Vineis, Paolo

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.

Objective Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions These data suggest several plausible genetic links between DLBCL and SLE.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. Relatives of DLBCL patients are at elevated risk for DLBCL. In small genome-wide association studies (GWAS) in which all NHL subtypes were combined, no conclusive loci for DLBCL have been previously identified in individuals of European background, whereas a recent study conducted in East Asia identified a locus at 3q27. Methods: To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of three new GWAS and one prior scan, totaling 3,857 DLBCL cases and 7,666 controls of European ancestry. Imputation was used to combine all the data using the 1000 Genomes Project release v3 and IMPUTE2. Based on these findings, we selected 6 promising SNPs for genotyping in an additional 202 cases and 3,431 controls, which were then included in a second meta-analysis. SNPTEST was used to estimate odds ratios (ORs), using the additive model and adjusting for age, gender and significant eigenvectors. Results: In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; OR=2.33, P=1.60x10-20), rs13255292 and rs4733601 at 8q24.21 (PVT1; OR=1.23, P=4.86x10-12 and OR=1.18, P=1.63x10-8, respectively), rs2523607 at 6p21.33 (HLA-B; OR=1.34, 3.35x10-9) and rs2681416 at 3q13.33 (CD86; OR=1.20, P=6.04x10-9). The two 8q24.21 SNPs displayed minimal linkage disequilibrium (r2=0.03) and conditional analysis supported their independence. We did not observe a notable signal for a locus previously reported for DLBCL on 3q27 in East Asia, rs6773854 (OR=1.06, P=0.81). We estimated that common SNPs, including but not limited to the loci discovered in this study, explain approximately 16% of the variance for DLBCL risk overall. Discussion: The susceptibility locus at 6p25.3 maps near a plausible DLBCL candidate gene, EXOC2 (exocyst complex component 2), which interacts with Ral proteins, and disruption of the Ral-exocyst regulatory node impacts cellular and developmental processes associated with malignant transformation and progression. The two 8q24.21 variants are approximately 1Mb telomeric to the 8q24 region linked with multiple cancers including CLL. Both variants are positioned in close proximity to PVT1, which is a non-coding RNA implicated in the MYC activation, and MYC is known to be deregulated in some DLBCLs. The locus at 3q13.33 maps to CD86 (B7-2), a B-7 family member that along with CD80 (B7-1) is essential in cognate interactions between T- and B-lymphocytes; both play key roles in immunodeficiency, autoimmune diseases, and in anti-tumor immunity. Finally, we had multiple signals in the HLA region, the strongest of which was at 6p21.33 near HLA-B. HLA-B encodes the HLA class I heavy chain paralogue, which heterodimerizes with a light chain (β2 microglobulin) and plays a central role in presenting intracellularly processed self or foreign antigens to CD8+ cytotoxic T lymphocytes. Class I molecules have been extensively linked to the risk of a variety of immune-mediated diseases and cancers including DLBCL. Conclusions: These data provide substantial new evidence for genetic susceptibility to this B-cell malignancy, and point towards pathways involved in immune recognition and immune function in the pathogenesis of DLBCL. Citation Format: James R. Cerhan, Sonja I. Berndt, Joseph Vijai, Hervé Ghesquières, James McKay, Sophia S. Wang, Zhaoming Wang, Meredith Yeager, Alexandra Nieters, David Cox, Alain Monnereau, Christopher Flowers, Anneclaire J. De Roos, Angela R. Brooks-Wilson, Qing Lan, Gianluca Severi, Mads Melbye, Rebecca D. Jackson, Lauren R. Teras, Mark Purdue, Claire Vajdic, Demetrius Albanes, Kimberly A. Bertrand, Anne Zeleniuch-Jacquotte, Simon Crouch, Yawei Zhang, Paolo Vineis, Susan L. Slager, Karin E. Smedby, Gilles Salles, Christine F. Skibola, Nathaniel Rothman, Stephen J. Chanock, on behalf of the NHL GWAS Project. Genome-wide association study identifies multiple susceptibility loci for diffuse large B-cell 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 LB-272. doi:10.1158/1538-7445.AM2014-LB-272

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

Abstract Despite limited discovery stages (<1,125 cases), genome-wide association studies (GWAS) have successfully identified 13 loci associated with risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL); however, these loci only explain a portion of the heritability. To identify additional genetic loci associated with CLL susceptibility, we conducted the largest meta-analysis of GWAS, to date, including 3,100 CLL cases and 7,667 controls of European ancestry from 25 independent studies genotyped on four different SNP microarrays. Association testing was conducted assuming a log-additive genetic model, adjusting for age, sex, and significant principal components. Meta-analyses were performed using the fixed effects inverse variance method based on the beta estimates and standard errors from each study. Promising loci were taken forward for replication in three additional studies totaling 788 cases and 4,872 controls. In the meta-analysis of both the discovery and replication studies, we conclusively identified ten independent SNPs in nine novel loci that reached genome-wide significance (P<5 x 10−8): 10q23.31 (FAS; P=1.22x10−14), 18q21.33 (BCL2; P=2.66x10−12 and P=7.76x10−11), 11p15.5 (C11orf21; P=2.15x10−10), 4q25 (LEF1; P=4.24x10−10), 2q33.1 (CASP8; P=2.50x10−9), 9p21.3 (CDKN2B-AS1; P=1.27x10−8), 18q21.32 (PMAIP1; P=2.51x10−8), 15q15.1 (BMF; P=2.71x10−10), and 2p22.2 (QPCT; P=1.68x10−8) as well as an independent signal at an established locus (2q13, ACOXL, P=2.08x10−18). We also found evidence for two additional promising loci that reached marginal genome-wide significance (P<2.0x10−7) at 8q22.3 (ODF1; P=5.40x10−8) and 5p15.33 (TERT; P=1.92x10−7). Although further studies are required, the proximity of five of the novel loci to genes involved in apoptosis suggests a possible unifying underlying biological mechanism. Together with the previously established loci, these genetic loci explain ~17% of the familial risk of CLL. Citation Format: Sonja I. Berndt, Christine F. Skibola, Vijai Joseph, Nicola J. Camp, Alexandra Nieters, Zhaoming Wang, Wendy Cozen, Alain Monnereau, Rachel S. Kelly, Silvia de Sanjose, Martha S. Linet, Elio Riboli, Paolo Vineis, Henrik Hjalgrim, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, Susan L. Slager. Meta-analysis of genome-wide association studies identifies multiple loci associated with chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-23. doi:10.1158/1538-7445.AM2013-LB-23

AbstractWe performed a pooled analysis of data on atopic disease and risk of non–Hodgkin lymphoma (NHL) from 13 case-control studies, including 13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed 2 years or more before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were computed in two-stage random-effects or joint fixed-effects models, and adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, specific allergy (excluding hay fever, asthma, and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with a history of allergy (OR, 0.80; 95% CI, 0.68–0.94) and reduced B-cell NHL risk was associated with history of hay fever (OR, 0.85; 95% CI, 0.77–0.95) and allergy (OR, 0.84; 95% CI, 0.76–0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic—those with hay fever, allergy, or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study shows evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy. [Cancer Res 2009;69(16):6482–9]

Abstract Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081–9)

Abstract Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.