Person: Poole, Elizabeth M.
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Publication Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA
(Springer Science + Business Media, 2013) Earp, Madalene A.; Kelemen, Linda E.; Magliocco, Anthony M.; Swenerton, Kenneth D.; Chenevix-Trench, Georgia; Lu, Yi; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Fasching, Peter A.; Lambrechts, Diether; Despierre, Evelyn; Vergote, Ignace; Lambrechts, Sandrina; Doherty, Jennifer A.; Rossing, Mary Anne; Chang-Claude, Jenny; Rudolph, Anja; Friel, Grace; Moysich, Kirsten B.; Odunsi, Kunle; Sucheston-Campbell, Lara; Lurie, Galina; Goodman, Marc T.; Carney, Michael E.; Thompson, Pamela J.; Runnebaum, Ingo B.; Dürst, Matthias; Hillemanns, Peter; Dörk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.; Butzow, Ralf; Bunker, Clareann H.; Modugno, Francesmary; Edwards, Robert P.; Ness, Roberta B.; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Jensen, Allan; Kjær, Susanne K.; Høgdall, Claus K.; Høgdall, Estrid; Lundvall, Lene; Sellers, Thomas A.; Fridley, Brooke L.; Goode, Ellen L.; Cunningham, Julie M.; Vierkant, Robert A.; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; Southey, Melissa C.; Liang, Dong; Wu, Xifeng; Lu, Karen; Hildebrandt, Michelle A. T.; Levine, Douglas A.; Bisogna, Maria; Schildkraut, Joellen M.; Iversen, Edwin S.; Weber, Rachel Palmieri; Berchuck, Andrew; Cramer, Daniel; Terry, Kathryn; Poole, Elizabeth M.; Tworoger, Shelley; Bandera, Elisa V.; Chandran, Urmila; Orlow, Irene; Olson, Sara H.; Wik, Elisabeth; Salvesen, Helga B.; Bjorge, Line; Halle, Mari K.; van Altena, Anne M.; Aben, Katja K. H.; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; Pejovic, Tanja; Bean, Yukie T.; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Garcia-Closas, Montserrat; Dicks, Ed; Dennis, Joe; Easton, Douglas F.; Song, Honglin; Tyrer, Jonathan P.; Pharoah, Paul D. P.; Eccles, Diana; Campbell, Ian G.; Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph H.; Flanagan, James M.; Paul, James; Brown, Robert; Phelan, Catherine M.; Risch, Harvey A.; McLaughlin, John R.; Narod, Steven A.; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Pearce, Celeste L.; Pike, Malcolm C.; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Szafron, Lukasz M.; Kupryjanczyk, Jolanta; Cook, Linda S.; Le, Nhu D.; Brooks-Wilson, AngelaEpithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS (56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low malignant potential (LMP) serous, and 24 for invasive serous EOC), selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging 6 loci were associated with subtype-specific EOC risk at P<0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR=1.17, P=0.029, n=1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P=0.014, n=2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR=0.86, P=0.0043, n=892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR=0.84, P=0.0007) and LMP serous EOC risk remained statistically significant at P<0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
Publication Risk of Ovarian Cancer and the NF- B Pathway: Genetic Association with IL1A and TNFSF10
(American Association for Cancer Research (AACR), 2013) Charbonneau, B.; Block, M. S.; Bamlet, W. R.; Vierkant, R. A.; Kalli, K. R.; Fogarty, Z.; Rider, D. N.; Sellers, T. A.; Tworoger, Shelley; Poole, Elizabeth M.; Risch, H. A.; Salvesen, H. B.; Kiemeney, L. A.; Baglietto, L.; Giles, G. G.; Severi, G.; Trabert, B.; Wentzensen, N.; Chenevix-Trench, G.; Whittemore, A. S.; Sieh, W.; Chang-Claude, J.; Bandera, E. V.; Orlow, I.; Terry, Kathryn; Goodman, M. T.; Thompson, P. J.; Cook, L. S.; Rossing, M. A.; Ness, R. B.; Narod, S. A.; Kupryjanczyk, J.; Lu, K.; Butzow, R.; Dork, T.; Pejovic, T.; Campbell, I.; Le, N. D.; Bunker, C. H.; Bogdanova, N.; Runnebaum, I. B.; Eccles, D.; Paul, J.; Wu, A. H.; Gayther, S. A.; Hogdall, E.; Heitz, F.; Kaye, S. B.; Karlan, B. Y.; Anton-Culver, H.; Gronwald, J.; Hogdall, C. K.; Lambrechts, D.; Fasching, P. A.; Menon, U.; Schildkraut, J.; Pearce, C. L.; Levine, D. A.; Kjaer, S. K.; Cramer, Daniel; Flanagan, J. M.; Phelan, C. M.; Brown, Robert; Massuger, L. F. A. G.; Song, H.; Doherty, J. A.; Krakstad, C.; Liang, D.; Odunsi, K.; Berchuck, A.; Jensen, A.; Lubinski, J.; Nevanlinna, H.; Bean, Y. T.; Lurie, G.; Ziogas, A.; Walsh, C.; Despierre, E.; Brinton, L.; Hein, A.; Rudolph, A.; Dansonka-Mieszkowska, A.; Olson, S. H.; Harter, P.; Tyrer, J.; Vitonis, A. F.; Brooks-Wilson, A.; Aben, K. K.; Pike, M. C.; Ramus, S. J.; Wik, E.; Cybulski, C.; Lin, J.; Sucheston, L.; Edwards, Robert; McGuire, V.; Lester, J.; du Bois, A.; Lundvall, L.; Wang-Gohrke, S.; Szafron, L. M.; Lambrechts, S.; Yang, H.; Beckmann, M. W.; Pelttari, L. M.; Van Altena, A. M.; van den Berg, D.; Halle, M. K.; Gentry-Maharaj, A.; Schwaab, I.; Chandran, U.; Menkiszak, J.; Ekici, A. B.; Wilkens, L. R.; Leminen, A.; Modugno, F.; Friel, G.; Rothstein, J. H.; Vergote, I.; Garcia-Closas, M.; Hildebrandt, M. A. T.; Sobiczewski, P.; Kelemen, L. E.; Pharoah, P. D. P.; Moysich, K.; Knutson, K. L.; Cunningham, J. M.; Fridley, B. L.; Goode, E. L.A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.