Fredericksen, Zachary S.

Abstract Background: Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and may develop in the setting of inflammation and immune dysfunction. Small scale evaluations have suggested that common genetic variation in candidate genes related to immune function may predispose to the development of NHL. Here we report a comprehensive analysis of variants within genes associated with immunity and inflammation and risk of NHL. Methods: We used ParAllele’s Immune and Inflammation panel of 9,412 single nucleotide polymorphisms (SNPs) from 1,450 immune/inflammation genes as a discovery tool in a clinic-based study of 458 NHL cases and 484 frequency matched controls seen at the Mayo Clinic from 2002–2005. The panel included 537 coding non-synonymous SNPs (nsSNPs), with the remainder of the SNPs selected as tags from HapMap (tagSNPs) to provide coverage of the candidate genes (r2 = 0.8 and minor allele frequency >0.05). To assess the association of individual SNPs with risk of NHL, we calculated Odds Ratios (ORs) and 95% confidence intervals, adjusted for age and gender. 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. Associations between haplotypes from each gene and the risk of NHL were calculated using a score test implemented in HAPLO.SCORE. We also modeled the main effects for all independent (r2 <0.25) SNPs from a gene in a multivariate logistic regression model. Results: The mean age at diagnosis was 60 years for cases and 58% were male; in controls the mean age at enrollment was 61.6 years and 55% were male. In the gene analyses, the strongest findings (p≤0.001 from multiple SNP logistic regression or haplotype analysis) were for cAMP responsive element binding protein 1 (CREB1; p=0.0004), fibrinogen alpha chain (FGA; p=0.0006), TNF receptor-associated factor 1 (TRAF1; p=0.001), dual specificity phosphatase 2 (DUSP2; p=0.001), and fibrinogen gamma chain (FGG; p=0.001). In the nsSNP analyses, the strongest findings (p≤0.01) were for integrin β3 (ITGB3) L59P (OR=0.64, 0.50–0.83), Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) H328R (OR=0.72, 0.57–0.91), transporter 2, ATP-binding cassette (TAP2) T665A (OR=1.32, 1.07–1.63), HLA-B associated transcript 2 (BAT2) V1895L (OR=0.60, 0.42–0.85), and complement component 7 (C7) T587P (OR=1.39, 1.07–1.80). Conclusions. Our results suggest that genetic variability in genes associated with antigen processing (CREB1 and TAP2), lymphocyte trafficking (B3GNT3), immune activation (TRAF1, BAT2), complement and coagulation pathways (FGA, FGG, ITGB3, C7), and MAPK signaling (DUSP2) may be important in the etiology of NHL, and should be pursued in replication studies.

Abstract Background: Inhibitors of HMG-CoA reductase (“statins”) are effective in reducing the risk of cardiovascular disease. Preclinical data from rodents suggested that they may increase the incidence of some cancers, including lymphoma. However, monitoring of randomized trials in humans have generally found decreased cancer risks, and these findings have been supported by a growing number of observational studies, including three recent reports of a protective association in NHL. The suggested anti-carcinogenic mechanisms for statins include their impact on inflammatory (including a shift from a Th1 to Th2 profile) and angiogenesis pathways, as well as the induction of apoptosis by modulation of signaling pathways, all of which are of biologic relevance in NHL. Methods: We evaluated the history of statin use and risk of NHL in a clinic-based study of 243 newly diagnosed NHL cases and 499 frequency matched controls enrolled at the Mayo Clinic from 2002-2005. Risk factor data were collected using self-administered questionnaires, and included history of use of cholesterol lowering drugs two or more years before diagnosis (for cases) or enrollment (for controls); specific drug names were not available. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI), adjusting for age, gender, and residence. NHL subtypes were centrally reviewed, and subtype-specific risks were estimated using polychotomous logistic regression. Results. The mean age at diagnosis was 59.5 years for cases and 55% were men; among controls, the mean age at enrollment was 61.8 years and 54% were men. Twenty-one percent of the cases reported ever using statins compared to 30% of the controls, supporting a lower risk of NHL for ever users (OR=0.69; 95% CI 0.47–1.00). The lowest risk was seen for the longest users; i.e., compared to never users, person who had 10 or more years of use had the greatest reduction in risk (OR=0.52; 95% CI 0.24–1.10). A history of high cholesterol was also inversely associated with risk of NHL (OR=0.72; 95% CI 0.55–0.93). However, the association for the type of treatment for cholesterol lowering varied. Those who were medically treated had inverse association with risk of NHL (OR=0.63; 95% CI 0.46–0.86), while the no treatment and dietary change only groups were found to have no association with risk. The reduction in NHL risk with medical treatment was specific to statin use, as the use of other cholesterol lowering drugs was not associated with risk (OR=1.13; 95% CI 0.50–2.57). These results were not confounded by education, family history of NHL, body mass index, cigarette smoking or alcohol use. In subtype analysis, the inverse association was seen for diffuse large B-cell lymphoma (OR=0.27; 95% CI 0.08–0.90), but not for CLL/SLL or follicular NHL. Conclusions. Statin use was associated with a lower risk of developing NHL, particular diffuse large B-Cell lymphoma.

Abstract Background: B-cell non-Hodgkin lymphomas (NHL) are common lymphoid malignancies in which malignant B-cells arrested at various stages of differentiation proliferate within lymph nodes and occasionally other tissues. The microenvironment that supports the growth and survival of NHL B cells consists of a complex network of immune cells and cytokines and its specific composition has been shown to have significant clinical implications. The intratumoral immune cells include effector and regulatory T (Treg) lymphocytes that are more than simple residual elements from the normal lymph node structure. We previously explored whether the extent of T cell infiltration played a role in the clinical outcome of patients with B-cell NHL and found that an increased percentage of CD4+ T cells in the diagnostic biopsy of lymphoma patients significantly correlated with an improved 5-year overall survival. We have also shown that intratumoral Treg cells significantly suppress the anti-tumor response. Based on the fact that intratumoral T-cells are important in B-cell NHL, we evaluated whether genetic variation in genes that regulate the T-cell response may be associated with lymphoma risk. Methods: We genotyped 257 single nucleotide polymorphisms (SNPs) from 50 candidate genes related to T-cell differentiation and function in a clinic-based study of 441 Caucasian NHL cases and 475 frequency matched Caucasian controls seen at the Mayo Clinic from 2002–2005. Tagging and nsSNPs were selected from HapMap. The most prevalent homozygous genotype was used as the reference group and each SNP was modeled individually as having a log-additive effect, expressed as ordinal odds ratios (OR) per variant allele and 95% confidence intervals, in an age- and sex-adjusted logistic regression analysis. We also evaluated the consistency of the findings for the most common types of B-cell NHL - diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and CLL/SLL. For gene-level analyses, we used principal components (PC) analysis using all SNPs from a gene; those PCs that explained > 90% of the variability were then modeled in a logistic regression analysis and significance was determined using a likelihood ratio test. We also evaluated the association of haplotypes from each gene with risk of NHL using the score test implemented from HAPLO.SCORE. Results. The mean age at diagnosis was 60.1 years for cases and 58% were male; among controls, the mean age at enrollment was 61.7 years and 55% were men. In the PC gene analyses, PRF1 (perforin gene - involved in cytotoxicity; p=0.004), CD276 (B7-H3 gene - involved in co-stimulation; p=0.01), TBX21 (T-bet gene – regulates Th1 cell development; p=0.02), and IL6 (p=0.02) were significant at p<0.05; haplotype analysis showed similar results, with the addition of CARD15 (NOD2 gene – regulates Th1 responses; p=0.02). There were 2 SNPs in PRF1, and both the intronic SNP rs3758562 (OR=1.38; 1.13–1.69) and the synonymous coding SNP rs885821 (OR=0.80; 0.63–1.02) were associated with NHL risk overall and for each subtype. There were 2 SNPs in CD276, and both the intronic SNP rs7176654 (OR=1.29; 1.07–1.56) and the mrna-utr SNP rs3816661 (OR=0.82; 0.68–0.99) were associated with NHL risk overall and with the CLL/SLL and follicular NHL subtypes specifically. There were 2 SNPs in TBX21, and only the mrna-utr SNP rs7502875 (OR=0.73; 0.59–0.92) was associated with NHL risk overall and for each subtype. There were 11 SNPs in IL6, and the intronic SNP rs2069835 (OR=1.88; 1.24–2.84) and the locus-region SNP rs2069824 (OR=1.73; 1.20–2.50) were each associated with NHL risk overall and each subtype. Finally, there were 9 SNPs in CARD15, with only the nonsynonymous coding SNP rs5743291 (OR=1.43; 1.02–1.98) being associated with overall NHL risk, and risk was specific to FL. Conclusions. Genetic variation in several genes that play critical roles in T-cell maturation and function was associated with lymphoma risk. These genes appeared to be associated with the differentiation and function of effector T-cells particularly Th1 and Th17 cells. These results provide potentially important insights into the role of T-cells in lymphomagenesis.

Abstract Background: Reactive oxygen species cause DNA damage and altered immunologic responses, and have been linked to the development of NHL. Diets rich in fruits and vegetables are excellent sources of antioxidants, and vitamins C, E, polyphenols, and carotenoids, along with selected micronutrients such as zinc are thought to be responsible for most of the antioxidant activity in foods. We evaluated the hypothesis that vegetables, fruits and nutrients involved in antioxidant activity would protect against developing NHL. In a secondary analysis, we also assessed heterogeneity of this hypothesis for the most common subtypes of NHL: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma, and diffuse large B cell lymphoma (DLBCL). Methods: We evaluated dietary antioxidant intake and NHL risk in a clinic-based study of 416 newly diagnosed NHL cases and 926 frequency-matched controls enrolled at the Mayo Clinic from 2002–2007. Usual diet two years before diagnosis/enrollment was assessed using a self-administered, 128-item food frequency questionnaire. Dietary intake of antioxidants was estimated using the Food Processor SQL system, further supplemented with data from US Department of Agriculture nutrient databases. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, and total energy. NHL subtypes were centrally reviewed, and subtype-specific risks were estimated using polychotomous logistic regression. Results: The mean age at diagnosis was 60.8 years for cases and 57% were male; for controls, the mean age at enrollment was 60.8 years and 54% were men. NHL risk was inversely associated with intake of total vegetables (OR for highest compared to lowest quartile, 0.46; 95% CI 0.32–0.68; p-trend<0.001), and specifically green leafy (OR=0.54; 95% CI 0.39–0.76; p-trend<0.001) and cruciferous (OR=0.62; 95% CI 0.43–0.88; p-trend=0.02) vegetables, but not legumes or red/yellow/orange vegetables. There was no association with total fruit intake or intake of citrus fruits in particular. When modeled together, the association for green leafy vegetables was unchanged while the association for cruciferous vegetables attenuated (OR=0.75; 95% CI 0.50–1.13; p-trend=0.3). Higher intake of total vitamin A (OR=0.60; 95% CI 0.41–0.88; p-trend<0.001) and vitamin E (OR=0.53; 95% CI 0.34–0.82; p-trend<0.001), but not vitamin C, were associated with lower NHL risk. For vitamin A, there was no association with preformed Vitamin A, but there was an inverse association with beta-carotene (OR=0.56; 95% CI 0.39–0.81; p-trend<0.001); only weak inverse associations were observed for other carotenoids (lutein/zeaxanthin, lycopene, and cryptoxanthin). When modeled together, the inverse association for vitamin E was unchanged while the association for beta-carotene attenuated. For micronutrients, there were inverse associations for manganese (OR=0.60; 95% CI 0.40–0.90; p-trend=0.02), selenium (OR=0.47; 95% CI 0.27–0.80; p-trend=0.01), and zinc (OR=0.46; 95% CI 0.27–0.80; p-trend<0.001) but not copper; when modeled simultaneously, both manganese (p-trend=0.03) and zinc (p-trend=0.02) remained significantly and inversely associated with NHL risk. Further adjustment for education, family history of NHL, smoking, alcohol use, and body mass index did not alter these results. There was no NHL subtype heterogeneity for the associations with total vegetables, green leafy vegetables or vitamin E, while inverse associations were not observed for manganese and follicular lymphoma or zinc and CLL/SLL. Conclusion: Higher intakes of vegetables, particularly green leafy vegetables, vitamin E, manganese, and zinc were associated with lower risk of NHL. These finding extend a growing literature from case-control and cohort studies that support a protective role of foods and nutrients that function in antioxidant related pathways against development of NHL, and therefore may represent one of the few known modifiable risk factors for this cancer.

Abstract Abstract 3933 Poster Board III-869 Background Non-Hodgkin Lymphoma (NHL) is a malignancy of lymphocytes with few known risk factors identified to date. Members of the BCL2 and caspase gene families are known regulators of programmed cell death in these cells, and the t(14;18)(q32;q21) is the most commonly observed chromosomal translocation in NHL, a somatic event which results in constitutive BCL2 expression and inhibition of apoptosis. Further, recent pooled analyses of three case-control studies reported gene level associations for both BCL2L11 (Cancer Epidemiol Biomarkers Prev 2009;18:1259) and CASP9 (Blood 2009;114:264) with NHL risk. We therefore evaluated the hypothesis that germline variation in genes from the apoptosis pathway is associated with risk of developing NHL. Methods We genotyped 226 single nucleotide polymorphisms (SNPs) within 36 candidate BCL2-family and capsase-family member genes within the apoptosis pathway in a clinic-based study of 441 newly diagnosed NHL cases (within 9 months of first NHL diagnosis) and 475 frequency matched controls from Minnesota, Iowa, and Wisconsin who were seen at the Mayo Clinic from 2002-2005. Tagging SNPs were selected from HapMap for the following candidate genes: BCL2; BCLAF1; BCL2LA1; BCL2L1, 2, 10, 11, 12, 13, 14; BAD; BAX; BAG1, 3, 4, 5; BAK1; BID; BIK; BNIP2, 3; HRK; CASP1 – CASP10; APAF1; BIRC3; AIF1; and DFFB. Genotyping was completed using the ParAllele (now Affymetrix) Immune and Inflammation SNP panel, supplemented with 9 SNPs from a custom Illumina OPA. SNP call rate and per person call rate were >95% for all SNPs evaluated. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled individually as having a log-additive effect in a logistic regression model adjusted for age, sex, and residence. We used principal components analysis to assess the association with NHL risk at the gene level. Genes at p<0.05 were declared statistically significant, as were SNPs at p<0.05 from significant genes. Results The mean age at diagnosis for cases was 60.1 years, and 58% were male; among controls, the mean age at enrollment into the study was 61.7 years, and 55% were male. The most common NHL subtypes were chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 29%), follicular lymphoma (FL, 27%), and diffuse large B-cell lymphoma (DLBCL, 16%). In gene level analyses, BCL2L11 (also know as BIM) (p=0.0019), BLCAF1 (p=0.0097), BAG5 (p=0.026), and CASP9 (p=0.0022) were statistically significant at p<0.05. For BCL2L11, 2 of the 5 tagSNPs (both intronic) were significant at p<0.05 (rs6746608 and rs12613243). Both genotyped BCLAF1 tagSNPs (rs797558 and rs703193, both intronic) were significant, as was the single genotyped BAG5 tagSNP (rs7042474) from the non-coding region interval of an mRNA transcript. Three of the 7 genotyped CASP9 tagSNPs were significant (rs6685648, rs2020902, rs2042370, all intronic). Similar associations (as assessed by ordinal odds ratios) were observed for significant SNPs from BCLAF1, BAG5, BCL2L11 and CASP9 within the subtypes of CLL/SLL, FL, and DLBCL; however, caution is warranted in interpreting the subtype results due to small sample sizes. Conclusions Three genes from the BCL2 family (BCL2L11, BCLAF1, and BAG5) and one gene from the caspase family (CASP9) were associated with risk of NHL. This confirms gene level results for BCL2L11 and CASP9 in NHL overall and suggests a role for additional BCL2 family members in NHL etiology. In addition to extending these results to other populations, investigation of the functional significance of these genes and consideration of their upstream regulators and downstream targets should assist in clarifying the role of this pathway in lymphomagenesis. Furthermore, in the era of targeted therapeutics, identification of genetic variation in the apoptotic pathway may also assist in predicting prognosis as therapies targeting this pathway are developed. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology. Methods: To identify susceptibility immune genes, we conducted a 2-stage analysis of single-nucleotide polymorphisms (SNP) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the OR and 95% confidence intervals (CI). Results: In the pooled analysis, only the TAP2 coding SNP rs241447 (minor allele frequency = 0.26; Thr655Ala) at 6p21.3 (OR = 1.34, 95% CI 1.17–1.53) achieved statistical significance after accounting for multiple testing (P = 3.1 × 10−5). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR = 1.82, 95%CI 1.46–2.26; p = 6.9 × 10−8), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR = 1.38, 95% CI 1.08–1.77; P = 0.011), but not chronic lymphocytic leukemia (OR = 1.08; 95% CI 0.88–1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors. Conclusion: Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3. Impact: Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis. Cancer Epidemiol Biomarkers Prev; 21(10); 1799–806. ©2012 AACR.

Abstract Background. Several recent studies have reported an inverse relationship between sun exposure and non-Hodgkin (NHL) risk. One hypothesis is that vitamin D mediates this effect. We evaluated the association of sun exposure at various ages and common variants in vitamin D related genes with risk of NHL and its major subtypes. Methods. Newly diagnosed NHL cases (N=1023) and frequency matched controls (N=1254) were enrolled in a clinic-based case-control study conducted at the Mayo Clinic. Thirty-eight single nucleotide polymorphisms (SNPs) from 5 candidate genes relevant to vitamin D metabolism and sun sensitivity (IRF4, RXR, VDR, CYP24A1, CYP27B1) were genotyped. Participants also completed a detailed questionnaire, including self-reported sun exposure at ages 13-21, 22-40, and 41+ years. Odds ratios (OR), 95% confidence intervals (CI), and tests for trend and effect modification were estimated using unconditional logistic regression adjusted for age and gender. ORs are reported for the highest vs. lowest exposure category or as the ordinal OR for SNPs. Results. The mean age of diagnosis/enrollment was 61 years for cases and 60 years for controls. The most common subtypes were chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 34%), follicular (FL; 24%), and diffuse large B-cell (DLBCL; 18%) lymphomas. There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR=0.66, 95% CI 0.44-1.00; ptrend=0.04), which attenuated with increasing age at exposure. Exploratory analysis by NHL subtype indicated a trend toward a protective effect of sun exposure at ages 13-21 years for each of the major subtypes, though these estimates did not reach statistical significance. Of the 38 SNPs evaluated, there was a significant association for 3 SNPs in VDR and 1 SNP in CYP24A1: rs3819545 (OR=1.24, 95% CI 1.10-1.40, p=0.0004), rs2239186 (OR=1.22, 95% CI 1.05-1.41, p=0.009), and rs886441 (OR=0.82, 95% CI 0.70-0.96, p=0.02) for VDR and rs2762939 (OR=0.85, 95% CI 0.75-0.98, p=0.02) for CYP24A1. Both the VDR and CYP24A1 associations were observed for CLL/SLL, FL, but were attenuated for DLBCL. There was no evidence of any significant effect modification of sun exposure at ages 13-21 years by genotype in these four SNPs for NHL overall, or for NHL subtypes. Conclusions. We observed an inverse association between the frequency of sun exposure at ages 13-21 years and NHL risk, which attenuated for sun exposure at older ages, suggesting that early life exposure may be more relevant. While genetic variation in VDR and CYP24A1 were associated with NHL risk, there was no evidence for an interaction of sun exposure with these genes, suggesting that a sun association may not act through the vitamin D metabolism pathway. This would be consistent with a lack of association of circulating vitamin D with NHL risk recently published from the Cohort Consortium pooling project. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1894. doi:10.1158/1538-7445.AM2011-1894

Abstract Background: NHL is a malignancy of lymphocytes, and there is growing evidence for a role of immune dysfunction in the etiology of this malignancy. We conducted a 2-stage analysis of single nucleotide polymorphisms (SNPs) from 1,253 genes using the ParAllele (now Affymetrix) Immune and Inflammation Panel with risk of NHL. Methods: In Stage 1, we successfully genotyped 7,670 SNPs in a clinic-based study of 425 NHL cases and 465 frequency matched controls seen at the Mayo Clinic. Genes were tagged with SNPs from HapMap to provide coverage at r2 = 0.8 and minor allele frequency (MAF) &gt;0.05. In Stage 2, we genotyped the top 768 SNPs on an additional 584 cases and 768 controls from the Mayo Clinic Study, and then conducted a pooled analysis of all 1009 cases and 1233 controls. The association of individual SNPs with NHL risk was assessed using the Odds Ratios (ORs) and 95% confidence intervals, adjusted for age and gender. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled individually as having a log-additive effect. Results: Overall, the mean age at diagnosis was 62.0 years for cases and the mean age at enrollment for controls was 61.1 years. The most common subtypes were chronic lymphocytic leukemia (CLL, N=343), follicular lymphoma (FL, N=245), and diffuse large B-cell lymphoma (DLBCL, N=178). In the pooled analysis, there were 3 SNPs at p&lt;0.0004. The top SNP was rs241447 (MAF=0.26) from TAP2 at 6p21.3 (OR=1.34, 95% CI 1.17-1.53, p=0.00003). This SNP is a cSNP that leads to a missense change (Ala→Thr). The second SNP was rs2857597 (MAF=0.26) from AIF1, also at 6p21.3 (OR=0.77, 95% CI 0.67-0.88, p=0.0002). The region spanning these two SNPs had multiple risk SNPs with p&lt;0.01, including SNPs in BAT2 (rs3132453), BAT3 (rs2242656), C2 (rs7746553), HLA-DRA (rs8084, rs7192), and TAP2 (rs1894408). Of these SNPs, only rs241447 (TAP2) and rs7192 (HLA-DRA) displayed any substantial LD (r2=0.84, all other r2&lt;0.25). The third SNP was rs754505 (MAF=0.07) from NFATC1 at 18q23 (OR=0.63, 95% CI 0.49-0.81, p=0.0003). There were 4 additional SNPs in this gene with a p&lt;0.05 (rs7240932, rs396127, rs177820, rs183374). In subtype analysis, the SNPs from 6p21.3 showed the strongest associations with FL (including the TAP2 SNP rs241447, p=6.9 × 10−8), although there were also associations with CLL (except for the TAP2 and C2 SNPs) and DLBCL (except for the HLA-DRA SNPs). For NFATC1 the associations were similar across the main NHL subtypes. Conclusions: We identified strong associations with NHL risk in the 6p21.3 region, which includes the MHC locus. Our results were particularly striking for FL and supports recent GWAS and candidate gene studies that implicate this region. We also identified NFATC1 as a susceptibility gene. NFATC1 is known to regulate the expression of growth and survival genes including MYC, TNF, CD40L, and BAFF, all of which have also been linked to lymphomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2761. doi:10.1158/1538-7445.AM2011-2761

Nodular sclerosing Hodgkin lymphoma (NSHL) is a distinct, highly heritable Hodgkin lymphoma subtype. We undertook a genome-wide meta-analysis of 393 European-origin adolescent/young adult NSHL patients and 3315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We identified 3 single nucleotide polymorphisms (SNPs) on chromosome 6p21.32 that were significantly associated with NSHL risk: rs9268542 (P = 5.35 × 10−10), rs204999 (P = 1.44 × 10−9), and rs2858870 (P = 1.69 × 10−8). We also confirmed a previously reported association in the same region, rs6903608 (P = 3.52 × 10−10). rs204999 and rs2858870 were weakly correlated (r2 = 0.257), and the remaining pairs of SNPs were not correlated (r2 < 0.1). In an independent set of 113 NSHL cases and 214 controls, 2 SNPs were significantly associated with NSHL and a third showed a comparable odds ratio (OR). These SNPs are found on 2 haplotypes associated with NSHL risk (rs204999-rs9268528-rs9268542-rs6903608-rs2858870; AGGCT, OR = 1.7, P = 1.71 × 10−6; GAATC, OR = 0.4, P = 1.16 × 10−4). All individuals with the GAATC haplotype also carried the HLA class II DRB1*0701 allele. In a separate analysis, the DRB1*0701 allele was associated with a decreased risk of NSHL (OR = 0.5, 95% confidence interval = 0.4, 0.7). These data support the importance of the HLA class II region in NSHL etiology.