Citations

Objective Previous studies have suggested that statin pretreatment prevents contrast-induced nephropathy (CIN). However, single randomised trials are limited in their number of patients. This meta-analysis aims to assess the role of statin use in CIN prevention, as well as to determine patient subgroups that will benefit from statin pre-treatment. Methodology We searched PubMed, EMBASE, Web of science and the Cochrane Central Register of Controlled Trials databases for randomised controlled trials (RCT) comparing statin pretreatment versus placebo for preventing CIN. Our main outcome was the risk of CIN within 1–5 days after contrast administration. Results Data analysed from nine randomised studies with a total of 5143 patients, where 2559 received statins and 2584 received placebo, showed that statin pretreatment was associated with significant reduction in risk of CIN (MH-RR=0.47, 95% CI 0.34 to 0.64, Z=4.49, p<0.00001). This beneficial effect of statin was also seen in patients with baseline renal impairment (MH-RR=0.46, 95% CI 0.29 to 0.72, p=0.0008) and also those who were cotreated with NAC (MH-RR=0.46, 95% CI 0.25 to 0.83, p=0.01). Conclusions Statin pretreatment leads to significant reduction in CIN, and should be strongly considered in all patients who are planned for diagnostic and interventional procedures involving contrast-media administration.

Abstract Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. This concept has recently been exploited in the development of PARP inhibitors as novel chemotherapeutics for breast cancer. While PARP is not essential in normal cells, BRCA mutant cells are dependent on it for their survival. This led to the successful treatment of BRCA mutant tumors of the breast, ovary, and prostate with the oral PARP inhibitor, olaparib. Therapeutic strategies based on such synthetic-lethal (SL) interactions can enable drug targeting of cancer-specific alterations for otherwise undruggable tumor suppressors. Large-scale analyses of genetic interaction networks in model organisms like yeast suggest that disease-specific networks should not only give rise to destructive phenotypes (e.g. uncontrolled cell growth), but will also present unique vulnerabilities that can be exploited for novel therapies. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We have used a combination of computational and experimental approach whereby yeast interactions between human orthologs are filtered by cancer association and prioritized by genomic features, and candidates from the prioritized list are then validated in human cell lines using an RNA interference approach. As a proof of principle, we utilized this approach to discover two previously unknown synthetic lethal/sick interactions, one between SMARCB1 (yeast SNF5) and PSMA4 (yeast PRE9), and another between ASPSCR1 (yeast UBX4) and PSMC2 (yeast RPT1) based on shRNA double knock-down in normal human fibroblast cells. These interactions suggest potentially new therapeutic targets for SMARCB1 and ASPSCR1 mutated cancers, and more broadly, illustrate the potential of this cross-species approach. Citation Format: Michael K. Asiedu, Raamesh Deshpande, Mitchell Klebig, Shari Sutor, Elena Kuzmin, Jeff Piotrowski, Seung Ho Shin, Michael Costanzo, Charles Boone, Dennis A. Wigle, Chad L Myers. A comparative genomic approach for identifying synthetic lethal interactions in human cancer. [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-234. doi:10.1158/1538-7445.AM2013-LB-234

Abstract Ovarian cancer is the fifth leading cause of cancer death among women in the United States. Despite advances in treatment for other cancers, ovarian cancer patient prognosis has not improved significantly since the advent of platinum-based chemotherapy. It is a highly heterogeneous disease with at least four distinct histological subtypes: serous, mucinous, endometrioid, and clear cell. However, no subtype- or biomarker-specific therapies are approved for ovarian cancer. Identifying targeted therapies is crucial to improving clinical outcomes. Specific therapies will likely vary based on tumor histology and biomarkers. Expression of estrogen receptor alpha (ER) is a well established biomarker of response to endocrine therapies in breast cancer. Despite the success of anti-estrogen therapies in treating breast cancer, little attention has been given to their potential in ovarian cancer. However, epidemiologic studies show that approximately 70% of epithelial ovarian tumors express ER, particularly serous and endometrioid subtypes, and that estrogen plays a role in ovarian cancer etiology. Further, clinical data suggest that a subset of ovarian cancer patients can be successfully treated with endocrine therapy. We hypothesize that some ovarian tumors require estrogen for growth and that predictive biomarkers will identify patients who will benefit from endocrine therapy. Using cell line models, we examined the response of ovarian cancer cells to estrogen (E2) and anti-estrogens with regard to gene expression and cell proliferation. E2 induces expression of canonical ER target genes (e.g. GREB1) in these cells, suggesting that they are estrogen-responsive. We observe that 4-hydroxytamoxifen and fulvestrant inhibit growth of ovarian cancer cells including the chemo-resistant line PEO4. Gene expression microarray studies identified additional E2-regulated genes in ovarian cancer cells that may be utilized as biomarkers of ER activity. We are expanding our studies to in vivo models (human primary tumor xenografts) to evaluate the role of E2 in driving tumor progression and determine the efficacy of anti-estrogens in treating serous ovarian cancer. There is a critical need for targeted therapies in ovarian cancer. Our studies will determine if endocrine responsiveness correlates with gene expression of specific biomarkers, which may lead to the identification of predictive clinical markers of response to endocrine therapy. Citation Format: Courtney L. Andersen, Matthew J. Sikora, Paul Haluska, Steffi Oesterreich. Identifying biomarkers of estrogen response in models of serous ovarian cancer. [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 94. doi:10.1158/1538-7445.AM2013-94

Abstract The Polycomb repressive complex 2 (PRC2) is important for maintenance of stem cell pluripotency and suppression of cell differentiation by promoting histone H3 lysine 27 trimethylation (H3K27me3) and transcriptional repression of differentiation regulatory genes. Here we show that the tumor suppressor protein BRCA1 interacts with EZH2 and other components of PRC2 in mouse embryonic stem (ES) and human breast cancer cells. The BRCA1-binding region in EZH2 overlaps with the non-coding RNA (ncRNA)-binding domain, and BRCA1 expression inhibits the binding of EZH2 to the HOTAIR ncRNA. Decreased expression of BRCA1 causes EZH2 re-targeting genome wide and elevates H3K27me3 levels at PRC2 target loci in both mouse ES and human breast cancer cells. BRCA1 deficiency blocks ES cell differentiation and enhances breast cancer migration and invasion in an EZH2-dependent manner. These results reveal that BRCA1 is a key negative modulator of PRC2 and that loss of BRCA1 inhibits ES cell differentiation and enhances cancer aggressive phenotypes via augmented PRC2 function. Citation Format: Xianzhou Zeng, Shuai Chen, Lan Wang, Haojie Huang. BRCA1 is a negative modulator of the PRC2 complex. [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 5358. doi:10.1158/1538-7445.AM2013-5358

Abstract Tumor infiltrating regulatory T cells (Tregs) appear to play a role in survival in a number of solid tumors, including ovarian cancer. We assessed genetic variation via tag SNPs (N=749) in 25 Treg associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. SNPs were selected based on r2 ≥ 0.8, MAF ≥ 0.05, 5 kb upstream and downstream from the gene. We had SNP and outcome data for ovarian cancer from 10,084 combined ovarian cancer cases, including 5,248 high grade serous, 1,452 endometrioid, 661 mucinous, and 795 clear cell cases of European descent across multiple studies from the Ovarian Cancer Association Consortium (OCAC). Cox proportional hazards regression modeling was used to estimate per-allele hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with overall survival, adjusting for age at diagnosis, population substructure PCs, study site, histology (for the all case analysis), tumor stage, tumor grade and oral contraceptive use. The strongest associations were found for endometrioid histologic subtype and IL2RA SNPs (maximum r2=0.67) rs11256497 [HR=1.42, 95% CI: 1.22-1.64; p=5.7 x 10−6], rs791587 [HR=1.36, 95% CI: 1.17-1.57; p=6.2 x 10−5], rs2476491 [HR=1.40, 95% CI: 1.19-1.64; p=5.6 x 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17-1.57; p=7.9 x 10−5], as well as clear cell ovarian cancer and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54-0.82; p=9.3 x 10−5]. No other associations were observed at p&lt;1 x 10−4. Overall, this study provided evidence that variation in genes related to Tregs, particularly IL2RA and CTLA4, influence ovarian cancer survival. Citation Format: Bridget Charbonneau, Keith Knutson, Robert A. Vierkant, Julie M. Cunningham, Zachary C. Fogarty, Kimberly R. Kalli, Matthew J. Maurer, Ann L. Oberg, Brooke L. Fridley, Claudia C. Preston, Paul D.P. Pharoah, Susan J. Ramus, Catherine M. Phelan, Kunle Odunsi, Kirsten Moysich, Ellen L. Goode. Polymorphisms in regulatory T cell related genes and ovarian cancer survival. [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 4844. doi:10.1158/1538-7445.AM2013-4844

Abstract Background: Variation in mitochondrial genes in cancer cells alters the mitochondrial bioenergetic and biosynthetic state, which mediates cross-talk between mitochondria and the nucleus to modulate many cellular processes. The objective of this study was to comprehensively evaluate mitochondria-nuclear cross-talk in terms of SNP-SNP interactions associated with invasive epithelial ovarian cancer (EOC) risk, which may play an important role in unveiling the underlying mechanism of this complex lethal disease. Methods: Our analyses were based on 1,938 invasive EOC cases and 2,009 controls with greater than 80% European ancestry from five case-control studies genotyped using the Illumina 610quad chip. We evaluated 2,488 SNPs in over 1,500 genes in eight mitochondria-related pathways (apoptosis, oxidation-reduction, epithelial-mesenchymal transition, immunomoduation, transmembrane transport, small GTPases, BRCA1-interactors and circadian rhythm). SNPs with strong linkage disequilibrium of r2 &gt; 0.8 were excluded. We examined 2-way SNP-SNP interactions associated with invasive EOC risk using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach. Bootstrapping was further performed to select important variables and reduce false positive findings. Based on the scree plot using 1,000 bootstrap samples, the factors with more than 4% of bootstrap frequency were defined as significant factors. We then included each identified factors separately in model adjusting for study site and first principal component representing European ancestry. Results: Five significant SNP-SNP interactions were observed: (rs2270799 in IQSEC3 (12p13.33) + rs933305 in CUX2 (12q24.3), (p= 6.3x10−5); rs6063251 in PREX1 (20q13.3) + rs9705 in SLC39A8 (4q22-q24), (p= 3.5x10−5); rs933305 in CUX2 (12q24.3) + rs1712957 in ARHGAP15 (2q22.2-q22.3), (p=4.2x10−7), rs2861828 in SLIT1 (10q23.3-q24) + rs6063251 in PREX1 (20q13.3), (p=2.5x10−7); rs10954593 in SEMA3C (7q21-q31) + rs933305 in CUX2 (12q24.3), (p=2.8x10−3). Four of the five interactions involved SNPs from genes in the small GTPases pathway (IQSEC3; PREX1 (twice) and ARHGAP15). In addition, three of the five interaction pairs involved the CUX2 gene. This gene encodes a protein which contains three CUT domains and a homeodomain, which are DNA-binding motifs. The main mitochondrial SNP-SNP interaction involved the nuclear mitochondria gene SLC39A8. Conclusions: Our results suggest that genetic variation in mitochondrial-related pathways may be associated with invasive EOC risk. These findings highlight important genes/pathways that may interact as a network to influence invasive EOC risk and may generate novel therapeutic targets. External validation will be done using other independent studies for future analyses. Citation Format: Hui-Yi Lin, Ya-Yu Tsai, Y. Ann Chen, Zhihua Chen, Xiaotao Qu, Ellen L. Goode, Joellen Schildkraut, Edwin Iversen, Steven A. Narod, Thomas A. Sellers, Catherine M. Phelan. SNP-SNP interactions in mitochondria-related pathways are associated with invasive Epithelial Ovarian Cancer (EOC) risk . [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 4839. doi:10.1158/1538-7445.AM2013-4839

Abstract Background: Genetic and environmental factors influence colorectal cancer (CRC) risk. Previous studies have provided additional etiologic insight by examining multiplicative gene-environment interactions for individual susceptibility loci. However, individual loci confer only modest risks, which may limit statistical power and clinical significance. A genetic risk score comprising known CRC loci may provide a more comprehensive assessment of risk. Further, there is a paucity of data on the role of additive gene-environment interactions, which may have greater public health implications than multiplicative interactions. We thus evaluated both additive and multiplicative interactions between a genetic risk score and 15 key environmental factors on risk of CRC. Methods: We conducted an analysis of 10,491 CRC cases and 10,725 controls of European ancestry in 7 cohort and 6 case-control studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) or Colon Cancer Family Registry (CCFR). To provide a global measure of genetic predisposition, information across multiple risk variants was combined by calculating a genetic risk score based on 24 polymorphisms near 21 genetic loci identified in previous genome-wide association studies. For the genetic score and environmental factors, the reference category corresponded to that associated with lower CRC risk. We tested for additive interactions by estimating relative excess risk due to interactions (RERIs) using logistic regression; for multiplicative interactions we used an empirical-Bayes approach. Nominal P values ≤ 0.05 were considered statistically significant. Results: After adjustment for age, sex, center, study, principal components, and total energy, as appropriate, we observed super-additive gene-environment interactions for CRC risk between the genetic risk score and body mass index (RERI=0.15; 95% CI: 0.00-0.31), ever smoking (RERI=0.14; 95% CI: 0.00-0.28), pack-years of smoking (RERI=0.23; 95% CI: 0.05-0.41), postmenopausal hormone therapy use (RERI=0.38; 95% CI: 0.17-0.59), and intake of processed meat (RERI=0.23; 95% CI: 0.06-0.40). Of the 15 environmental risk factors, 12 showed RERIs &gt; 0 – suggesting an overall trend toward super-additive interactions for these factors. In addition, we observed evidence of sub-multiplicative interactions for use of aspirin and non-steroidal anti-inflammatory drugs. There were no other statistically significant multiplicative interactions. Conclusions: We observed evidence for super-additive effects of genetic predisposition and environmental risk factors on risk of CRC. Our findings suggest that certain environmental risk factors have stronger effects on absolute risk among individuals with higher genetic risk of CRC. If confirmed in future studies, these results may have implications for targeted prevention strategies. Citation Format: Mengmeng Du, Sonja I. Berndt, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew Chan, Jenny Chang-Claude, Stephen J. Chanock, Nilanjan Chatterjee, David V. Conti, David Duggan, Jane C. Figueiredo, Steven Gallinger, Jian Gong, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, John L. Hopper, Li Hsu, Thomas J. Hudson, Carolyn M. Hutter, Eric J. Jacobs, Mark A. Jenkins, Shuo Jiao, Laurence N. Kolonel, Peter Kraft, Loic Le Marchand, Mathieu Lemire, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert E. Schoen, Fredrick R. Schumacher, Daniela Seminara, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Aung Ko Win, Emily White, Brent W. Zanke, Ulrike Peters. Additive and multiplicative gene-environment interactions for colorectal cancer risk. [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 4831. doi:10.1158/1538-7445.AM2013-4831

Abstract In searching for a role for genetic variation in susceptibility to lung cancer, we postulated that miRNA modulating SNPs within smoking behavior associated genes, such as the nicotinic acetylcholine and dopamine receptor families, could modulate susceptibility to tobacco carcinogens and lung cancer risk. Bioinformatic analyses of these gene families identified 5 SNPs predicted to modulate a miRNA binding site. We assessed these SNPs in the National Cancer Institute-MD case-control study (European American [EA] & African Americans [AA] n=1,438). rs686 in DRD1 (dopamine receptor D1) was associated with a reduced risk of lung cancer after adjustment for age, gender and race (OR 0.63, 95% C.I. 0.47-0.85; P=0.002). As DRD1 mediates dopamine signaling following nicotine exposure, we reasoned that the rs686 variant associates with lung cancer risk via modulation of the nicotine reward pathway. However, adjustment for smoking both in terms of smoking status and pack-years did not significantly modulate the association (OR 0.57, 95% C.I. 0.40-0.81, P=0002). In addition, age at smoking initiation, pack-years of smoking and levels of urinary nicotine metabolites (cotinine and hydroxycotinine) did not vary across rs686 genotypes. Moreover, in an analysis of a never smoking cohort from Mayo Clinic, rs686 was also associated with a reduced risk of lung cancer (OR 0.77, 95% C.I. 0.62-0.97; P=0.027; n=629) (pooled analysis OR 0.61, 95% C.I. 0.47-0.78; P&lt;0.0001; n=2,067). Intriguingly, the association between rs686 and lung cancer risk was only observed in subjects exposed to tobacco smoke during childhood (EA smokers: [OR 0.63, 95% C.I. 0.45-0.88; P=0.007] EA never smokers [OR 0.64, 95% C.I. 0.49-0.85; P=0.002] AA smokers OR 0.31, 95% C.I. 0.11-0.89; P=0.029) (model adjusted as above and for education, adult-second-hand smoke exposure). To further explore a relationship between tobacco and DRD1, we exposed lung cancer cell lines to increasing doses of nicotine and observed a significant increase in DRD1 expression (P=0.009). As DRD1 lies within a CpG island, we are currently testing if this regulation occurs via epigenetic modulation of the DRD1 promoter. While a direct role for DRD1 in lung cancer has not previously been reported, a recent report linked DRD to the cancer stem cell hypothesis. Indeed, our work demonstrates that DRD1 is significantly upregulated in lung cells with cancer stem-like properties. Furthermore, miR-296, predicted to bind to variant rs686 allele, is increased in paired lung cancer tissues (P=0.0003), thus linking a decrease in DRD1 with reduced lung cancer risk. Collectively, our work suggests a novel lung cancer pathway whereby rs686 in DRD1 counteracts the increase in DRD1 imposed by exposure to tobacco smoke in both current and never smokers. Furthermore, it hints at a novel role for the dopamine receptor/signaling pathway in lung carcinogenesis. Citation Format: Brid M. Ryan, Ana I. Robles, Andrew C. McClary, Elise Bowman, Kirsi Vahakangas, Susan Olivo-Marston, Ping Yang, Jin Jen, Curtis C. Harris. Interaction between DRD1 and childhood exposure to environmental tobacco smoke modulates lung cancer risk in smokers and never smokers. [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 4581. doi:10.1158/1538-7445.AM2013-4581

Abstract Since most GWAS hits fall in non-coding regions of the genome and long non-coding RNAs (lncRNAs) are emerging as drivers of carcinogenesis, we hypothesized that SNPs in lncRNAs influence epithelial ovarian cancer (EOC) risk. A comprehensive lncRNA database (lncRNA db) that contained 104 human lncRNAs when downloaded in November 2011 was used to identify 1,737 variants in 63 unique lncRNAs that were represented in three genome-wide association studies from North America, the United Kingdom, and Poland (3,995 EOC cases and 3,277 controls of European background). SNPs with MAF &lt;5% were excluded, and missing genotypes were inferred with Mach using the HapMap CEU population. Unconditional logistic regression treating alternate alleles as an ordinal variable was used to evaluate individual SNP-EOC risk associations. Subgroup analysis was conducted for serous adenocarcinomas (N= 2,066), the main histologic subtype of EOC. Models were adjusted for study and European ancestry using the first two principal components (PCs). We reduced correlated signals (r2 ≥ 0.8) within each lncRNA and kept the most statistically significant variants based on Wald tests, resulting in 651 SNPs for further analyses. Fisher's product method was used to aggregate evidence of multiple variants within each lncRNA using 10,000 permutations. To adjust for multiple comparisons, a false discovery rate (FDR) of 10% was used. A replication phase was carried out for top-ranked SNPs from an additional 9,854 EOC cases (5,802 serous) and 17,633 controls genotyped through an international effort known as the Collaborative Oncological Gene-Environment study (COGS). Four lncRNAs, WT1-AS (p = 0.005, n = 2 SNPs), Hoxa11as (p = 0.013, n = 2), AK082072 (p = 0.016, n = 4) and H19 (p = 0.020, n = 2), were significantly associated with EOC risk among all histologies (FDR ≤ 10%). The SNP in WT1-AS most significantly associated with EOC risk was rs3809061 (T&gt;C) (minor allele frequency= 36%, odds ratio (OR) = 0.91, CI: 0.84-0.97, p = 0.008). Among serous cases, rs3809061 was also protective (OR = 0.92, p = 0.04). These findings were replicated by a correlated SNP rs2301250 (r2 = 0.84) evaluated in COGS among serous cases (OR = 0.94, CI: 0.90-0.99, p = 0.009) and less significant among all histologies (OR = 0.96, CI: 0.93-1.00, p = 0.054). We further interrogated its functional role by performing an expression quantitative trait locus analysis on WTI-AS mRNA expression using the Cancer Genome Atlas (TCGA) data (N = 462 serous cases). WT1-AS expression was significantly higher among carriers of the variant allele (compared to TT homozygotes) using the Mann-Whitney U test (p = 0.001). WT1-AS is the antisense and possible regulator of WT1, a tumor suppressor gene reported to be prognostic in advanced EOC. These findings implicate germline lncRNA variants associated with EOC risk that merit further investigation. Citation Format: Yian Ann Chen, Zhihua Chen, Jennifer Permuth-Wey, Ya-Yu Tsai, Hui-Yi Lin, Xiaotao Qu, Kate Lawrenson, David Fenstermacher, Catherine M. Phelan, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Rebecca Sutphen, Michael J. Birrer, Nicolas Wentzensen, Joellen M. Schildkraut, Ellen L. Goode, Paul Pharoah, Thomas Sellers. Variants in long non-coding RNAs are associated with epithelial ovarian cancer risk in a pooled analysis of three genome-wide association studies. [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 4579. doi:10.1158/1538-7445.AM2013-4579

Abstract Background: Gliomas are primary malignant brain tumors with significant morbidity and mortality. Single nucleotide polymorphisms (SNPs) mapped to 8q24 have been shown to be associated with glioma development. Recently, we identified seven SNPs (through tag SNP genotyping/imputation, pooled next-generation sequencing using long-range PCR, and validation SNP genotyping) that are highly associated with the risk of developing glioma. After stratifying by histologic and tumor subtype, one SNP, rs55705857, in the 8q24.21 region near CCDC26 was significantly associated with oligodendroglial tumors and IDH mutated astrocytic gliomas with high odds ratios (ORs ∼6.0) (Jenkins et al. Nature Genet. 44:1122;2012). By array comparative genomic hybridization (aCGH), a significant proportion of oligodendroglial tumors and IDH mutated astrocytomas have been shown to duplicate 8q24 (Kitange et al., Genes Chr Cancer 42:68;2005; Nousmehr et al. Cancer Cell 17:510;2010). We were interested in learning if the germline risk allele of rs55705857 is associated with gliomas that duplicate 8q24. We were also interested in learning if the risk allele is preferentially gained in gliomas that duplicate 8q24. Methods: We performed aCGH on 217 tumor samples. rs55705857 germline genotype was available on 120 of the patients; of which 30 carried the risk (G) allele. In addition, we sequenced the rs55805857 region in 48 gliomas, 15 of which exhibited gain or duplication of chromosome 8, 8q, or 8q24. The ratio of the Sanger-sequencing peak heights at and around rs55705857 was used to determine which allele (risk or wild-type) was gained. Results: All 15 duplications included rs55705857 and the immediately adjacent regions. Of the 30 patients who carried the germline risk (G) allele for rs55707857, 8 (26.7%) exhibited duplication of 8q24 upon aCGH analysis of their glioma. Of the 90 patients who only carried the wild-type (A) allele, 7 (7.5%) exhibited duplications of 8q24 upon aCGH analysis of their glioma. This difference in proportion is statistically significant (p=0.024, Fischer exact test). Of the 15 tumors with duplication of 8q24, 8 came from patients who were germline rs55705857 heterozygotes (AG). Of these 8 germline heterozygotes with duplication of 8q24, 4 gained the risk (G) allele, 2 gained the wild-type (A) allele and 2 exhibited gain of both alleles in their tumor specimens. Conclusions: While the results require replication, our data suggest that carrying the risk allele for rs55705857 predisposes to the development of gliomas that subsequently duplicate 8q24. However, gliomas with duplication of 8q24 do not preferentially gain the risk rs55705857 allele. This result implies that, while the duplication always includes the rs55705857 region, the risk allele or region is not the direct target of the duplication. Citation Format: Amanda L. Rynearson, Kirsten A. Schowalter, Stephanie R. Fink, Thomas M. Kollmeyer, Chandralekha Halder, Gobinda Sarkar, Alissa A. Caron, Rachel A. Pauley, Daniel H. Lachance, Brian Patrick O'Neill, Robert B. Jenkins. The germline rs55705857 risk allele is not preferentially gained in gliomas with 8q24 duplication. [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 4207. doi:10.1158/1538-7445.AM2013-4207