1):4001.
30.Reddy A, Zhang J, Davis NS, et al. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017;171(2):481-494.e15.
31.Schmitz R, Wright GW, Huang DW, et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018;378(15):1396-1407.
32.Lin Y-C, Boone M, Meuris L, et al. Genome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations. Nat Commun. 2014;5(1):4767.
33.Meissner B, Kridel R, Lim RS, et al. The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma. Blood. 2013;121(16):3161-3164.
34.Ahmed M, Zhang L, Nomie K, Lam L, Wang M. Gene mutations and actionable genetic lesions in mantle cell lymphoma. Oncotarget. 2016;7(36):58638-58648.
35.Smith RWP, Anderson RC, Smith JWS, Brook M, Richardson WA, Gray NK. DAZAP1, an RNA-binding protein required for development and spermatogenesis, can regulate mRNA translation. RNA. 2011;17(7):1282-1295.
36.Paronetto MP, Miñana B, Valcárcel J. The Ewing sarcoma protein regulates DNA damage-induced alternative splicing. Mol Cell. 2011;43(3):353-368.
37.Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208(7):1389-1401.
38.Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476(7360):298-303.
39.Lin Y-T, Yen PH. A novel nucleocytoplasmic shuttling sequence of DAZAP1, a testis-abundant RNA-binding protein. RNA. 2006;12(8):1486-1493.
40.Dai T, Vera Y, Salido EC, Yen PH. Characterization of the mouse Dazap1 gene encoding an RNA-binding protein that interacts with infertility factors DAZ and DAZL. BMC Genomics. 2001;2(1):6.
41.Choudhury R, Roy SG, Tsai YS, Tripathy A, Graves LM, Wang Z. The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration. Nat Commun. 2014;5(1):3078.
42.Uren PJ, Bahrami-Samani E, de Araujo PR, et al. High-throughput analyses of hnRNP H1 dissects its multi-functional aspect. RNA Biol. 2016;13(4):400-411.
43.Khodadoust MS, Olsson N, Wagar LE, et al. Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens. Nature. 2017;543(7647):723-727.
44.Rule S, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia. 2018;32(8):1799-1803.
45.Grande BM, Gerhard DS, Jiang A, et al. Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood. 2019;133(12):1313-1324.
46.Rossbach O, Hung L-H, Schreiner S, et al. Auto- and cross-regulation of the hnRNP L proteins by alternative splicing. Mol Cell Biol. 2009;29(6):1442-1451.
47.Martinez FJ, Pratt GA, Van Nostrand EL, et al. Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System. Neuron. 2016;92(4):780-795.
48.Ferrero S, Rossi D, Rinaldi A, et al. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study [published online ahead of print 19 September 2019]. Haematologica. doi:haematol.2018.214056.
49.Änkö M-L, Müller-McNicoll M, Brandl H, et al. The RNA-binding landscapes of 2 SR proteins reveal unique functions and binding to diverse RNA classes. Genome Biol. 2012;13(3):R17.
50.Saltzman AL, Pan Q, Blencowe BJ. Regulation of alternative splicing by the core spliceosomal machinery. Genes Dev. 2011;25(4):373-384.
51.Pereverzev AP, Gurskaya NG, Ermakova GV, et al. Method for quantitative analysis of nonsense-mediated mRNA decay at the single cell level. Sci Rep. 2015;5(1):7729.
52.Noensie EN, Dietz HC. A strategy for disease gene identification through nonsense-mediated mRNA decay inhibition. Nat Biotechnol. 2001;19(5):434-439.
53.Yang P, Zhang W, Wang J, Liu Y, An R, Jing H. Genomic landscape and prognostic analysis of mantle cell lymphoma. Cancer Gene Ther. 2018;25(5-6):129-140.
54.Grünewald TGP, Cidre-Aranaz F, Surdez D, et al. Ewing sarcoma. Nat Rev Dis Primers. 2018;4(1):5.
55.Sanchez G, Delattre O, Auboeuf D, Dutertre M. Coupled alteration of transcription and splicing by a single oncogene: boosting the effect on cyclin D1 activity. Cell Cycle. 2008;7(15):2299-2305.
56.Chen H-Y, Yu Y-H, Yen PH. DAZAP1 regulates the splicing of Crem, Crisp2 and Pot1a transcripts. Nucleic Acids Res. 2013;41(21):9858-9869.
57.Honoré B, Baandrup U, Vorum H. Heterogeneous nuclear ribonucleoproteins F and H/H′ show differential expression in normal and selected cancer tissues. Exp Cell Res. 2004;294(1):199-209.
58.Rauch J, O』Neill E, Mack B, et al. Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. Cancer Res. 2010;70(4):1679-1688.
59.Sun Y-L, Liu F, Liu F, Zhao X-H. Protein and gene expression characteristics of heterogeneous nuclear ribonucleoprotein H1 in esophageal squamous cell carcinoma. World J Gastroenterol. 2016;22(32):7322-7331.
60.Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016;135(8):851-867.
61.Wang E, Aslanzadeh V, Papa F, Zhu H, de la Grange P, Cambi F. Global profiling of alternative splicing events and gene expression regulated by hnRNPH/F. PLoS One. 2012;7(12):e51266.
62.Änkö M-L, Morales L, Henry I, Beyer A, Neugebauer KM. Global analysis reveals SRp20- and SRp75-specific mRNPs in cycling and neural cells. Nat Struct Mol Biol. 2010;17(8):962-970.
63.Jumaa H, Nielsen PJ. The splicing factor SRp20 modifies splicing of its own mRNA and ASF/SF2 antagonizes this regulation. EMBO J. 1997;16(16):5077-5085.
64.Pervouchine D, Popov Y, Berry A, Borsari B, Frankish A, Guigó R. Integrative transcriptomic analysis suggests new autoregulatory splicing events coupled with nonsense-mediated mRNA decay. Nucleic Acids Res. 2019;47(10):5293-5306.
65.Cannell IG, Merrick KA, Morandell S, et al. A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy. Cancer Cell. 2015;28(5):623-637.
66.Díaz-Muñoz MD, Turner M. Uncovering the Role of RNA-Binding Proteins in Gene Expression in the Immune System. Front Immunol. 2018;9:1094.
67.Saha S, Murmu KC, Biswas M, et al. Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia. Front Oncol. 2019;9:692.
68.LeFave CV, Squatrito M, Vorlova S, et al. Splicing factor hnRNPH drives an oncogenic splicing switch in gliomas. EMBO J. 2011;30(19):4084-4097.
69.Golan-Gerstl R, Cohen M, Shilo A, et al. Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. Cancer Res. 2011;71(13):4464-4472.
70.Xu C, Xie N, Su Y, et al. HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation [published online ahead of print 20 December 2019]. Cell Death Differ. 2019;
71.Hong S. RNA Binding Protein as an Emerging Therapeutic Target for Cancer Prevention and Treatment. J Cancer Prev. 2017;22(4):203-210.
72.Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2011;44(1):47-52.
73.Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood. 2011;118(26):6904-6908.
74.Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365(26):2497-2506.
75.Wang L, Brooks AN, Fan J, et al. Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia. Cancer Cell. 2016;30(5):750-763.
76.Ten Hacken E, Valentin R, Regis FFD, et al. Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight. 2018;3(19):e121438.
77.Te Raa GD, Derks IA, Navrkalova V, et al. The impact of SF3B1 mutations in CLL on the DNA-damage response. Leukemia. 2015;29(5):1133-1142.
© 2020 by The American Society of Hematology
This program is developed by Focus Insight with the permission of American Society of Hematology, Inc. The content are excerpted from the journal Blood. Copyright © 2019 The American Society of Hematology. All rights reserved. 「American Society of Hematology」, 「ASH」 and the ASH Logo are registered trademarks of the American Society of Hematology.