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2838 Extranodal Marginal Zone Lymphomas Show Recurrent Mutations in DNA Repair Genes, Cancer-Associated Proliferative Signaling and NOTCH1 Signaling Pathways, Regardless of Anatomic Site

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational—Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Research, adult, Translational Research, Lymphomas, non-Hodgkin lymphoma, genomics, B Cell lymphoma, Diseases, indolent lymphoma, Lymphoid Malignancies, Biological Processes, molecular biology, Technology and Procedures, Study Population, Human, pathogenesis, omics technologies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Jennifer R Chapman-Fredricks, MD1*, Devang Thakkar2*, Juan Pablo Alderuccio, MD3, Kikkeri N Naresh, MD, MBBS4, Sarah L. Ondrejka, DO5*, Eric D. Hsi, MD6, Mina L Xu, MD7*, Nathan Paulson8*, Jean L. Koff, MD, MSc9, David L. Jaye, MD10, Jonathon B. Cohen, MD, MS11, Anne Ortved Gang, MD, PhD12*, Rebecca J Leeman-Neill, MD, PhD13, Tushar Dave, MS14*, Lanie Happ, PhD15*, Cassandra Love14, Sasan Zandi, MD, PhD16, Hina Naushad, MD17*, Emily F Mason, MD, PhD18,19*, Abner Louissaint Jr., MD, PhD20, Haley Martin20*, Choon Kiat Ong, PhD21, Raju Pillai, MD22*, Mette Ø Pedersen, MD PhD23*, C. Cameron Yin, MD, PhD24, William Choi, MBBS, MRCP25, Rex Kwok Him Au-Yeung, MBBS26*, Marja-Liisa Karjalainen-Lindsberg, MD, PhD27*, Amy Chadburn, MD28, Vincent Sarno29*, Matthew McKinney, MD30, Payal Sojitra, MD31*, Andrew G Evans, MD, PhD32, Amir Behdad, MD33*, Carlos Galvez, MD34, Chee Leong Cheng, FRCPA, FRCPath, MBBS35*, Magdalena Czader, MD, PhD36, Jiong Yan37*, Sandeep S. Dave, MD, MS38 and Izidore S. Lossos, MD39

1Division of Hematopathology, University of Miami, Sylvester Comprehensive Cancer Center, Miami
2Duke University, Durham, NC
3Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL
4Fred Hutchinson Cancer Center, Seattle, WA
5Cleveland Clinic, Cleveland, OH
6Wake Forest Baptist Medical Center, Winston Salem, NC
7Yale University School of Medicine and Yale Cancer Center, New Haven, CT
8Department of Pathology, Stanford University, Palo Alto, CA
9Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
10Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Dunwoody, GA
11Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
12Dept. of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
13Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY
14Duke University Medical Center, Durham, NC
15Data Driven Bioscience, Durham, NC
16Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
17University of Nebraska Medical Center, Omaha, NE
18De, Vanderbilt University Medical Center, Nashville, TN
19Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville
20Massachusetts General Hospital, Boston, MA
21National Cancer Center Singapore, Singapore, Singapore
22Department of Pathology, City of Hope National Medical Center, Duarte, CA
23Copenhagen University Hospital, Herlev, Denmark
24The University of Texas MD Anderson Cancer Center, Houston, TX
25Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, HKG
26Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
27Helsinki University Hospital, Helsinki, Finland
28Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
29Weill Cornell Medicine, New York, NY
30Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, NC
31Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
32Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
33Northwestern University Feinberg School of Medicine, Chicago, IL
34Division of Hematology and Oncology, University of Illinois at Chicago, Chicago, IL
35National Cancer Centre Singapore, Singapore, Singapore
36Indiana University School of Medicine, Indianapolis, IN
37University of Toronto, Toronto, ON, Canada
38Duke Cancer Institute, Duke University, Durham, NC
39Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL

Extranodal marginal zone lymphomas (EMZL) are usually indolent B cell lymphomas arising in acquired mucosa-associated lymphoid tissue (MALT) as a result of chronic antigen stimulation from infection or autoimmune processes. EMZLs occurring at different MALT sites have shared and unique genetic events including site-associated chromosomal structural changes and mutations. While large scale genetic analyses of EMZL are lacking, previous small studies have shown that EMZL often show activation of NF-κB through chronic stimulation of the B cell receptor and other cooperating genetic events that include somatic mutations, most frequently in TNFAIP3. Here, we report the largest whole exome sequencing (WES) and copy number (CN) analysis to date in EMZL.

Formalin-fixed paraffin-embedded (FFPE) samples of EMZL were collected as part of the Atlas of Blood Cancer Genomes (ABCG) consortium. All cases underwent central pathology review by expert hematopathologists and diagnoses were confirmed as defined by the 2016 WHO classification. We defined global CN gains and losses at log2 fold change value of ±0.3, a value used by many CN tools. DNA and RNA WES were performed using the Illumina platform and DNA and RNA reads aligned to the GRCh38 genome and transcriptome, respectively. Exonic variants were identified and filtered using normal samples and population-based databases to identify putative driver mutations which were then aggregated at the gene level. Mutational analysis was done on samples that passed quality filtering.

225 unique diagnostic specimens were collected from 24 academic hematopathology departments. Cases originated from North America (USA and Canada, 86%), Europe (8%), and Asia (Singapore and China, 6%). 72 tumors were excluded due to inadequate mean coverage related to size of the biopsy or its quality. CN analysis and WES to identify non-silent mutations was performed in 153 unique EMZL including ocular adnexal (31), stomach (26), lung (23), salivary gland (23), and other extranodal locations (50). Average patient age was 63 years (range 53-71 years), female: male ratio of 1.6.

Mutation calls identified 718 variants (613 missense mutations and 105 truncating mutations) across 59 putative driver genes detected in ≥5% cases across all the anatomic locations. Among the most commonly mutated genes, we detected genes previously reported to be altered by targeted sequencing in EMZL (e.g., SPEN (12%), TNFAIP3 (A20) (8%), CREBBP (8%), TBL1XR1 (7%), and others) confirming our filtering strategy. A total of 44 focal CN alterations (24 gains and 20 CN losses) were detected for our set of recurrently mutated genes. Global CN gains included chromosome 3 (6%), 6p (7%), 8 (3%), 12 (4%), and 18 (5%) and losses in 21p (10%). Previously described tumor suppressor genes such as TNFAIP3 showed a typical pattern of alterations consisting of CN losses (6q23.3 deletion in 6%) and/or mostly truncating mutations (8%). Combining DNA mutations and CN alterations, the number of genetic lesions per tumor sample in the 59 putative driver genes ranged from 1 to 21, with an average load of 4.9 aberrations per case, consistent with previous genetic studies in other types of MZL lymphoma. The most frequent mutations across all sites were IGLL5 (22%), KMT2C (15%), KMT2D (14%), SPEN (12%), PRDM2 (11%), and NCOR1 (10%). Analysis using Elsevier Pathway Collection, BioPlanet 2019 and Go Biological Process 2021 revealed adjusted statistically significant enrichment of aberrations in genes in NOTCH signaling, DNA repair, cancer-associated sustaining of proliferative signaling, cancer associated histone methylation and positive regulation of transcription, by DNA-templated (GO:0045893) and RNA polymerase II (GO:0045944). Many of the mutated genes were previously not reported in EMZL. Some of the mutations were shared by tumors at different anatomic locations while some were more unique. Mutations in TET2, previous reported as specific for thyroid EMZL, were also detected in ocular adnexa, gastric and salivary gland MZL. Mutations in PTPRD, previously suggested as specific for NMZL, were detected also in EMZL. Overall, this analysis of a large number of samples from different anatomic locations further refines the mutational landscape in EMZL and provides novel clues on pathogenesis. More detailed analyses of mutations, CN variations and RNA expression will be presented at the meeting.

Disclosures: Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Pyramid: Consultancy; Agios: Consultancy. Hsi: Eli Lilly: Research Funding; Astellas: Consultancy; Novartis: Consultancy; Abcon: Consultancy; Abbvie: Research Funding; Cytomx: Consultancy; Abcon: Current holder of stock options in a privately-held company; Virtuoso: Research Funding. Xu: Blueprint Medicines: Consultancy; Pure Marrow: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy. Koff: Atara BioTherapeutics: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Viracta Therapeutics: Research Funding. Cohen: Takeda: Research Funding; Genentech: Research Funding; BMS/Celgene: Research Funding; Astrazeneca: Consultancy, Research Funding; HutchMed: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy; Kite Pharma/Gilead: Consultancy; Lilly Oncology/Eli Lilly: Consultancy, Research Funding; Aptitude Health: Consultancy; Novartis: Research Funding. Love: Data Driven Biosciences: Consultancy, Current holder of stock options in a privately-held company. Louissaint: Lymphoma Research Foundation: Research Funding. Ong: SymBio Pharmaceuticals Limited: Research Funding. Chadburn: Leica Biosystems: Membership on an entity's Board of Directors or advisory committees; USCAP: Honoraria; Lieca Biosystems: Consultancy; NorthShore University HealthSystem (Eavanston IL: Honoraria; U Chicago: Honoraria. McKinney: Celgene: Consultancy; Incyte: Research Funding; Molecular Templates: Research Funding; UNUM: Research Funding; Epizyme: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Beigene: Research Funding; Denovo Biopharma: Research Funding; Pharmacyclics: Research Funding; Nordic Nanovector: Research Funding; BMS: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Atara: Research Funding; LOXO: Research Funding; Cellactor: Research Funding; Kite/Gilead: Honoraria; Seattle Genetics: Honoraria; Molecular Templates: Honoraria; BTG: Honoraria; Pharmacyclics: Honoraria; Verastem: Honoraria; Genentech: Honoraria; Celgene: Honoraria; Kite/Gilead: Speakers Bureau; ADC therapeutics: Speakers Bureau. Evans: Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding. Behdad: Leica: Honoraria; advisory committee: Membership on an entity's Board of Directors or advisory committees; Leica: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Foundation Medicine/Roche China: Honoraria; Thermofisher scientific: Honoraria. Czader: Beckman Coulter: Membership on an entity's Board of Directors or advisory committees. Dave: Data Driven Biosciences: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months; Lantern Pharma Inc.: Other: Data Driven Biosciences conducted some of Lantern Pharma's pre-clinical studies. Lossos: LRF: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; NCI: Research Funding.

*signifies non-member of ASH