Citations

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT–CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in‐depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, p = 8.3 × 10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2 = 0.07, D′ = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10−5), rs4583925 (p = 4.0 × 10−5) and rs2735948 (p = 5.0 × 10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

Abstract Background: Genome wide association studies (GWAS) have recently identified 8 loci identified with multiple myeloma (MM) susceptibility. We hypothesized that germ line genetic variants may also affect MM progression. We performed the first GWAS of MM survival, by conducting a meta-analysis of two existing studies at University of California San Francisco (UCSF) and the Mayo Clinic, and replicating findings in the International Multiple Myeloma rESEarch (IMMEnSE) consortium. Methods: The UCSF study included 353 MM patients genotyped on an Illumina Omni5 and Illumina 660 array. The Mayo clinic study included 239 MM patients genotyped on an Affymetrix 6.0 array. We imputed missing genotypes using the 1000 Genomes dataset and performed a GWAS for survival using proportional hazards models adjusting for age and gender and genetic ancestry using principal components analysis. We conducted a meta-analysis of the results from the two GWAS. We replicated the top SNPs in the IMMEnSE cohort which included 772 patients with survival data from 7 European countries and one North American site. We used the dataset from Grundberg et al (Nat Genetics 2012) to test for an association between SNPs associated with survival and gene expression in immortalized lymphocytes. We used gene expression data from Zhan et al (Blood 2006) to analyze the association between expression and survival. Results: In meta-analysis, we found a genome wide significant association between SNPs on a region at 16p13 and survival (rs72773978; p=2.9x10e-10). Patients with the minor allele were at increased risk for mortality (HR 2.73; 95% CI: 1.99 - 3.73). The top associated SNPs were all in strong linkage disequilibrium and were centered over the gene FOPNL. We replicated the association in the IMMEnSE cohort and found a significant association between the top SNP from the discovery dataset (rs72773978 p=0.037). We used previously published data to determine the association between gene expression and the top associated SNPs from the GWAS. The top SNP (rs72773978) was not in previously published eQTL databases, so we used rs7201759 which was also associated with survival in our data (p=3.8x10e-10) as a proxy. The minor allele for this SNP was associated with increased levels of expression of FOPNL (p=9x10e-5), but not with expression of any other genes within a 1 megabase region. Finally, we also observed an association between increased expression of FOPNL and shorter survival (HR: 2.62 per standard deviation.; 95% CI: 1.08 - 6.32). Conclusion: Germ line variants at 16p13 near the FOPNL gene are associated with survival among MM patients. FOPNL is thought to be involved in centrosomal function, and centrosomal activity has previously been associated with survival in MM patients. Our results support this previous observation. Furthermore, they suggest that germ line variants could also be useful in assessing prognosis for patients with MM. Citation Format: Elad Ziv, Eric Dean, Donglei Hu, Alessandro Martino, Daniel Serie, Daniele Campa, Blake Aftab, Paige Bracci, Gabriele Buda, Jennifer Caswell, Charles Dumontet, Marek Dudziński, Laura Fejerman, Alexandra Greenberg, Scott Hunstman, Artur Jurczyszyn, Krzysztof Jamroziak, Shaji Kumar, Herlander Marques, Thomas Martin, Joaquin Martinez-Lopez, Vincent Rajkumar, Juan Sainz, Annette Juul Vangsted, Marzena Watek, Jeffrey Wolf, Susan Slager, Federico Canzian, Celine Vachon. Genome wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. [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 5078. doi:10.1158/1538-7445.AM2014-5078

Abstract Background. Follicular lymphoma (FL) is an indolent B-cell malignancy with a variable clinical course that may transform to more aggressive forms of lymphoma. Previous modestly powered GWAS have reported multiple FL susceptibility loci in the HLA class I and II regions at 6p21.32-33, but novel non-HLA susceptibility loci and the genetic architecture of FL associations in the HLA region remain to be elucidated. Methods. We conducted the largest GWAS of FL to date consisting of 2,142 cases and 6,221 controls of European ancestry from 22 studies scanned on the Illumina OmniExpress. After imputation of common SNPs using IMPUTE2 and 1,000 Genomes Project v3 data, we conducted a meta-analysis of these data with two previous FL GWAS (n=586 cases, 1,537 controls) and replicated top hits in an additional 629 cases and 4,283 controls. Expression quantitative trait loci (eQTL) analyses were performed to evaluate the effects of associated variants on gene expression. Classical HLA allele imputations and stepwise regression analyses are underway to further characterize the HLA associations. Results. In the joint meta-analysis, the strongest association with FL risk was observed in the HLA region, where a large number of SNPs showed genome-wide significance (P<5x10-8 to P= 1.84x10-84), particularly in HLA class II at 6p21.32 where several HLA eQTLs were identified (P < 0.05). Outside HLA, we identified four novel loci associated with FL at 11q23.3 (CXCR5, rs4938573; P=3.14x10-15), 11q24.3 (ETS1, rs4937362; P=3.33x10-9), 3q13.33 (CD86, rs2681416; P=9.79x10-11) and 3q28 (LPP, rs6444305, P=2.55x10-8). These novel susceptibility loci were located in four biologically relevant genes involved in immune regulation: CXCR5 and its ligand, CXCL13, are involved in guiding B-cells into the B-cell zones of secondary lymphoid organs as well as T-cell migration. ETS1 is expressed in lymphoid cells and regulates immune cell function including differentiation, survival, and proliferation. CD86 and CD80 are classic members of the B7 costimulatory pathway that is important in maintaining immune function, suppression of autoimmunity and antitumor surveillance. LPP encodes a LIM domain-containing protein of the zyxin family and participates in cell adhesion, cell migration, proliferation and transcription dynamics. Conclusions. This large GWAS provides further support for the important role of common genetic variation in non-HLA genes and further evidence of the key role that HLA immune-regulatory genes play in the pathogenesis of FL. Citation Format: Christine F. Skibola, Sonja I. Berndt, James R. Cerhan, Zhaoming Wang, Joseph Vijai, Lucia Conde, Paul de Bakker, Sophia S. Wang, Claire M. Vajdic, Brenda M. Birmann, Susan L. Slager, James McKay, Paige M. Bracci, Alexandra Nieters, Qing Lan, Angela R. Brooks-Wilson, Martha S. Linet, Demetrius Albanes, John J. Spinelli, Roel C.H. Vermeulen, Mark P. Purdue, Meredith Yaeger, Lauren R. Teras, Silvia de Sanjose, Alain Monnereau, Simon Crouch, Jia Nee Foo, Henrik Hjalgrim, Gianluca Severi, Brian K. Link, Kimberly A. Bertrand, Yawei Zhang, Karin E. Smedby, Stephen J. Chanock, Nathaniel Rothman, NHL GWAS Consortium. Meta-analysis of genome-wide association studies identifies novel susceptibility loci for follicular 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 5072. doi:10.1158/1538-7445.AM2014-5072

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 Introduction Pancreatic cancer is a highly lethal malignancy due to late diagnosis and aggressiveness of the tumor. Characterization of high-risk populations for monitoring, intervention and early detection remains challenging. Obesity and diabetes are potentially modifiable contributors to pancreatic cancer. Genetic factors modifying the risk of obesity- and diabetes-induced pancreatic cancer have previously not been fully investigated at the genome-wide level. Hypothesis There are potential genetic factors modifying the associations between obesity/diabetes and pancreatic cancer. Methods Integrating genotype with risk factor data from a GWAS for the Pancreatic Cancer Case Control Consortium, we performed a genome-wide gene-environment interaction (G x E) scan for 457,688 SNPs in a discovery study of 2,028 cases and 2,109 controls using state-of-the-art methods including case-only (CO), case-control (CC), Empirical Hierarchical Bayes (EHB), Empirical-Bayes test (EB) and three 2-step approaches (DG2, EG2, DGEG2). Results We detected a genome-wide significant (P < 1.09 x 10-7 ) interaction of diabetes with rs13061928 (in CNTN4) in CO (P = 8.8 x 10-8 ), which was independent of diabetes in control group (P = 0.08). The minor allele was in a synergism with diabetes on the cancer risk: diabetics carrying GA/AA genotype had a 3.39-fold (95% CI: 2.47-4.65) increased disease risk compared with non-diabetics carrying GG genotype. Consistently, the SNP-diabetes interaction had a high ranking statistic in EHB (No.1) and high p-value ranks for EG2 and DGEG2 methods (No.1, P= 5.44 x 10-5). Conclusions These observations, once validated/confirmed, may help define at-risk subpopulation and initiate targeted intervention and prevention of pancreatic cancer. Genome-wide G x E analysis requires larger sample size than genetic main effects scan; combining the CO method with alternative methods may be the optimal scheme for genome-wide G x E analysis. Citation Format: Hongwei Tang, Eric J. Duell, Harvey A. Risch Risch, Sara H. Olson, H. Bas Bueno-de-Mesquita, Steven Gallinger, Elizabeth A. Holly, Gloria M. Petersen, Paige M. Bracci, Robert R. McWilliams, Mazda Jenab, Elio Riboli, Anne Tjønneland, Marie Christine Boutron-Ruault, Rudolf Kaaks, Dimitrios Trichopoulos, Salvatore Panico, Malin Sund, Petra H. M Peeters, Kay-Tee Khaw, Christopher I Amos, Donghui Li, Peng Wei. Genome-wide gene-diabetes and gene-obesity interaction scan in the pancreatic cancer case control consortium. [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 2214. doi:10.1158/1538-7445.AM2014-2214

Genomewide association studies (GWAS) and candidate‐gene studies have implicated single‐nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case‐control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate‐gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate‐gene studies was associated in the full case‐control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate‐gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.

AbstractMany common genetic variants have been associated with non-Hodgkin lymphoma (NHL), but individual study results are often conflicting. To confirm the role of putative risk alleles in B-cell NHL etiology, we performed a validation genotyping study of 67 candidate single nucleotide polymorphisms within InterLymph, a large international consortium of NHL case-control studies. A meta-analysis was performed on data from 5633 B-cell NHL cases and 7034 controls from 8 InterLymph studies. rs3789068 in the proapoptotic BCL2L11 gene was associated with an increased risk for B-cell NHL (odds ratio = 1.21, P random = 2.21 × 10−11), with similar risk estimates for common B-cell subtypes. PRRC2A rs3132453 in the HLA complex class III region conferred a reduced risk of B-cell NHL (odds ratio = 0.68, P random = 1.07 × 10−9) and was likewise evident for common B-cell subtypes. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes.

Summary A recent meta‐analysis of three genome‐wide association studies of chronic lymphocytic leukaemia ( CLL ) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non‐ H odgkin lymphoma ( NHL ) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P = 0·01; rs210142: P = 6·8 × 10 −3 ). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.

Abstract We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10−16). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

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]