Schildkraut, Joellen

Abstract Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with >50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1). Citation Format: Quinn T. Ostrom, Kathleen M. Egan, L. Burt Nabors, Travis Gerke, Reid C. Thompson, Jeffrey J. Olson, Renato LaRocca, Sajeel Chowdhary, Jeanette E. Eckel-Passow, Georgina Armstrong, John K. Wiencke, Christopher I. Amos, Jonine L. Bernstein, Elizabeth B. Claus, Dora Il'yasova, Christoffer Johansen, Daniel H. Lachance, Rose Lai, Ryan T. Merrell, Sara H. Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Melissa L. Bondy, Jill S. Barnholtz-Sloan. Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 233.

Abstract BACKGROUND: Incidence of glioma varies significantly by sex, and most glioma histologies occur with greater incidence in males. Previous analyses have examined the impact of estrogen exposure as a risk factor for these tumors, but have found results of varying significance and low effect size. There may be differences in effect of previously discovered risk alleles that contribute to sex differences. METHODS: Using data collected for three previous glioma GWAS in European-ancestry populations (MD Anderson Cancer Center, the San Francisco Adult Glioma Study, and the Glioma International Case Control Study) we assessed sex-specific effects for 14 previously identified and 13 newly identified glioma risk SNPs (27 total) overall and for glioblastoma (GBM) and non-GBM tumors separately. There were 3,892 male cases (59% GBM), 4,522 male controls, 2,500 female cases (52% GBM) and 4,940 female controls. Sex-specific odds ratios (ORM and ORF), 95% confidence intervals (95% CI) and p values (pM and pF) were generated using stratified logistic regression models. Data from each study were analyzed separately and combined using inverse variance weighted meta-analysis. Results were considered statistically significant at p<6.2x10-4. RESULTS: In GBM, rs11979158 (7p11.2, pM=1.01x10-10, ORM=1.43 [95% CI: 1.28-1.59]; pF=3.43x10-3, ORF=1.22 [95% CI: 1.07-1.39]) and rs2562152 (16p13.3, pM=5.59x10-4, ORM=1.23 [95% CI: 1.09-1.39]; pF=1.22x10-1, ORF=1.12 [95% CI: 0.97-1.29]) had significant effect in males only. In non-GBM gliomas, rs12076373 (1q44, pM=3.56x10-7, ORM=1.41, 95% CI: 1.23-1.61; pF=1.76x10-2, ORF=1.20, 95% CI: 1.03-1.38), rs11979158 (7p11.2, pM=1.77x10-5, ORM=1.32 [95% CI: 1.16-1.49]; pF=2.73x10-1, ORF=1.08 [95% CI: 0.94-1.24]), and rs3751667 (16p13.3, pM=9.44x10-7, ORM=1.30 [95% CI: 1.17-1.44]; pF=5.18x10-2, ORF=1.13 [95% CI: 1.00-1.28]) had significant effect in males only. Effect size for rs55705857 (8q24.21) varied significantly by sex, with ORM=2.63 (95% CI: 2.24-3.09, pM=4.42x10-32), as compared to ORF=3.95 (95% CI: 3.28-4.76, pF=1.82x10-47). A sensitivity analysis was performed due to allele frequency heterogeneity by study and results did not change. CONCLUSIONS: Sex differences and other demographic differences in cancer susceptibility can provide important clues to etiology, and these differences can be leveraged for discovery in genetic association studies. Significant differences in effect size may suggest variation in genetic effect of risk alleles or in unidentified risk factors that vary in prevalence or effect by sex. There may also be differences in the distribution of molecular subtypes within each histology by sex. Further investigation using an agnostic approach may further elucidate the relationship between effect of risk alleles and sex. Citation Format: Quinn T. Ostrom, Ben Kinnersley, Margaret Wrensch, Jeanette E. Eckel-Passow, Georgina Armstrong, Terri Rice, Yanwen Chen, John Wiencke, Lucie McCoy, Helen Hansen, Christopher Amos, Jonine L. Bernstein, Elizabeth B. Claus, Dora Il'yasova, Christoffer Johansen, Daniel Lachance, Rose Lai, Ching C. Lau, Ryan T. Merrell, Sara H. Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Melissa Bondy, Jill S. Barnholtz-Sloan. Estimating sex-specific effects of genetic loci associated with glioma risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1315. doi:10.1158/1538-7445.AM2017-1315

Abstract Epithelial ovarian cancer (EOC) is a rare but deadly disease for which there is notably poorer survival in women of African Ancestry (AA) compared to women of European Ancestry (EA). Previous EA-based genome-wide association studies (GWAS) have identified 30 common, low penetrant EOC susceptibility alleles. Using the custom-designed 533,631 SNP Illumina OncoArray and imputation to ~12 million genetic variants in the 1000 Genomes Phase 3, we conducted a GWAS in 755 AA EOC cases, including 537 high-grade serous ovarian cancer (HGSOC) cases, and 1,235 AA controls from the Ovarian Cancer Association Consortium (OCAC). We identified novel susceptibility loci with suggestive evidence of association with EOC, based on a threshold of P<1x10-6, at three distinct loci including 10p15.1 (lead SNP rs4525119, intronic to AKR1C3, P=4.9 x 10-7, minor allele frequency [MAF]=0.33), 3p25.3 (lead SNP rs7643459, intronic to LOC101927394, P=8.4 x 10-7, MAF=0.36), and 4q13.3 (lead SNP rs4286604, 15 kb 3’ of UGT2A1, P=8.5x10-7, MAF=0.27). In analysis of HGSOC, we identified suggestive evidence of association at six distinct loci including 5q11.2 (lead SNP rs37792, 132 kb 5’ of FST, P=6.0x10-8, MAF=0.34), Xq27.2 (lead SNP rs57403204, 81 kb 3' of MAGEC1, P=1.7x10-7, MAF=0.06), 10p15.1 (lead SNP rs79079890, LOC105376360 intronic, P=3.0x10-7, MAF=0.03), 17p25.1 (lead SNP rs66459581, 5 kb 5’ of PRPSAP1, P=5.1x10-7, MAF=0.23), 15p12 (lead SNP rs116046250, GABRG3 intronic, P=8.7x10-7, MAF=0.05), and 4q21.21 (lead SNP rs192876988, 30 kb 3’ of GK2, P=9.2x10-7, MAF=0.05). These SNPs showed no evidence of association with risk in the OCAC EA GWAS including up to 23,543 EOC cases and 29,444 controls. Of the SNPs identified with suggestive evidence of association in our GWAS, two are located near genes known to regulate hormones and previously reported in relation to diseases of the ovary (AKR1C3 and FST), two have been linked to cancer (AKR1C3 and MAGEC1) and one represents testis-specific expression (GK2). Of the 30 SNPs identified previously in a EA EOC GWAS, we observed nominally significant associations (P<0.05) with consistent direction of effect for eight SNPs in AA women. Our investigation presents evidence of (1) variants for EOC shared among EA and AA women and (2) novel EOC risk loci of importance for AA women. Citation Format: Ani Manichaikul, Lauren C. Peres, Xin-Qun Wang, Kate Lawrenson, Sarah Abbott, Ann G. Schwartz, Anna H. Wu, Edward Peters, Patricia G. Moorman, Michele L. Cote, Melissa Bondy, Linda Kelemen, Ellen L. Goode, Jill Barnholtz-Sloan, Simon A. Gather, Andrew Berchuck, Jennifer A. Doherty, Paul Pharoah, Joellen Schildkraut. Identification of novel epithelial ovarian cancer loci in women of African ancestry from the Ovarian Cancer Association Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1307. doi:10.1158/1538-7445.AM2017-1307

Abstract Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.