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Abstract Background Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. Methods A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10−8. Results Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10−10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10−8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10−9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10−10). Conclusions Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

Abstract Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10−8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance–weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00–1.30) and MZL (OR = 1.09; 95% CI, 1.01–1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83–0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99–1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Abstract Genome-wide association studies (GWAS) have revealed that 25 regions in 24 genes are associated with adult diffuse glioma development. These regions were identified by performing GWAS of glioma overall and GWAS by pathology (GBM and nonGBM). Subsequently, these regions have been evaluated for associations with specific molecular subtypes. The 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly-classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. TERT promoter mutation has also been shown to be associated with age at diagnosis and patient outcome. We hypothesized that germline variants may increase susceptibility to, or interact with, these somatic alterations to accelerate the development of specific molecular subtypes of glioma. To test our hypothesis, we performed a GWAS by glioma molecular subtype – as defined by presence or absence of IDH and TERT somatic mutation and 1p/19q codeletion – utilizing a two-stage design and subsequent meta analysis that included 3001 total glioma cases and 2697 total controls. Data were imputed using the Michigan Server and logistic regression was used, adjusting for age and sex. The Cancer Genome Atlas (TCGA) data were used to perform an expression quantitative trait loci (eQTL) analysis on candidate germline variants. Variants in 2q37 and 7p22 were associated with IDH-mutated glioma (meta analysis p< 5x10-8). The eQTL analyses demonstrated significant associations between 2q37 variants and expression of nearby genes as well as associations between 7p22 variants and nearby genes (p< 0.0001). In conclusion, we identified and validated novel germline variants in two genes that are associated with etiology of IDH-mutated adult diffuse glioma.

Abstract Introduction The 2-3 fold excess risk of multiple myeloma (MM) among family members of cases suggests a heritable contribution to risk. Recently, a genome-wide association study (GWAS) identified two genome-wide significant and one promising novel loci associated with multiple myeloma risk. To confirm these associations and identify additional novel risk loci, we performed a four-center, genome-wide association meta-analysis. Methods A fixed effects model was used for the meta-analysis which included a total of 1248 cases and 1485 controls, all of European descent, genotyped and analyzed at four separate centers with samples contributed by 10 studies. After quality control and imputation using the 1000 Genomes Project, the analysis included ∼9.5 million variants (λ=1.024). Associations between (single nucleotide polymorphisms) SNP genotypes and MM risk were evaluated under a log-additive model of inheritance, with each study adjusting for age, sex, and up to 10 principal components to control for population stratification. Promising results were replicated in an independent set of 1587 cases and 1770 controls using TaqMan, for a total of 2835 and 3255 cases and controls, respectively, in a combined meta-analysis. Results The discovery meta-analysis did not reveal any genome-wide significant associations (defined as p<5 x 10-8). We used a novel pruning algorithm to identify the top 35 most promising single nucleotide polymorphisms (SNPs) to advance to replication. We successfully genotyped 22 SNPs in the replication set. In the combined discovery and replication meta-analysis, rs1345359 at 12q23.1 was the most strongly associated SNP (P=9 x 10-8, Table 1). The variant allele C was associated with reduced risk (odds ratio discovery set [OR]= 0.69, OR replication set = 0.78, OR combined = 0.74). A second locus at 20q13.2 (rs150220835), was associated with a two-fold increased risk (P=1.22 x 10-6), a borderline increased risk (P=0.0900) and 45% increased risk (P=2.44 X 10-5) in the discovery, replication, and combined analysis sets respectively (Table 1). We also confirmed the association between MM risk and two previously published SNPs (rs4487645, p=0.0007and rs105251, p=0.0044) (Broderick et al., Nat. Genet., 2011). The third previously suggested SNP (rs6746082) was of nominal significance (p=0.0517) in the meta-analysis. Discussion We confirmed the association between MM risk and two previously published SNPs and identified a possible association with a novel SNP in chromosome 12q23.1 (rs1345359). This SNP is not located in a gene nor associated with biofeatures in ENCODE, thus further examination of correlated SNPs is necessary to identify a functional SNP linked to this locus. We also found suggestive evidence for a second locus at 20q13.2 requiring additional replication. Larger studies would improve risk variant discovery for this rare hematologic malignancy. Disclosures: Wolf: Celgene: Honoraria, Research Funding; Millenium: Honoraria; Onyx: Honoraria. Anderson:Celgene, Millennium, BMS, Onyx: Membership on an entity’s Board of Directors or advisory committees; Acetylon, Oncopep: Scientific Founder , Scientific Founder Other.

Abstract Background. A recent meta-analysis of 9 case-control and 5 cohort studies reported a positive association of transfusion history with risk of NHL (RR=1.20; 95% CI 1.07-1.35), which was only evident in cohort (RR=1.25) and not case-control (RR=1.05) studies (Castillo et al., Blood 2010;116:2897-2907). Risk was similar in men and women, and for transfusions before or after 1992. In subset analyses, elevated risk was only apparent for chronic lymphocytic leukemia (CLL) and not diffuse large B-Cell lymphoma (DLBCL) or follicular lymphoma, but power was low. To further investigate these findings, particularly from studies conducted after 1990, better assess confounding, and address heterogeneity by NHL subtypes, we conducted an individual-level, pooled analysis of 13 case-control studies in the InterLymph Consortium (including 11 studies conducted after 1990; 8 studies were not included in the published meta-analysis). Methods. There were a total of 10,805 cases and 14,026 controls with transfusion data from 13 studies conducted in Europe, North America, and Australia. Transfusion history and other risk factors were self-reported in interviewer-administered or self-administered questionnaires. All risk factor data were harmonized centrally, and cases were grouped into NHL subtypes according to the WHO classification using guidelines from the InterLymph Pathology Working Group. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, adjusted for age, sex, and study center. Results. The median age at diagnosis was 60 years for cases (range, 18-97) and 59 years for controls (range, 16-97). The overall prevalence of a history of any transfusion in controls was 15.5%, was higher in women (18.6%) than men (13.0%), and increased with age, but was not associated with race/ethnicity (Asian, Black, Hispanic, White, other) or geographic region after adjusting for age and sex. Among whites, history of any transfusion was inversely associated with NHL risk among men (OR=0.74; 95% CI 0.65-0.83) but not women (OR=0.92; 95% CI 0.83-1.03); there were no significant results for other race/ethnicity groups, and ORs were highly variable and imprecise due to small sample sizes. Thus analyses were restricted to white men, where there was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion. Further adjustment for socioeconomic status, body mass index, smoking, alcohol use or hepatitis C virus (HCV) seropositivity did not alter these results. The associations were stronger in hospital-based (OR=0.56; 95% CI 0.45-0.70) than population-based (OR=0.84; 95% CI 0.72-0.98) studies, and were stronger in studies from Southern Europe (OR=0.53; 95% CI 0.36-0.79) than northern Europe (OR=0.67; 95% CI 0.53-0.83) or North America (OR=0.82; 95% CI 0.70-0.98). For NHL subtypes, statistically significant inverse associations were observed for follicular lymphoma (OR=0.70; 95% CI 0.56-0.88), DLBCL (OR=0.72; 95% CI 0.59-0.87), and CLL/SLL (OR=0.67; 95% CI 0.52-0.87), whereas weaker and non-statistically significant associations were observed for mantle cell (OR=0.81; 95% CI 0.54-1.23), marginal zone (OR=0.78; 95% CI 0.54-1.15), lymphoplasmacytic (OR=0.82; 95% CI 0.47-1.42) and peripheral T-cell (OR=0.83; 95% CI 0.49-1.40) lymphomas. Conclusion. Contrary to earlier results, transfusion history was inversely associated with risk of NHL and the common subtypes of follicular lymphoma, DLBCL and CLL/SLL among white men, whereas associations were null among white women and other racial/ethnic groups. These results were not explained by confounding by lifestyle factors or HCV seropositivity, era of first transfusion, hospital versus population-based study design, or geographic location. Despite dramatic changes in transfusion practice over the past 40 years, results were similar for decade of first transfusion, suggesting secular trends are a less likely explanation. Our results are unexpected and bias cannot be ruled out. Further studies, particularly cohort studies, are needed to clarify the role of transfusion history in NHL risk. Disclosures No relevant conflicts of interest to declare.

AbstractEpidemiologic studies show an increased risk of non‐Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen‐stimulation in one disease leads to another. Here we assess shared genetic risk in genome‐wide‐association‐studies (GWAS).Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B‐cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta‐analysis.Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta‐analysis (combing AD with NHL) implicated genes of apoptosis and telomere length.This GWAS‐based analysis four NHL subtypes and three ADs revealed few weakly‐associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Abstract Background: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. Methods: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. Results: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Conclusions: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. Impact: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.