Tsai, Ya-Yu

PURPOSE This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDHmutant/co-deleted v IDHwild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

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 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. Transmembrane transport (GO:0055085) is the process whereby a solute/hormone/ion/iron is transported from one side of a membrane to the other. Disruption of these processes leads to defects in homeostasis which contributes to cancer risk. We hypothesized that germline single nucleotide polymorphisms (SNPs) in the cellular transport genes are associated with EOC risk and histopathology subtype. Methods. We genotyped 305 SNPs from 120 cellular transport related genes in 14,525 cases and 23,448 controls of European ancestry, 387 African, and 2,388 Asian ancestries from 43 studies in the Ovarian Cancer Association Consortium (OCAC). A custom Illumina iSelect designed for the Collaborative Oncological Gene-environment Study (COGS) was used. For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous (n=8,369), mucinous (n=943), endometroid (n=2,067) and clear cell (n=1,024) carcinoma) were analyzed, while for women of African and Asian ancestry only the serous subtype was analyzed adjusting for study site and first 5 principal components. Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. We fitted a log-additive genetic model. Results. In women of European ancestry, the strongest evidence of an association for all invasive EOCs was the iron transport gene, HEPH rs17216603 (OR=0.85, 95%CI=0.78-0.93, P=2.8x10−4), which was also the most significant association for serous histological subtype (OR=0.81, 95%CI=0.73-0.91, P=2.0x10−4). For endometrioid EOC, the strongest association was observed in the glucuronidation gene, UGT1A5 rs11563251 (OR=0.82, 95%CI=0.73-0.92, P=6.6x10−4). For clear cell and mucinous EOC, the thyroid hormone transport protein, SERPINA7 rs1804495 showed the strongest associations (OR=1.06, 95%CI=1.06-1.38, P=0.0041) and (OR=0.85, 95%CI=0.73-0.98, P=0.0407), respectively. For women of African ancestry, the strongest association for serous EOC was the glutathione conjugation gene, MGST rs6488840 (OR=0.55, 95%CI=0.37-0.82, P=0.0035). This SNP was not significant in women of European or Asian ancestry. In women of Asian ancestry, the HEPH rs17216603 (OR=1.45, 95%CI=1.15-1.83, P=0.0019) demonstrated the strongest association, although the directionality of risk was reversed compared to European women. Conclusions. Our results suggest that variation in transmembrane transport genes may influence EOC risk and histopathologic subtype in women of European, African and Asian ancestries, highlighting the differences in the disease etiology across populations. Additional epidemiological and functional studies are warranted to elucidate translational and clinical utility of these associations. Citation Format: Ganna Chornokur, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Chen Zhihua, Ya-Yu Tsai, Ellen L. Goode, Julie M. Cunningham, Edwin Iversen, Susan J. Ramus, Andrew Berchuk, Joellen M. Schildkraut, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Paul Pharoah, Thomas A. Sellers, Catherine M. Phelan. Variation in transmembrane transport genes influence epithelial ovarian cancer risk and histopathologic subtype. [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 3644. doi:10.1158/1538-7445.AM2013-3644

Abstract Introduction The epithelial-mesenchymal transition (EMT) pathway contributes to epithelial ovarian cancer (EOC) progression. Previously we identified associations of single nucleotide polymorphisms (SNPs) in EMT-related genes and EOC risk (data not shown). To further investigate the role of EMT-related gene variants in EOC and to derive more reliable risk estimates, we evaluated associations for 795 SNPs from 278 EMT-related genes in a replication study of 43 studies within the Ovarian Cancer Association Consortium (OCAC). Methods The study population included 14,736 cases and 23,448 controls of European ancestry, 89 cases and 200 controls of African ancestry, and 249 cases and 1574 controls of Asian ancestry. The 795 SNPs were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, while for women of African and Asian ancestries only the serous subtype was analyzed. SNP analyses were conducted using unconditional logistic regression under a log-additive model separately for women of each ancestry. All analyses were adjusted for study site and population substructure within each ancestry. Results For women of European ancestry, the strongest evidence of an association for invasive cancers combined was observed for IGF1R rs10794486 (OR=1.05, 95%CI=1.02-1.09, P=0.002), which was also associated with serous (P=0.019), but not the other histological subtypes. In the histological subtype-specific analysis, the most significant association for serous was observed at NRP2 rs3771044 (OR=1.09, 95%CI=1.03-1.15, P=0.00014), for endometroid at rs1770247 (13q31.3, OR=1.16, 95%CI=1.07-1.25, P=0.00028), for clear cell at rs4848300 (2q13, OR=0.84, 95%CI=0.76-0.93, P=0.00099) and for mucinous at SEMA4B rs8030039 (OR=1.09, 95%CI=1.01-1.17, P=0.00019). For women of African ancestry, the strongest association for serous histological subtype was observed at F9 rs6048 (OR=1.71, 95%CI=1.17-2.50, P=0.006). This SNP was not significant in women of European or Asian ancestry. The strongest association for women of Asian ancestry was IGF1R rs10794486 (OR=1.68, 95%CI=1.16-2.45, P=0.007), which was also significant in women of European, but not African, ancestry. Conclusion Findings from this large study provide additional evidence that variants in EMT-related genes may be associated with ovarian cancer risk and that EMT susceptibility loci may differ by ovarian cancer histological subtypes. Furthermore, the findings suggest that susceptibility locus for the serous subtype may be different for women of African ancestry. Future studies are warranted to confirm these findings. Citation Format: Ernest K. Amankwah, Jonathan Tyrer, Hui-Yi Lin, Ya-Yu Tsai, Zhihua Chen, Gang Han, Xiaotao Qu, Ellen Goode, Julie Cunninghan, Edward Iverson, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven Narod, Paul Pharoah, Thomas A. Sellers, Catherine Phelan. Epithelial-mesenchymal transition (EMT) gene variants influence epithelial ovarian cancer risk in women of European, African and Asian ancestry. [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 1352. doi:10.1158/1538-7445.AM2013-1352

Abstract Background: Circadian rhythms of biological processes are regulated by endogenous clock genes and clock-controlled genes. Aberrant expression of circadian clock genes may have important consequences on the transactivation of downstream targets that control the cell cycle and cellular proliferation potentially promoting carcinogenesis. Animal models indicate that several circadian rhythm genes are expressed in the ovaries, where they influence and are influenced by estrous cycles. The goal of the current study was to examine the association of circadian gene variants and epithelial ovarian cancer (EOC) risk. Methods: Thirty-one SNPs from five circadian genes (i.e., ARNTL, CRY2, KLF10, NPAS2, PER3, TIMELESS) were genotyped in 14,736 cases and 23,448 control women of European ancestry from 43 studies in the Ovarian Cancer Association Consortium (OCAC), on a custom Illumina iSelect designed for the Collaborative Oncological Gene-Environment Study (COGS). Both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, SNP analyses were conducted using unconditional logistic regression under a log-additive model. All analyses were adjusted for study site and population substructure. Results: Eleven SNPs were found to be associated with ovarian cancer risk. The SNPs most associated with serous cancer risk were KLF10 rs2513928 (OR=.95 p=6.1x10−3), rs2513927 (OR=1.05 p=6.1x10−3), rs2511703 (OR=1.05 p=9.8x10−3), rs3191333 (OR=1.05, p=1.5x10−2) and NPAS2 rs13012930 (OR=.95, p=3.5x10−2). Endometroid cancer risk was significantly associated with ARNTL SNPs rs10732458 (OR=1.3, p=1.0x10−2) and rs7117836 (OR=1.2, p=4.6x10−2), while clear cell cancer risk was associated with ARNTL rs1562438 (OR=.88, p=1.5x10−2), rs1026071 (OR=.89, p=1.8x10−2), and rs3816360 (OR=.91, p=4.8x10−2) and KLF10 rs2388232 (OR=1.1, p=3.3x10−2). No variants were significantly associated with mucinous cancer risk. Four SNPs in KLF10 were associated with cancer invasiveness; they were rs2513928 (OR=.95, p=1.8x10−3), rs3191333 (OR=1.04, p=1.4x10−2), rs2513927 (OR=1.04, p=1.9x10−2), and rs2511703 (OR=1.03, p=2.8x10−2). Conclusions: Data from the current study suggest that polymorphisms in circadian genes ARNTL, KLF10, and NPAS2 are significantly associated with ovarian cancer histopathologic subtypes and invasiveness. These findings merit further investigation and replication. Funding: R01 CA149429 Citation Format: Heather Jim, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Ellen L. Goode, Zhihua Chen, Ya-Yu Tsai, Julie M. Cunningham, Edward Iversen, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven A. Narod, Thomas A. Sellers, Paul Pharoah, Catherine M. Phelan. Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness. [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 4850. doi:10.1158/1538-7445.AM2013-4850 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract Population stratification in case-control studies can result from differences in ancestral make-up between cases and controls due to sampling variation. Ancestry is therefore routinely estimated and controlled for in these studies. Although less common, it is also possible for ancestry to truly be associated to the disease of interest. Controlling for ancestry can then compromise the power to detect variants that underlie both ancestry and disease. Using data from a multi-center case-control study of epithelial ovarian cancer (OC) among women of European-American ethnicity in which case-control samples were drawn from four geographically distinct North-American sites, we developed a three-step method to investigate whether the stratification observed across the four sites is due to chance or to a non-spurious association between European ancestry and OC. First, we collapsed genome-wide data into two principal components (PCs) that represent the major axes of European ancestral variation, which correspond to north-south and to west-east geographical clines. Next, we determined the discriminant function based on these two PCs that best separates cases and controls for each individual study site and we used the largest angle between the four discriminant function vectors as a measure of similarity ranging from 0 degrees, where all four vectors are exactly the same, to 180 degrees where two of the vectors face exactly opposite directions. If stratification is due to sampling, it is unlikely that the four sites will present similar discriminant functions by chance alone. We then gauged significance of similarity by permuting the case control status across individuals within each site and recalculating the maximum angle between the discriminant function vectors, thus obtaining a null distribution for the statistic. We found that all four sites present the greatest separation between cases and controls on the west-east axis of ancestral variation, with a higher proportion of ovarian cancer cases presenting western ancestry. The largest angle between the four discriminant function vectors observed was of 36.5 degrees. Permutation testing showed this level of similarity between the functions to have a p-value &lt; 0.01 and suggests that OC risk is somehow tied to European ancestry. It remains to be seen whether shared culture or other exposures such as parity or oral contraceptive use explain this connection or whether genetic variants underlie it and are potentially being missed due to routine ancestry control in association testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1678. doi:1538-7445.AM2012-1678

Abstract DNA copy number variations (CNVs) are a significant and ubiquitous source of human genetic variation. However, the influence of CNVs on cancer susceptibility remains poorly understood. Out of 83 genome-wide association studies (GWAS) on cancer to date, only a few studies found significant associations on germline CNVs and cancer. Here we analyzed data from our ongoing two-stage GWAS of four North American case-control studies to test the hypothesis that CNVs in germline DNA from peripheral blood lymphocytes may serve as risk factors for epithelial ovarian cancer (EOC). To reduce disease heterogeneity, we focused on the subset of cases with serous histology. The analysis was therefore based on 942 serous ovarian cancer patients and 1,682 healthy controls who were genotyped using the Illumina 610K quad array. Subjects with extreme noise and genomic waviness in log R ratio (LR) were excluded prior to segmentation; principal component analysis was performed to adjust for batch effects. CNV segmentation was performed on LR data from 22 autosomes using circular binary segmentation embedded in the Copy Number Analysis Module from Golden Helix SNP Variation Suite version 7. Copy number segment covariates were discretized based on the thresholds that signify a transition between copy number states (deletion/no deletion; duplication/no duplication) after the segmentation. Unconditional logistic regression on a log-additive model was used to evaluate the association between copy number states and serous EOC risk after adjusting for study sites. By comparing single marker copy number states at 388,958 SNPs on 22 autosomes, we observed a total of 134 SNPs significantly associated with risk of serous EOC with a p value below 10−6. Associations with deletion polymorphisms were observed on chromosomes 7, 8, 14, and 18 when controlling for false discovery rate at 1%; no duplication polymorphisms were significant. We observed a large deletion at chromosome 14 that occurred in 8.9% of cases but in only 3.9% of controls, with a p value of 5.59×10−8 (Odds Ratio (OR): 2.56, 95% confidence interval (CI): 1.82-3.60). Another common deletion on chromosome 7 occurred in 8.8% of cases and only 4.3% of controls (p=3.83×10−6; OR: 2.23, 95% CI: 1.60-3.10). Two additional regions on chromosomes 8 and 18 with deletion events less than 5% were also identified. Women who harbored the deletion on chromosome 8 were at lower risk of developing serous ovarian cancer (p=4.83×10−8; OR: 0.04, 95% CI: 0.01-0.30). Women who carried the deletion on chromosome 18 had an increased risk for serous EOC (p=9.04×10−7; OR: 7.26, 95% CI: 2.94-17.97). Further validation of these four regions using independent data sets is currently underway. In summary, this is the largest reported genome-wide study of CNVs and serous EOC risk. These preliminary results suggested that germline CNVs may play an important role in ovarian cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1649. doi:1538-7445.AM2012-1649

Abstract Mi(cro)RNAs are short non-coding RNA molecules that play a key role in carcinogenesis by regulating tumor suppressors and oncogenes. Published data has implicated miRNAs in ovarian cancer (OC) development and progression, and we hypothesize that single nucleotide polymorphisms (SNPs) in sites of miRNA: messenger RNA (mRNA) binding may influence OC risk by altering expression levels of targeted mRNAs. To evaluate associations between SNPs in miRNA binding sites and OC risk, we used bioinformatics tools and public databases to identify miRNA binding SNPs relevant to ovarian cancer. We then evaluated the frequency of approximately 1,100 SNPs in ∼20,000 epithelial OC cases and 20,000 controls represented in the international Collaborative Oncological Gene-environment Study. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) between genotypes and case status, with adjustment for the first five principal components representing European ancestry. Log-additive genetic models were applied to each SNP, modeling the number of copies of the minor allele. Subgroup analysis was conducted for serous adenocarcinomas, the most predominant histologic subtype of epithelial OC. Preliminary analysis of 11,215 invasive epithelial OCs and 15,910 controls included four SNPs with P&lt;10−6 and 1 SNP with P&lt;10−5. Analysis of 6,215 invasive serous adenocarcinomas revealed two SNPs with P&lt;10−7 and three SNPs with P&lt;10−6. Noteworthy is rs6104808, a C&gt;T SNP predicted to reside in a highly conserved miRNA binding site of BTBD3 (BTB POZ domain containing 3), a transcription factor suggested to be involved in cell proliferation, cancer progression, and response to platinum-based chemotherapy. rs6104808 was associated with a decreased risk of OC overall (OR (95% CI): 0.42 (0.28-0.62), P=1.26 x 10−5)), and the association was stronger among cases with serous adenocarcinoma (OR (95% CI): 0.30 (0.17-0.50), P=9.89 x 10−6)). This represents the largest, most comprehensive epidemiologic study to date to evaluate associations between miRNA binding site SNPs and OC susceptibility. Although based on a preliminary analysis, these data suggest a significant role and putative biological mechanism for common germline variants in miRNA binding sites leading to cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2927. doi:1538-7445.AM2012-2927