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2976 HIV-Associated Diffuse Large B-Cell Lymphoma Shows Different Genomic Patterns between EBV-Positive and EBV-Negative Tumors

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Research, Viral, Adult, Translational Research, Lymphomas, B Cell lymphoma, Genomics, Bioinformatics, Diseases, Infectious Diseases, Aggressive lymphoma, Lymphoid Malignancies, Biological Processes, Molecular biology, Technology and Procedures, Study Population, Human, Pathogenesis, Molecular testing, Pathology
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Joo Y. Song, MD1, Jibin Zhang, Ph.D.2*, David W. Scott, MBChB, PhD3, Graham W. Slack, MD4*, Pedro Farinha4, Andreas Rosenwald, MD5*, German Ott, MD6*, Sarah L. Ondrejka, DO7, James R. Cook, MD, PhD7, Elías Campo8, Catalina Amador, MD9*, Jennifer R. Chapman-Fredricks, MD10*, Elaine S. Jaffe, MD11, Timothy C. Greiner, MS, MD12*, Victoria Bedell13*, Alanna Maguire, PhD14, Phillipp W. Raess, MD, PhD15*, Weiwei Zhang, Ph.D12*, Madhu P. Menon, MD, PhD16*, Julia Davidson17*, Krystie Chew18*, Alex F. Herrera, MD17, Andrew L. Feldman, MD19, Anamarija M. Perry, MD20, Alexandra M. Levine, MD17, John Carpten, PhD17*, Steven T. Rosen, MD21, Lisa M. Rimsza, MD22 and Wing Chung Chan, MD1

1Department of Pathology, City of Hope National Medical Center, Duarte, CA
2City of Hope National Medical Center, Duarte, CA
3Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
4Department of Pathology, University of British Columbia, Vancouver, BC, Canada
5Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
6Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
7Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH
8Hematopathology Section, Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
9Division of Hematopathology, University of Miami, Miami, FL
10Department of Pathology and Laboratory Medicine, University of Miami, Miami, FL
11Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Great Falls, VA
12Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
13Department of Pathology, City of Hope, Duarte, CA
14Mayo Clinic, Phoenix, AZ
15Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR
16ARUP, Salt Lake city, UT
17City of Hope, Duarte, CA
18City of Hope, Los Angeles
19Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
20Department of Pathology, University of Michigan, Ann Arbor, MI
21Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA
22Department of Pathology and Laboratory Medicine, The University of Arizona, Tucson, AZ

Introduction:

HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) is a significant complication in HIV-positive individuals, presenting unique clinical challenges and a poorer prognosis compared to patients with de novo DLBCL. Epstein-Barr Virus (EBV) status is a critical factor influencing the pathogenesis, clinical behavior, and therapeutic responses in these lymphomas. Plasmablastic lymphomas (PBL) have shared some overlapping genomic abnormalities with HIV-DLBCL including MYC rearrangements. This study aims to elucidate the differences in the genetic profiles and pathway activations between EBV(+) and EBV(-) HIV-DLBCL through comprehensive genomic profiling.

Methods:

Cases of DLBCL were identified in patients living with HIV from a multi-institute cooperative group. Cases of Burkitt lymphoma and PBL were excluded. We performed whole exome sequencing (WES) on 106 tumors of HIV-DLBCL and RNA sequencing on 39 tumors and mapped the reads to hg38 reference genome using BWA and STAR, respectively. EBV status of cases was determined by in situ hybridization and/or reads mapped on EBV genome in sequencing data. Somatic mutations were identified using variant callers (Strelka2, Mutect2) with WES data. For those mutated genes in COSMIC, allele frequency cutoff was set at 0.03. Mutations with an artifact score larger than 0.7 in SOBDetector and those located in segmental duplications were further removed. They were annotated with Ensembl Variant Effect Predictor, manually checked, and plotted with maftools. RNAseq read counts aligned to each gene were obtained by featureCounts and DEseq2 was used for differential expression (DE) analysis between EBV positive and negative groups. Pathway analysis with the DE genes was performed using GSEA. FISH analysis was performed using MYC, BCL2, and BCL6 break-apart probes.

Results:

There were 41 cases of EBV(+) HIV-DLBCL and 65 cases of EBV(-) HIV-DLBCL. FISH of EBV(+) HIV-DLBCL identified 42% (3/7) with MYC rearrangement (MYCr), none with BCL2 rearrangements (BCL2r) (0/6), and 33% (2/6) positive for BCL6 rearrangement (BCL6r) with 1 tumor having a MYCr/BCL6r. For EBV(-) HIV-DLBCL, there were 35% with a MYCr (6/17), 18% with BCL2r (2/11), and 27% with a BCL6r (3/11) with 2 tumors with MYCr/BCL6r, and 1 tumor with MYCr/BCL2r/BCL6r.

The most frequent mutations seen in EBV(+) HIV-DLBCL were STAT3 (32%), DDX3X (22%), and TP53 (15%). For EBV(-) HIV-DLBCL, the most frequent mutations were KMT2D (25%), TP53 (23%), GNA13 (22%), and TET2 (22%). Pathways that were most commonly associated with EBV(+) HIV-DLBCL were JAK/STAT (42%) (STAT3, JAK1) and NF-kB (39%)(DDX3X, TNFAIP3) while EBV(-) HIV-DLBCL was associated with epigenetic modifiers (62%)(KMT2D, TET2, EP300), JAK/STAT (45%)(SOCS1, JAK3) and PI3K/mTOR (40%)(GNA13, MTOR). Significant disparities between EBV(+) and EBV(-) were KMT2D (24% vs 50%, P=0.0025), TET2 (10% vs 26%, P=0.008), SOCS1 (29% vs 39%, P=0.04), DDX3X (15% vs 5%, P=0.03), and GNA13 (5% vs 24%, P=0.001). RAS mutations (KRAS, NRAS) were infrequent in HIV-DLBCL (EBV(+), 12%; EBV(-), 6%), in contrast to prior studies of PBL. Gene expression profiling showed enrichment of MYC targets, oxidative phosphorylation, and the mTORC pathway in EBV(+) as compared to EBV(-) HIV-DLBCL.

Conclusion:

EBV(+) HIV-DLBCL show a distinct mutational profile compared to EBV(-) HIV-DLBCL, with EBV(+) cases showing frequent mutations with STAT3 and DDX3X in contrast to EBV(-) cases with frequent mutations associated with epigenetic modification pathways (KMT2D, TET2). These genetic profiles underscore the need for tailored therapeutic approaches depending on EBV status. Although the analysis is limited and requires confirmation in a larger cohort, this is the largest study at present evaluating these tumors.

Disclosures: Scott: Roche: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Veracyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZenenca: Consultancy, Honoraria; Roche/Genentech: Research Funding; Nanostring: Patents & Royalties: use of gene expresssion to subtype aggressive lymphoma. Herrera: Roche/Genentech: Consultancy, Research Funding; AbbVie: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Adicet Bio: Consultancy; Caribou Biosciences: Consultancy; Regeneron: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Tubulis: Consultancy; Gilead Sciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Genmab: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Allogene Therapeutics: Consultancy; Karyopharm: Consultancy; KiTE Pharma: Research Funding. Feldman: Zeno Pharmaceuticals: Patents & Royalties; Seattle Genetics: Research Funding. Rosen: Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rimsza: MCL35 assay: Other: Inventor of intellectual property for the MCL35 assay.

*signifies non-member of ASH