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4339 Genome-Wide Meta-Analysis Identifies Multiple Germline Genetic Variants Associated with Increased Risk of Follicular Lymphoma

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster III
Hematology Disease Topics & Pathways:
Research, Adult, Translational Research, Lymphomas, B Cell lymphoma, Genomics, Diseases, Lymphoid Malignancies, Biological Processes, Technology and Procedures, Study Population, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Vijai Joseph, PhD1*, Alyssa I Clay-Gilmour, PhD2,3, Hanla Park, Ph.D.4*, Charles Breeze, Ph.D.5*, Lara E. Sucheston-Campbell, PhD, MS6, Joshua Arias7*, Rosalie Griffin Waller, PhD8*, Murat Güler9*, Alexandra Nieters10*, Karin Ekstroem Smedby, MD11, Ólafur Birgir Davídsson, Ph.D.12*, Sophia S. Wang, PhD13*, Qing Lan, Ph.D.14*, Henrik Hjalgrim, MD, DMSc15,16*, Susan L. Slager, PhD8, James McKay, Ph.D.17*, James R. Cerhan, MD, PhD8, Sonja I. Berndt, PhD, PharmD5* and Nathaniel Rothman, M.D, M.P.H.5*

1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC
3Department of Epidemiology and Biostatistics, University of South Carolina, Simpsonville, SC
4International Agency for Research on Cancer, Lyon, France
5Division of Cancer Epidemiology and Genetics, National Cancer Institute / National Institute of Health, Bethesda, MD
6College of Pharmacy, The Ohio State University, Pleasanton, CA
7Division of Cancer Epidemiology and Genetics, National Cancer Insititute, National Institute of Health, Bethesda, MD
8Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
9German Cancer Research Center, Heidelberg, Germany
10Institute for Immunodeficiency, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
11Karolinks Institutet, Stockholm, Sweden
12Danish Cancer Institute, Copenhagen, Denmark
13City of Hope Comprehensive Cancer Center, Duarte, CA
14Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
15The Danish Cancer Society, Copenhagen, Denmark
16Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
17Genomic Epidemiology branch, International Agency for Research on Cancer/World Health Organization (IARC/WHO), Lyon, FRA

Introduction: Follicular lymphoma (FL) is the most common indolent subtype of non-Hodgkin lymphoma. Family history is a risk factor. Genome-wide association studies (GWAS) have identified several germline variants, especially within the HLA region, to be associated with an increased risk of FL, but these variants only explain a fraction (16%) of heritability. Here, we present novel findings from GWAS of FL uncovering multiple germline genetic variants contributing to disease susceptibility.

Methods: A GWAS was performed comprised of a discovery analysis in 6,508 FL cases and 64,183 controls of European ancestry followed by a replication of the most significant variants (P<5x10-7) in 2,745 FL cases and 782,226 controls from the biobanks of UK, Copenhagen Hospital, FinnGen and Mayo Clinic . At 9,253 FL cases and 846,409 FL free controls imputed genome-wide, this is the largest FL GWAS of European genetic ancestry to date. HLA alleles were imputed, and Class I and Class II signals were analysed at the amino acid level. A transcriptome wide association study (TWAS) was performed using FUSION investigate relationship to expression in GTEx and Young Finns Study in whole blood and cross-tissue . Functional annotations were done using FUMA, F-MAGMA, Open Targets and FORGE. Colocalization was conducted using CoLoC with whole blood gene expression data to understand causal variants. Mendelian randomization (MR) was performed on blood cell traits and leukocyte telomere lengths (LTL) to infer their relationships with FL genetic risk.

Results: We replicated the previously published susceptibility loci within and outside the HLA region, finding two additional independent SNPs at two known loci (P < 5 x10-8) and discovered thirteen novel, genome-wide significant loci located at chromosome 2q13, 3p13, 3p24.1,3q13, 3q24.1, 4q31.21, 6p21, 6p22, 7q31, 10p14, 10q22, 10q23, 17q12, 19p13 and 20p11 with P < 5 x10-8. These SNPs were located near genes that show relevance for B-cell biology, such as BCL2L11, FOXP1, CD86, EOMES, IZKF3, PRF1, KLF2 NKX2-2 and HLA Class I and Class II genes. TWAS uncovered a role for H2AX, IGKV2-29, IMP, UBE4A and IKZF3 and provided directionality of effect for associated transcripts. Colocalization analysis corroborated a positive association with IKZF3 expression showing a robust correlation with FL risk variants (posterior probability PP4>0.7). In addition, several genome-wide significant variants in IKZF3 colocalize with eQTLs across tissues. IKZF3 (Aiolos) is part of the Ikaros family of transcription factors, critically important to the regulation of B-cell development and function. Therapeutic strategies leveraging Immunomodulatory imide drugs (IMiDs) to degrade IKZF3 have shown efficacy in multiple myeloma, and we speculate may also have potential benefits in FL by enhancing anti-tumor immunity and disrupting malignant B-cell function. Gene-set analysis showed blood and spleen to be the most relevant tissues for FL risk variants with lymphocyte activation and immune cell type differentiation genes demonstrating enrichment based on gene-ontology terms. Associated traits included allergies, respiratory diseases (e.g., asthma phenotypes), inflammatory bowel diseases, type 1 diabetes (T1D), lipid levels and commonly measured blood cell traits, with some SNPs showing evidence of colocalization with select blood traits. Interestingly, no causal association to blood traits was observed using MR; however, MR analyses did reveal a strong association with LTL. For the HLA loci, FL shows a diverse set of amino acid associations in HLA Class I and Class II genes that extends beyond what is known from autoimmune disease associations, such as rheumatoid arthritis or T1D. Our study also reveals interesting biological insights about FL susceptibility, such as a novel locus intragenic to FOXP1, an activated oncogene preferentially expressed in FL and DLBCL tumors, but rarely observed in Hodgkin’s lymphoma. High levels of FOXP1 are known to result in poor survival in FL.

Conclusion: This large GWAS of FL has identified multiple susceptibility variants, uncovering interesting gene candidates for further pathophysiological characterization of FL risk and B-cell development. It suggests new biological pathways and genes that could be potential leads for drug development and targeting treatment, in addition to identifying genetically high-risk populations for FL susceptibility.

Disclosures: Sucheston-Campbell: Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ekstroem Smedby: Abbvie: Honoraria; InCyte: Honoraria. Cerhan: GenMab: Research Funding; Genentech: Research Funding; BMS: Research Funding; Protagonist Therapeutics: Other: SMC.

*signifies non-member of ASH