Citations

Abstract Abstract 3903 The clinical utility of 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography-computed tomography (PET-CT) scans in the management of patients with chronic lymphocytic leukemia (CLL) has not been clearly defined. CLL cells typically have low FDG avidity and the addition of the PET component has not been shown to improve the utility of CT scans in the management of patients with CLL. However, patients with CLL are at increased risk of developing FDG avid complications including more aggressive lymphomas, other second malignancies, and infections for which FDG PET-CT scans are a useful imaging modality. We hypothesized that FDG PET-CT scans are sensitive tests for evaluation of these complications in patients with CLL. Patients and Methods: This observational study was performed with IRB approval. We studied all 4030 CLL patients seen at least once in the Division of Hematology at Mayo Clinic Rochester between January 1, 2006 and December 31, 2011 using data prospectively collected into the Mayo Clinic CLL database. We reviewed the clinical and radiological records of the 272 (7%) patients who underwent 526 FDG PET-CT scans of the trunk during this time period to determine the indication for PET-CT scan, results of imaging, and the effects of the use of PET/CT scan on management. Results: Four hundred and seventy two (90%) of the 526 PET-CT scans were reported as abnormal. Of these, 78 (17%) scans were useful in directing a tissue biopsy of high FDG avidity lesions. Of the 37 (8%) positive PET-CT scans that facilitated the diagnosis of new complications of CLL, 21 (4%) scans led to a diagnosis of diffuse large B cell lymphoma and 9 (2%) scans led to a diagnosis of a solid malignancy. The FDG component of 22 PET-CT scans done because of clinical suspicion of complications of CLL were negative, and thus useful in management of these patients. PET-CT scans showed progressive CLL in 138 (29%) studies but in these patients, the PET component of the scan did not provide additional information about the status of the patients' CLL compared to the CT component alone. Conclusions: FDG PET-CT scans are not of proven value in staging CLL or determining response to treatment. However, our data suggest that they could be of considerable value in evaluation for complications, especially more aggressive lymphomas, other cancers, and infections that complicate the course of CLL. Disclosures: Off Label Use: Phase I study using PGG beta glucan in CLL. Zent:Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding.

Abstract Abstract 684 Background. Obesity has been associated with an increased risk of developing of lymphoma, particularly DLBCL. Genetic variation in several energy balance genes, including leptin (LEP), its receptor LEPR, ghrelin (GHRL) and neuropeptide Y (NPY) have been shown to modulate risk of lymphoma, although their impact on survival is not known. In contrast, recent studies suggest that patients either overweight (Body Mass Index (BMI), 25 to<30 kg/m2) or obese (≥30 kg/m2) may have a superior prognosis in DLBCL, although its impact in FL and in the current treatment era is not known. We evaluated the association of BMI at the time of diagnosis, 2 years prior to diagnosis and at ages 18, 35 and 50 years, along with germline genetic variation in selected energy balance genes with event-free (EFS) and overall (OS) survival in DLBCL and FL. Methods. We evaluated these associations in a prospective cohort of newly diagnosed DLBCL (N=764) and FL (N=649) patients enrolled at the Mayo Clinic and University of Iowa from 2002–2009 as part of the Molecular Epidemiology Resource. Peripheral blood DNA, clinical data and self-reported historical weights were collected at enrollment. Patients received standard disease treatment strategies, and were systematically followed for disease progression, re-treatment, and death. Single nucleotide polymorphisms (SNPs) were genotyped as part of a custom Illumina iSelect panel. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled as having a log-additive effect in the regression model. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of the obesity measures and SNPs with outcome, adjusted for treatment class and subtype specific prognostic factors (IPI, FLIPI). Results. For DLBCL patients (median age 63 years, range 18–92) the median follow-up was 47 months (range 0–101); 58% had an IPI 0–1 risk disease; and 87% received immunochemotherapy. For FL patients (median age 60 years, range 25–94), the median follow-up was 60 months (range 11–110); 24% had FLIPI score 3–5; and main initial treatments were observation (32%), rituximab (R)-monotherapy (12%), CVP +/−R (19%), and anthracycline +/−R (22%). The main results for BMI and prognosis are reported in the Table. For DLBCL, obese patients at diagnosis had better EFS and OS; this association was weaker for BMI at age 50 and 35 years. In contrast, for FL, overweight and obese patients at diagnosis had a poorer EFS and OS, and this was also observed for BMIs two years before diagnosis and at ages 50 and 35 years. In FL, the LEP SNP rs2167270 was associated with inferior EFS (HR=1.25; 95%CI 1.05–1.49) and OS (HR=1.28; 95%CI 0.90–1.83). The NPYSNP rs16147 was associated with inferior FL OS (HR=1.50; 95%CI 1.03–2.17) but was not associated with EFS. None of the energy balance and metabolism SNPs were associated with DLBCL EFS or OS. Conclusions. Higher BMI prior to and at diagnosis, as well as SNPs in LEP and NPY,were significantly associated with FL prognosis, with inferior outcomes in overweight and obese patients. These novel findings in the modern treatment era suggest an important role of obesity pathways in FL prognosis. In DLBCL, we confirm the recent findings of improved survival in DLBCL in obese patients, and extend this to the modern treatment era and BMI earlier in life. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2342 Poster Board II-319 PURPOSE: Numerous clinical and biologic parameters are able to predict time to first treatment (TFT) and overall survival (OS) for patients with CLL. The utility of prognostic testing in CLL patients may vary based on age at diagnosis given the higher mortality from other causes among older individuals. The goals of the present study were to i) evaluate differences in natural history of CLL patients based on age at diagnosis, ii) compare survival to age-matched individuals in the general population, and iii) determine the age-stratified utility of prognostic testing. METHODS: All 2487 CLL/SLL patients diagnosed between January 1995 and June 2008 and cared for in the Mayo Clinic Division of Hematology were categorized by age at diagnosis (<55 years, 55-64 years, 65-74 years, or ≥75 years) and evaluated for differences in clinical characteristics, TFT, and OS using chi-square tests. IGHV gene mutation analysis, ZAP-70 status, CD38 status, and cytogenetics abnormalities by interphase FISH testing were performed as part of clinical and/or research studies using methods previously described by our group. Cox regression was used to evaluate the ability of prognostic parameters to predict clinical outcome stratified by age at diagnosis. Patient survival was compared to that of the age matched Minnesota population. RESULTS: When grouped by age, 593 patients were age <55, 713 age 55-64, 748 age 65-74, and 433 age ≥75 at diagnosis. As of last follow-up, 268, 282, 296, and 108 patients in these age groups have been treated, respectively and 112, 171, 254, and 199 patients have died. Survival decreased as the age at diagnosis increased (p<0.001). OS of CLL patients was significantly shorter than that of the age-matched general population for patients age <55 years (p<0.001), 55-64 years (p<0.001), and 65-74 years (p<0.001) at diagnosis but not those ≥75 years (p=0.136). Among Rai stage 0 patients, survival was also shorter than that of the age-matched general population for CLL patients age <55 years (p<0.001), 55-64 years (p<0.001), and 65-74 years (p<0.001) but not those ≥ age 75 at diagnosis (p=0.07). No statistically significant differences were observed in CD38 status, IGHV mutation status, ZAP-70 status or the frequency of common cytogenetic abnormalities on FISH based on age at diagnosis category. Consistent with prior reports, all of these parameters were powerful predictors of TFT and OS for the overall cohort on univariate analysis (all p<0.001 for both TFT and OS). Given the variation in TFT and OS based on age at diagnosis, we next evaluated the utility of these prognostic parameters for predicting TFT and OS in each age category after adjusting for stage. CD38, IGHV mutation, and ZAP-70 each predicted TFT independent of stage for all age groups (all p <0.05). FISH results predicted TFT independent of stage for patients age 55-64 and 65-74 however did not reach statistical significance for those age <55 (p=0.18) or ≥75 (p=0.07). The utility of these parameters for predicting OS independent of stage was less consistent and varied by age. IGHV predicted OS independent of stage for patients <age 55 (p<0.001), 55-64 (p=0.007), and 65-74 (p'0.001) but was not a significant predictor of OS among those ≥75 (p=0.15). CD38, ZAP-70, and FISH each predicted survival independent of stage for only 2 of the 4 age categories (ZAP-70 for age <55 and 55-64; FISH for age <55 and 65-74; CD38 for 55-64 and ≥75). CONCLUSIONS: Survival of CLL patients is shorter than that of the age-matched general population for individuals age <75 at diagnosis regardless of disease stage. In contrast, survival does not differ from the age-matched general population among CLL patients ≥age 75 at diagnosis. Prognostic testing using CD38, IGHV mutation, and ZAP-70 is useful for predicting TFT independent of stage for CLL patients of all ages (including those ≥age 75) but has less value for predicting OS particularly as the age at diagnosis increases. IGHV appeared to be the best predictor of OS independent of stage among all patients age <75. Unexpectedly, prognostic testing had little utility for predicting OS independent of stage among patients age ≥75. These findings have important implications regarding the use of prognostic tests in patients with CLL as well as the use of test results to select patients for clinical trials testing early treatment for asymptomatic individuals. Disclosures: Shanafelt: Cephalon: Research Funding; Celgene: Research Funding; Polyphenon Pharma : Research Funding; Hospira: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Bayer Health Care Pharmaceuticals: Research Funding. Kay:Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees; Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding. Zent:Genentech, Bayer, Genzyme, Novartis: Research Funding.

Abstract Abstract 3637 Background: A recent large genome-wide association study confirmed the important role of the major histocompatibility complex in classical Hodgkin Lymphoma (cHL) susceptibility (rs6903608), but also identified significant associations with genetic variants outside of the HLA region at chromosomal regions 2p16.1 (REL, rs1432295), 8q24.21 (PVT1, rs2608053, rs2019960), and 10p14 (GATA3, rs501764, rs485411). These single nucleotide polymorphisms (SNPs) are localized in or near important genes involved in lymphoma pathogenesis: REL, which encodes for c-rel, is a member of NFkB pathway; PVT1, which is downstream of the MYC locus, encodes for non-coding microRNAs, some of which have oncogenic properties; and GATA3, which is a critical transcriptional factor for priming lymphoid T-cells for Th2 phenotype, is aberrantly expressed in HL. We investigated whether these six SNPs described in cHL etiology also influence the outcome of newly diagnosed cHL patients in two independent cohorts. Patients and Methods: The first cohort consisted of 342 cHL patients from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) who were prospectively enrolled between 1998 and 2002. The second cohort consisted of 259 patients prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). DNA for genotyping was extracted from a blood samples collected at diagnosis, and genotyping was conducted using Taqman technology (ABI Prism 7000, Applied Biosystems) for HLA-DRA, PVT1, GATA3 and PCR-based restriction fragment length polymorphism for REL in GELA cohort and Illumina iSelect for the 6 SNPs in MER cohort. Both cohorts were followed for disease progression, re-treatment and death. In the GELA series, the median age was 32 years (range, 15–93), 57% were male, and 72% had an Ann Arbor stage I–II. Histology was nodular sclerosis in 84%, and 29% of available cases (n=40/140) were EBV positive. In the MER series, the median age was 38 years (range, 18–89), 53% were male, and 53% had an Ann Arbor stage I-II. Nodular sclerosis was the most common subtype (62%) and 23 of 115 available cases were EBV positive (20%). The International Prognostic Score (IPS) was 0–1 in 46% and 52% of GELA and MER patients, respectively. ABVD regimen was used for 60% and 88% of the GELA and MER patients, respectively. The 5-year progression free survival (PFS) was 83% and 75% in GELA and MER cohorts, respectively. We estimated the prognostic value of each individual SNP for PFS for allelic and genotypic (dominant and recessive) modes of transmission in each series. In order to increase power, we then performed a meta-analysis of the two studies. Results: Consistent with prior reports, the minor allele frequencies for REL (rs1432295), HLA-DRA (rs6903608), PVT1 (rs2608053), PVT1 (rs2019960), GATA3 (rs501764) and GATA3 (rs485411) were 0.44, 0.50, 0.43, 0.29, 0.22, 0.28 in the GELA and 0.46, 0.41, 0.46, 0.27, 0.25, 0.31 in the MER series, respectively. In GELA, GATA3 (rs501767) was associated with PFS in the ordinal model (HR=1.66, 95%CI 1.11–2.49, P=.01), while there were suggestive associations for PVT1 (rs2608053) (HR=1.76, 95%CI 0.95–3.26, P=.07) and REL (rs1432295) (HR=0.63, 95%CI 0.37–1.06, P=.08) in the dominant model. In the MER, PVT1 (rs2608053) was associated with PFS in the ordinal model (HR=1.42, 95%CI 0.99–2.03, P=.06), while there was a suggestive association with HLA-DRA (rs6903608) in the dominant model (HR=0.64, 95%CI 0.39–1.05, P=.08) for whole cohort but also for EBV negative cHL (HR=0.41, 95%CI 0.17–0.99, P=.05). In a meta-analysis of the two studies, PVT1 (rs2608053) was significantly associated with PFS in the ordinal (HR=1.34, 95%CI 1.04–1.73, P=.02) and the dominant (HR=1.88, 95%CI 1.20–2.95, P=.006) models. Further adjustment for IPS had minimal impact on these associations (ordinal HR=1.30, 95%CI 1.00–1.70; dominant HR=1.78, 95%CI 1.13–2.83). Patients with PVT1(rs2608053) GG, GA, AA genotypes had a 5-year PFS rate of 83%, 74% and 73% in GELA and 86%, 70%, and 73% in the MER, respectively. Conclusions: The non-HLA cHL susceptibility locus PVT1 (rs2608053) was associated with PFS in two independent cohorts of cHL cases, and after adjustment for the IPS. While associations with GATA3 and REL were only observed in one of the studies, their evaluation in other studies is warranted. Functional studies of PVT1 in cHL pathogenesis should be pursued. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4410 BACKGROUND Autoimmune cytopenia occurs in 5%-10% of patients with CLL. Treatment for patients with both autoimmune cytopenia and progressive CLL is challenging due to poor tolerance of myelosuppression, and the risk of exacerbation of autoimmune cytopenia by purine analogues. METHODS We identified 20 patients from our CLL database of approximately 3000 patients who were treated with a chemoimmunotherapy regimen of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for both autoimmune cytopenia and progressive CLL from January 2000-December 2008 at Mayo Clinic Rochester. RESULTS Autoimmune cytopenia responded in 19 patients (14 CR and 5 PR) with a median time to progression (TTP) of 13.6 months (range 5 – 29). Five patients remain in sustained remission at last follow up (range 15 – 30 months) and 4 patients have had recurrent autoimmune cytopenia requiring re-treatment. Six patients required maintenance corticosteroid therapy after completing R-CVP. Progressive CLL responded to treatment in 17 patients (9 CR/CCR, 8 PR by NCI-WG 1996 criteria) with a median TTP of 6.3 months (range 1-40 months). Fourteen patients have required additional treatment for progressive CLL at a median of 5.4 months (range 4-22 months). Five patients have not required additional treatment for either CLL or autoimmune cytopenia at 15 -30 months after completing treatment. R-CVP treatment toxicity included 3 patients with grade 3-4 infections, 2 with grade 1 peripheral neuropathy, and one with grade 3 drug-induced pneumonitis. No patient required blood cell transfusions after the completion of cycle 1 of therapy. CONCLUSIONS Although R-CVP is an effective and tolerable therapy for patients with simultaneous autoimmune cytopenia and progressive CLL requiring therapy, the duration of response is suboptimal. Clinical trials testing alternative treatment strategies are needed for this patient population. Disclosures: Zent: Genentech, Bayer, Genzyme, Novartis: Research Funding. Shanafelt:Cephalon: Research Funding; Celgene: Research Funding; Polyphenon Pharma : Research Funding; Hospira: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Bayer Health Care Pharmaceuticals: Research Funding. Kay:Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees; Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding.

Abstract Abstract 440 Background: Complement plays a central role in innate immunity, and also functions as a regulator of the overall immune response, including T-cell responses. We recently reported that germline genetic variation in C2, C5, C7 and C9 was associated with risk of developing non-Hodgkin lymphoma (Br J Haematol 2009;145:614). Here we evaluate whether complement genes are associated with event-free survival (EFS) in follicular lymphoma. Methods: We genotyped 166 single nucleotide polymorphisms (SNPs) from 32 complement pathway genes in a prospective cohort study of 115 newly diagnosed follicular lymphoma patients enrolled at the Mayo Clinic from 2002-2005 as part of the Lymphoma SPORE. All patients were systematically followed through 2008 for EFS (defined as disease progression, retreatment, or death due to any cause). Tagging and nsSNPs were selected from HapMap for the genes encoding complement proteins and their key regulators (C1QB, C1QG, C1QR1, C1QTNF7, C1RL, C1S, C2, C3, C3AR1, C4BPA, C4BPB, C5, C5R1, C6, C7, C8B, C9, BF, CFH, CFHL5, CFHR1, CGHR4, CLU, CR1 (CD35), CR2 (CD21), DF, MASP2, MBL2, MCP (CD46), DAF (CD55), CD59 and SERPING1). Cox regression was used to estimate Hazard Ratios (HRs) for individual SNPs with EFS. The most prevalent homozygous genotype was used as the reference group, and each polymorphism was modeled individually as having a log-additive effect in the regression model. For gene-level analyses, we used a principal components based gene-level test. All models were adjusted for sex, FLIPI, follicular grade III, and initial treatment. Results. The median age at diagnosis was 61 years (range, 25-85). 57 (50%) of the patients had an event, at a median follow-up of 59 months (range, 33-73) for living patients. In gene-level analyses, CFH (p=0.004), CD55 (p=0.02), CFHR5 (p=0.02) and CFHR1 (p=0.02) were significant at p<0.05, and these genes had noteworthy q-values after consideration of multiple testing (q=0.04 for CFH and q=0.08 for CD55, CFHR5, and CFHR1). For CFH, 2 of the 11 tagSNPs (rs1329423, HR=0.46, p=0.001; and rs3766404, HR=2.0, p=0.003) were significantly associated with EFS, as was the nsSNP rs1065489 (amino acid change E936D: HR=0.39, p=0.004). For CD55, both tagSNPs (rs4844591, HR=0.58, p=0.03; and rs2564978, HR=0.58, p=0.03) were associated with EFS, as were 3 of 5 tagSNPs from CFHR5 (rs3748557, HR=0.52, p=0.03; rs12092294, HR=1.9, p=0.03; and rs6694672, HR=1.9, p=0.03) and the only tagSNP for CFHR1 (rs436719, HR=0.54, p=0.03). Conclusions. Genetic variation in CFH, CD55, CFHR5, and CFHR1 was associated with EFS in follicular lymphoma after adjustment for clinical variables. These genes are part of a gene cluster at 1q32-q32.1 involved in the regulation of C3. CD55 encodes a membrane complement regulatory protein which can allow tumor cells to evade complement attack. These results are being validated in a second set of SPORE patients. Support: P50 CA97274, R01 CA92153. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 140 Background: Peripheral T-cell lymphomas (PTCLs) have poor outcomes, and there is a lack of prognostic biomarkers and therapeutic targets to guide treatment. We recently proposed that the transcription factor, interferon regulatory factor-4 (IRF4, also called multiple myeloma oncogene-1 [MUM1]), might be oncogenic in PTCLs based on its expression in association with translocations between IRF4 and the T-cell receptor gene, TRA@. IRF4 is a therapeutic target in multiple myeloma, where high expression is a poor prognostic factor. In addition, at least two germline IRF4 single nucleotide polymorphisms (SNPs), rs12203592 and rs872071, are associated with IRF4 expression and disease risk and progression in various lymphoid neoplasms. However, the prognostic effects of IRF4/MUM1 expression and IRF4 SNPs in PTCLs are unknown. Methods: Forty seven newly diagnosed PTCL patients with available tissue were identified from the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource. There were 5 anaplastic large cell lymphomas, 14 cutaneous T-cell lymphomas (CTCLs), 6 cytotoxic T-cell lymphomas (cytTCLs: 4 extranodal NK/T-cell and 2 enteropathy type), and 22 PTCLs, not otherwise specified (NOS). Patients were diagnosed between September 2002 and February 2008 and systematically followed through March 2010 for overall survival (OS). Tumor cell IRF4/MUM1 expression was examined by immunohistochemistry on paraffin tissue sections (MUM1p clone; Dako). Positivity was defined as >30% of tumor cells with nuclear staining, as in previous studies. rs12203592 and rs872071 were genotyped in peripheral blood DNA. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for both IRF4/MUM1 expression and SNPs with OS. Chi-squared tests were used to assess the relationship between IRF4/MUM1 expression and IRF4 SNPs. Results: The median age at diagnosis was 60 years (range, 24–88). At a median follow-up of 62 months (range, 29–89), 22 (47%) of the patients had died. Fifteen (32%) of the 47 T-cell patients had IRF4/MUM1 positive tumors. IRF4/MUM1 positivity was associated with poorer overall survival (HR=4.3; 95% CI: 1.8–10.2; p=0.0008). This association was seen across PTCL subtypes, including PTCL, NOS (HR= 6.5; 95% CI: 1.5–27.7; p=0.01), CTCL (HR=13.4; 95% CI: 1.2–150.1; p=0.03), and cytTCL (HR=5.8; CI: 0.5–65.9; p=0.15). The minor allele (T) in SNP rs12203592 was positively associated with IRF4/MUM1 positivity in a dominant model, with IRF4/MUM1 expression in 60% of patients with CT or TT genotypes compared to 19% of patients with CC genotype (p=0.01). Patients with the CT/TT genotype at rs12203592 also had inferior overall survival (HR=3.7; 95% CI: 1.4–9.5; p=0.007). The rs872071 SNP showed no significant association with either IRF4/MUM1 expression (p=0.38) or overall survival (p=0.71). Conclusions: This study is the first to demonstrate that IRF4/MUM1 expression is poor prognostic factor in PTCLs. This association was observed across PTCL subtypes, including the most common subtype, PTCL, NOS. IRF4/MUM1 expression and poor survival in our patients also were associated with the minor allele (T) in the IRF4 SNP rs12203592; these findings are consistent with previous in vitro data showing the major allele (C) represses IRF4 promoter activity. Interestingly, rs872071 was not associated with IRF4/MUM1 expression or prognosis, similar to findings in multiple myeloma. In contrast, rs872071 is a risk and prognostic factor in chronic lymphocytic leukemia and classical Hodgkin lymphoma, diseases in which IRF4/MUM1 expression has been associated with favorable prognosis. IRF4/MUM1 expression is a poor prognostic factor in PTCLs. Disclosures: No relevant conflicts of interest to declare.

Abstract We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

AbstractBackgroundHuman pegivirus (HPgV) is a single-strand RNA virus belonging to the Flaviviridae. Although no definitive association between HPgV infection and disease has been identified, previous studies have suggested an association of HPgV viremia with risk of lymphomas.MethodsWe conducted a systematic review and meta-analysis, including 1 cohort study and 14 case-control studies, assessing the association of HPgV viremia with adult lymphomas. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, overall and by geographic region and lymphoma subtype.ResultsThe overall OR for lymphoma was 2.85 (95% CI, 1.98–4.11), with statistically significantly elevated ORs observed in 8 of 15 studies. There was a small amount of heterogeneity among studies (I2 = 28.9%; Q = 18.27, P = .16), and the funnel plot provided no evidence for publication bias. The strongest association with lymphoma risk was observed for studies from Southern Europe (OR, 5.68 [95% CI, 1.98–16.3]), whereas weaker ORs (with 95% CIs) were observed for studies from North America (2.24 [1.76–2.85]), Northern Europe (2.90 [.45–18.7), and the Middle East (2.51 [.87–7.27]), but all of similar magnitude. Participants with HPgV viremia had statistically significantly increased risks (OR [95% CI]) for developing diffuse large B-cell (3.29 [1.63–6.62]), follicular (3.01 [1.95–4.63]), marginal zone (1.90 [1.13–3.18]), and T-cell (2.11 [1.17–3.89]) lymphomas, while the risk for Hodgkin lymphoma (3.53 [.48–25.9]) and chronic lymphocytic leukemia (1.45 [.45–4.66]) were increased but did not achieve statistical significance.ConclusionsThis meta-analysis supports a positive association of HPgV viremia with lymphoma risk, overall and for the major lymphoma subtypes.

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.