Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma
Jessica Okosun, Csaba Bödör, Jun Wang, Shamzah Araf, Cheng-Yuan Yang, Chenyi Pan, Sören Boller, Davide Cittaro, Monika Bozek, Sameena Iqbal, Janet Matthews, David Wrench, Jacek Marzec, Kiran Tawana, Nikolay Popov, Ciaran O'Riain, Derville O'Shea, Emanuela Carlotti, Andrew Davies, Charles H Lawrie, Andras Matolcsy, Maria Calaminici, Andrew Norton, Richard J Byers, Charles Mein, Elia Stupka, T Andrew Lister, Georg Lenz, Silvia Montoto, John G Gribben, Yuhong Fan, Rudolf Grosschedl, Claude Chelala, Jude Fitzgibbon, Jessica Okosun, Csaba Bödör, Jun Wang, Shamzah Araf, Cheng-Yuan Yang, Chenyi Pan, Sören Boller, Davide Cittaro, Monika Bozek, Sameena Iqbal, Janet Matthews, David Wrench, Jacek Marzec, Kiran Tawana, Nikolay Popov, Ciaran O'Riain, Derville O'Shea, Emanuela Carlotti, Andrew Davies, Charles H Lawrie, Andras Matolcsy, Maria Calaminici, Andrew Norton, Richard J Byers, Charles Mein, Elia Stupka, T Andrew Lister, Georg Lenz, Silvia Montoto, John G Gribben, Yuhong Fan, Rudolf Grosschedl, Claude Chelala, Jude Fitzgibbon
Abstract
Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.
Figures
References
- Swenson WT, et al. Improved survival of follicular lymphoma patients in the United States. J Clin Oncol. 2005;23:5019–26.
- Al-Tourah AJ, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:5165–9.
- Montoto S, Fitzgibbon J. Transformation of indolent B-cell lymphomas. J Clin Oncol. 2011;29:1827–34.
- Montoto S, et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol. 2007;25:2426–33.
- Carlotti E, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone. Blood. 2009;113:3553–7.
- Eide MB, et al. Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones. Blood. 2010;116:1489–97.
- Ruminy P, et al. S(mu) mutation patterns suggest different progression pathways in follicular lymphoma: early direct or late from FL progenitor cells. Blood. 2008;112:1951–9.
- Weigert O, et al. Molecular ontogeny of donor-derived follicular lymphomas occurring after hematopoietic cell transplantation. Cancer Discov. 2012;2:47–55.
- Bödör C, et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia. 2011;25:726–9.
- Morin RD, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5.
- Morin RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.
- Pasqualucci L, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471:189–95.
- Lenz G, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319:1676–9.
- Davis RE, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88–92.
- Pasqualucci L, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.
- Zhang J, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110:1398–403.
- Bednar J, et al. Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc Natl Acad Sci U S A. 1998;95:14173–8.
- Croston GE, Kerrigan LA, Lira LM, Marshak DR, Kadonaga JT. Sequence-specific antirepression of histone H1-mediated inhibition of basal RNA polymerase II transcription. Science. 1991;251:643–9.
- Fan Y, et al. Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell. 2005;123:1199–212.
- Brown DT, Izard T, Misteli T. Mapping the interaction surface of linker histone H1(0) with the nucleosome of native chromatin in vivo. Nat Struct Mol Biol. 2006;13:250–5.
- Goytisolo FA, et al. Identification of two DNA-binding sites on the globular domain of histone H5. EMBO J. 1996;15:3421–9.
- Ramakrishnan V, Finch JT, Graziano V, Lee PL, Sweet RM. Crystal structure of globular domain of histone H5 and its implications for nucleosome binding. Nature. 1993;362:219–23.
- Vyas P, Brown DT. N- and C-terminal domains determine differential nucleosomal binding geometry and affinity of linker histone isotypes H1(0) and H1c. J Biol Chem. 2012;287:11778–87.
- Mottok A, et al. Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities. Blood. 2009;114:4503–6.
- Ritz O, et al. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood. 2009;114:1236–42.
- Baus D, et al. STAT6 and STAT1 are essential antagonistic regulators of cell survival in classical Hodgkin lymphoma cell line. Leukemia. 2009;23:1885–93.
- Mottok A, Renné C, Willenbrock K, Hansmann ML, Bräuninger A. Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood. 2007;110:3387–90.
- Ritz O, et al. STAT6 activity is regulated by SOCS-1 and modulates BCL-XL expression in primary mediastinal B-cell lymphoma. Leukemia. 2008;22:2106–10.
- Compagno M, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 2009;459:717–21.
- Ngo VN, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–9.
- Harvey RC, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116:4874–84.
- Hagman J, Belanger C, Travis A, Turck CW, Grosschedl R. Cloning and functional characterization of early B-cell factor, a regulator of lymphocyte-specific gene expression. Genes Dev. 1993;7:760–73.
- Treiber N, Treiber T, Zocher G, Grosschedl R. Structure of an Ebf1:DNA complex reveals unusual DNA recognition and structural homology with Rel proteins. Genes Dev. 2010;24:2270–5.
- Treiber T, et al. Early B cell factor 1 regulates B cell gene networks by activation, repression, and transcription- independent poising of chromatin. Immunity. 2010;32:714–25.
- Carter SL, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30:413–21.
- Green MR, et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood. 2013;121:1604–11.
- Treon SP, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367:826–33.
- Ladetto M, et al. A validated real-time quantitative PCR approach shows a correlation between tumor burden and successful ex vivo purging in follicular lymphoma patients. Exp Hematol. 2001;29:183–93.
- Van Loo P, et al. Allele-specific copy number analysis of tumors. Proc Natl Acad Sci U S A. 2010;107:16910–5.
- Saunders CT, et al. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics. 2012;28:1811–7.
- Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler etc. Bioinformatics. 2009;25(14):1754–1760.
- DePristo MA, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–8.
- Dayem Ullah AZ, Lemoine NR, Chelala C. SNPnexus: a web server for functional annotation of novel and publicly known genetic variants (2012 update) Nucleic Acids Res. 2012;40:W65–70.
- Koboldt DC, et al. VarScan2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22:568–76.
- Olshen AB, Venkatraman ES, Lucito R, Wigler M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics. 2004;5:557–72.
- Ye K, Schulz MH, Long Q, Apweiler R, Ning Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics. 2009;25:2865–2871.
- Rausch T, et al. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28:i333–i339.
- Chen K, et al. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat Methods. 2009;6:677–81.
- Saitou N, Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987;4:406–25.
- Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.
- Li H, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.
- Landau DA, Wu CJ. Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics. Genome Med. 2013;5:47.
- Pasqualucci L, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001;412:341–6.
- Khodabakhshi AH, et al. Recurrent targets of aberrant somatic hypermutation in lymphoma. Oncotarget. 2012;3:1308–19.
- Zhang Y, et al. Histone h1 depletion impairs embryonic stem cell differentiation. PLoS Genet. 2012;8:e1002691.
- Cao K, et al. High-resolution mapping of h1 linker histone variants in embryonic stem cells. PLoS Genet. 2013;9:e1003417.
- Fan Y, Skoultchi AI. Genetic analysis of H1 linker histone subtypes and their functions in mice. Methods Enzymol. 2004;377:85–107.
- Medrzycki M, Zhang Y, Cao K, Fan Y. Expression analysis of mammalian linker-histone subtypes. J Vis Exp. 2012;(61):3577.
Source: PubMed