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SUPPLEMENTARY APPENDIX Whole Exome Sequencing Identifies Mutational Signatures of Vitreoretinal Lymphoma

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SUPPLEMENTARY APPENDIX Whole Exome Sequencing Identifies Mutational Signatures of Vitreoretinal Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing identifies mutational signatures of vitreoretinal lymphoma Junwon Lee, 1* Borahm Kim, 2* Hyeonah Lee, 3 Heejung Park, 4 Suk Ho Byeon, 1 Jong Rak Choi, 2 Sung Chul Lee, 1 Seung-Tae Lee 2 and Christopher Seungkyu Lee 1 *JL and BK contributed equally as co-first authors 1Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine; 2Department of Laboratory Medi - cine, Yonsei University College of Medicine; 3Brain Korea 21 PLUS Project for Medical Science, Yonsei University and 4Department of pathology, Yonsei Uni - versity College of medicine, Seoul, South Korea Correspondence: CHRISTOPHER SEUNGKYU LEE - [email protected] SEUNG-TAE LEE - [email protected] doi:10.3324/haematol.2019.233783 Supplemental Data Supplemental Methods Supplemental Table 1 Supplemental Figure 1-5 Supplementary Methods Whole exome sequencing (WES) Genomic DNA was extracted using a QIAamp DNA Blood Mini Kit (Qiagen). The sequencing libraries for Exome‐sequencing were prepared using the Twist Human Core Exome Kit (Twist Bioscience). Paired‐end 100 bp read sequencing was performed on a NovaSeq system (Illumina). The paired‐end reads were mapped to the human genome (NCBI build 37) using BWA (version 0.7.12).1 The alignment was further refined by the functions of local realignment, base quality recalibration and indel realignment provided by GATK software 3.8-0. In order to identify single nucleotide variations (SNVs) and indels, we used HaplotypeCaller and Mutect2 from the GATK package (3.8-0), and VarScan2 (2.4.0). The results of these three algorithms were compared and merged.2-4 An R package, ExomeDepth (version 1.1.10), was used to detect exon- or gene-level copy number variation (CNV) in the target regions,5 followed by visualization using a base-level read depth normalization algorithm implemented in the DxSeq Analyzer (Dxome). In order to identify candidate somatic mutations from a large variant pool, we employed the following exclusion criteria: 1) variants identified in matched germline samples; 2) variants with population frequency >0.0001 using frequency data from the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/) and the Korean reference genome database (KRGDB, http://152.99.75.168/KRGDB/menuPages/firstInfo.jsp); 3) variants presumed to be artifacts generated either by the high throughput sequencing platform or due to errors in alignment. All of the filtered variants were further examined by visual verification using the Integrative Genomic Viewer 6. Meta-analysis of previous primary CNS lymphoma whole exome sequencing cohorts The frequency of mutated genes in our VRL cohort was compared to results from the meta- analysis of four PCNSL cohorts.7-10 Ophthalmologic evaluation All patients underwent a comprehensive ophthalmic examination at baseline and during each follow-up visit. These examinations included evaluation of best-corrected visual acuity (BCVA), slit- lamp biomicroscopy, ophthalmoscopy, and Optomap ultra-widefield imaging (Optos PLC, Dunfermline, Fife, Scotland, UK). Diagnostic vitrectomy and cytology All patients underwent diagnostic vitrectomy. Extreme caution was exercised when applying the vitreous sampling technique and during the subsequent processes to prevent cell degeneration or necrosis. A 23 or 25 gauge (G) three-port pars plana vitrectomy was gently performed (for vitreous sampling) with a cutting rate of 500-1,000 cuts/minute in order to minimize cell damage. The undiluted vitreous (1-2 ml) was first obtained for cytologic analysis and interleukin-6 and -10 examinations. The infusion was subsequently started, and a second diluted vitreous specimen was collected in a separate bottle using gentle vitreous cutting. The diluted samples were used for the following studies: WES; immunoglobulin clonality assays; bacterial cultures and staining; fungal cultures and staining; and polymerase chain reaction (PCR) for varicella zoster virus (VZV), herpes simplex virus (HSV) type 1 and 2, cytomegalovirus (CMV), toxoplasmosis, and tuberculosis. The samples were immediately delivered to the pathology laboratory without fixation.11-13 Interleukin measurements and immunoglobulin clonality assays IL-6 and 10 levels were manually measured using the Human IL-6, 10 Quantikine ELISA (R&D Systems, Minneapolis, Minnesota, USA), according to the manufacturer’s instructions. B-cell heavy chain and kappa light chain immunoglobulin clonality assays were conducted using the LymphoTrack Dx IGH FR1 Assay Panel and LymphoTrack Dx IGK Assay Panel (Invivoscribe, Inc., San Diego, CA, USA) according to the manufacturer's instructions. The results were analyzed using LymphoTrack software (Invivoscribe). References (Supplementary Methods) 1 Li H. Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics 2014; 30: 2843-2851. 2 Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 2013; 31: 213-219. 3 DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011; 43: 491-498. 4 Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 2012; 22: 568-576. 5 Plagnol V, Curtis J, Epstein M, Mok KY, Stebbings E, Grigoriadou S et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics 2012; 28: 2747-2754. 6 Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G et al. Integrative genomics viewer. Nat Biotechnol 2011; 29: 24-26. 7 Bruno A, Boisselier B, Labreche K, Marie Y, Polivka M, Jouvet A et al. Mutational analysis of primary central nervous system lymphoma. Oncotarget 2014; 5: 5065-5075. 8 Braggio E, Van Wier S, Ojha J, McPhail E, Asmann YW, Egan J et al. Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas. Clin Cancer Res 2015; 21: 3986-3994. 9 Vater I, Montesinos-Rongen M, Schlesner M, Haake A, Purschke F, Sprute R et al. The mutational pattern of primary lymphoma of the central nervous system determined by whole- exome sequencing. Leukemia 2015; 29: 677-685. 10 Nakamura T, Tateishi K, Niwa T, Matsushita Y, Tamura K, Kinoshita M et al. Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol 2016; 42: 279-290. 11 Gonzales JA, Chan CC. Biopsy techniques and yields in diagnosing primary intraocular lymphoma. Int Ophthalmol 2007; 27: 241-250. 12 Margolis R, Brasil OF, Lowder CY, Singh RP, Kaiser PK, Smith SD et al. Vitrectomy for the diagnosis and management of uveitis of unknown cause. Ophthalmology 2007; 114: 1893- 1897. 13 Rajagopal R, Harbour JW. Diagnostic testing and treatment choices in primary vitreoretinal lymphoma. Retina 2011; 31: 435-440. Supplemental Table 1. Identified nonsynonymous somatic mutations ID chrom.pos gene NM HGVSc HGVSp VAF 7 chr11:64522792-64522792 PYGM NM_005609.2 c.808C>T p.Arg270Ter 0.43 7 chr1:149858886-149858886 HIST2H2AC NM_003517.2 c.363delC p.Glu122LysfsTer? 0.24 7 chr1:203274840-203274840 BTG2 NM_006763.2 c.106A>T p.Lys36Ter 0.39 7 chr10:120354734-120354734 PRLHR NM_004248.2 c.23delG p.Gly8AlafsTer52 0.63 7 chr15:73735686-73735686 REC114 NM_001042367.1 c.159+1G>A 0.42 7 chr19:54974185-54974185 LENG9 NM_198988.1 c.591G>A p.Trp197Ter 0.46 7 chr2:173850159-173850159 RAPGEF4 NM_007023.3 c.1090-2A>C 0.38 7 chr3:120424952-120424952 RABL3 NM_173825.3 c.278delT p.Phe93SerfsTer5 0.57 7 chr4:22436941-22436941 ADGRA3 NM_145290.3 c.1436C>A p.Ser479Ter 0.36 7 chr5:34004765-34004765 AMACR NM_014324.5 c.465dupT p.Gly156TrpfsTer15 0.46 7 chr6:34827059-34827059 UHRF1BP1 NM_017754.3 c.2926C>T p.Gln976Ter 0.43 7 chr6:37139063-37139063 PIM1 NM_002648.3 c.403G>T p.Glu135Ter 0.45 7 chr6:106552954-106552954 PRDM1 NM_001198.3 c.919G>T p.Glu307Ter 0.86 7 chr1:156035898-156035898 RAB25 NM_020387.2 c.239+1G>A 0.55 7 chr10:135083399-135083399 ADAM8 NM_001109.4 c.1863+2T>C 0.31 7 chr19:22942297-22942297 ZNF99 NM_001080409.2 c.413dupC p.Thr139AsnfsTer10 0.22 7 chr2:64199311-64199312 VPS54 NM_016516.2 c.445_446delTT p.Leu149ThrfsTer4 0.57 7 chr4:15542617-15542617 CC2D2A NM_001080522.2 c.2161C>A p.Pro721Thr 0.47 7 chr7:117171037-117171037 CFTR NM_000492.3 c.358G>C p.Ala120Pro 0.47 7 chr10:55944907-55944907 PCDH15 NM_033056.3 c.1427C>T p.Thr476Ile 0.46 7 chr18:53255701-53255701 TCF4 NM_001083962.1 c.-453G>C 0.46 7 chr3:121712209-121712209 ILDR1 NM_001199799.1 c.1387C>T p.Arg463Cys 0.39 7 chr7:124503424-124503424 POT1 NM_015450.2 c.526G>A p.Gly176Arg 0.44 7 chr3:38182641-38182641 MYD88 NM_002468.4 c.794T>C p.Leu265Pro 0.48 7 chr9:103004944-103004944 INVS NM_014425.3 c.889G>A p.Ala297Thr 0.59 7 chr11:61727470-61727470 BEST1 NM_004183.3 c.1055C>G p.Ala352Gly 0.45 7 chr1:216850419-216850419 ESRRG NM_001134285.2 c.402A>T p.Gln134His 0.46 7 chr10:50870727-50870727 CHAT NM_020549.4 c.1876G>A p.Ala626Thr 0.43 7 chr12:53587630-53587630 ITGB7 NM_000889.1 c.1364T>A p.Leu455Gln 0.36 7 chr12:110221560-110221560 TRPV4 NM_021625.4 c.2482C>T p.Arg828Cys 0.33 7 chr15:54592460-54592460 UNC13C NM_001080534.1 c.4157C>T p.Pro1386Leu 0.36 7 chr15:94927336-94927336 MCTP2 NM_018349.3 c.1668G>C p.Trp556Cys 0.60 7 chr17:18055457-18055457 MYO15A
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