Burdett, Laurie

Introduction. Acquired severe aplastic anemia (SAA) is a life-threatening disorder characterized by severe progressive pancytopenia and hypocellular bone marrow. The etiology of acquired SAA is not understood but believed to be related to abnormal immune responses to environmental exposures. We conducted a genome-wide association study (GWAS) to identify common germline variants associated with SAA. Methods. We identified 895 patients with SAA who underwent related or unrelated hematopoietic cell transplant (HCT) with clinical data and pre-HCT blood samples available in the Center for International Blood and Marrow Transplant Research (CIBMTR) database and biorepository. Pre-HCT DNA was extracted from blood of patients with SAA and genome-wide genotyping was conducted using the Illumina OmniExpress array. We excluded 93 inherited bone marrow failure cases. The SAA cases were grouped cases into discovery and validation sets based on time of batch sample receipt. Analyses were limited to patients of European ancestry based on principal component analyses to minimize the potential effect of population stratification. Controls were genomically matched and selected from previously scanned cancer-free subjects at the Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, NCI. The final analysis included 534 acquired SAA cases (359 in the discovery set and 175 in the validation set), and 2,455 controls (1,396 in the discovery set, and 1,059 in the validation set). Results. Patients with SAA in this study received HCT between 1989-2015 at a median age of 21 years, 56% were male, and the median time between SAA diagnosis and HCT was 11 months. Strong genome-wide association signals were identified across the human leukocyte antigen (HLA) genes encoded at the major histocompatibility complex (MHC) on chromosome 6p21 (Figure 1). The top SNP was located in the P4 binding pocket of the HLA class II gene HLA-DPB1(rs1042151A>G, p.Met105Val, pooled-odds ratio [OR]=1.75, 95% confidence interval [CI]=1.50-2.03, p=1.94x10-13). The expression of HLA-DP in CD19+ cells from 175 healthy donors was significantly different by rs1042151 A>G genotype (p=2.04x10-6) (Figure 2). A second SNP near HLA-B, rs28367832G>A, also reached genome-wide significance (pooled-OR=1.49, 95% CI=1.22-1.78, p=7.27x10-9). Copy-number variant analysis and next generation sequencing also identified somatic, clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes in 8.6% of the SAA cases and none of the controls. Conclusion. This SAA GWAS identified strong association signals between common germline genetic variants in HLA class I and II genes and SAA. The main SNP is associated with changes in HLA-DP expression suggesting a key role for this locus in SAA etiology. This study adds further evidence to the connection between SAA and immune dysregulation. Disclosures Cerhan: Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Celgene: Research Funding. Lee:Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.

Abstract Marginal zone lymphomas (MZL) are a group of indolent non-Hodgkin's B-cell lymphomas (NHL) comprising extranodal MZL of mucosa-associated lymphoid tissue (MALT) type, splenic MZL and nodal MZL. MZL comprises 7-12% of adult NHLs. The genetic etiology of MZL is poorly understood. To better understand the genetic risk factors for MZL, we conducted the first genome-wide association study (GWAS) of this lymphoid malignancy. The GWAS included 824 MZL cases and 6,220 controls of European ancestry from 22 studies of NHL. Genotyping was carried out at the Cancer Genomics Research Laboratory (CGR) of NCI using Illumina Human OmniExpress arrays. Standard genotyping quality controls were performed. Imputation of common SNPs was performed using IMPUTE2 software and 1000 Genomes Project release version 3 data. Association testing was subsequently performed using SNPTEST, assuming a log-additive genetic model adjusting for age, gender and three significant eigenvectors. We identified one locus at 6p21.32 within the HLA class II region that attained genome-wide significance (P<5x10-8). When a small number of additional cases (n=58) and controls (n=66) genotyped using Taqman assays were included, rs9461741 (BTNL2) was associated with an increased risk of MZL (per-allele odds ratio = 2.38, 95% confidence interval: 1.74-3.24; P=4.32x10-8). Other SNPs at the 6p21.32 locus were also highly associated with MZL, suggesting that this is unlikely to be a chance finding. Promising signals yet to be confirmed were also observed on chromosomes 3 and 14. The BTNL2 protein has extracellular immunoglobulin domains and is expressed in multiple tissues including various immune organs and the gut and it inhibits T-cell activation. Genetic variability at BTNL2 has been associated with inflammatory and infectious phenotypes, highlighting the importance of this locus for immune diseases. In conclusion, findings from this GWAS identify the HLA class II region as an important susceptibility locus for MZL. Citation Format: Joseph Vijai, Zhaoming Wang, Sonja I. Berndt, Susan L. Slager, James R. Cerhan, Christine Skibola, Sophia S. Wang, Angela R. Brooks-Wilson, Silvia de Sanjose, Paige M. Bracci, Mads Melbye, Bengt Glimelius, Rebecca D. Jackson, Wendy Cozen, Nikolaus Becker, Lauren R. Teras, John J. Spinelli, Jenny Turner, Qing Lan, Mark P. Purdue, Kimberly A. Bertrand, Kenneth Offit, Paolo Vineis, Brian K. Link, Graham G. Giles, Anne Zelenuich-Jacquotte, Alain Monnereau, Maria Grazia Ennas, Demetrius Albanes, Laurie Burdett, Nathaniel Rothman, Stephen J. Chanock, Alexandra Nieters, On behalf of the NHL GWAS Consortium. A genome-wide association study suggests evidence of variants at 6p21.32 associated with marginal zone lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5071. doi:10.1158/1538-7445.AM2014-5071