47 results on '"Pearce, C L"'
Search Results
2. Carcinoma of the Testis: The Epidemiology and Etiology
- Author
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Pearce, C. L., Henderson, B. E., Ross, R. K., Baert, A. L., editor, Heuck, F. H. W., editor, Youker, J. E., editor, Brady, L. W., editor, Heilmann, H.-P., editor, Petrovich, Zbigniew, editor, Baert, Luc, editor, and Brady, Luther W., editor
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- 1999
- Full Text
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3. Mammographic density, MRI background parenchymal enhancement and breast cancer risk
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Pike, M. C. and Pearce, C. L.
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- 2013
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4. Estrogens, Progestins, and Risk of Breast Cancer
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Pike, M. C., primary, Wu, A. H., additional, Spicer, D. V., additional, Lee, S., additional, and Pearce, C. L., additional
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- 2007
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5. Investigation of divergent piperacillin and piperacillin/tazobactam activities to support appropriate formulary decisions: P548
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Jones, M. E., Pearce, C. L., Styers, D. A., Tench, S. L., Master, R. N., and Sahm, D. F.
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- 2005
6. Carcinoma of the Testis: The Epidemiology and Etiology
- Author
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Pearce, C. L., primary, Henderson, B. E., additional, and Ross, R. K., additional
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- 1999
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7. A Y chromosomal influence on prostate cancer risk: the multi-ethnic cohort study
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Paracchini, S, Pearce, C L, Kolonel, L N, Altshuler, D, Henderson, B E, and Tyler-Smith, C
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- 2003
8. Risk of Ovarian Cancer and the NF-? B Pathway: Genetic Association with IL1A and TNFSF10
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Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., 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, K., 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, D., Flanagan, J. M., Phelan, C. M., Brown, R., 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, R., 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., and Goode, E. L.
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- 2014
- Full Text
- View/download PDF
9. PALB2, CHEK2 and ATM rare variants and cancer risk:data from COGS
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Southey, M. C. (Melissa C.), Goldgar, D. E. (David E.), Winqvist, R. (Robert), Pylkäs, K. (Katri), Couch, F. (Fergus), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Dennis, J. (Joe), Michailidou, K. (Kyriaki), van Rensburg, E. J. (Elizabeth J.), Heikkinen, T. (Tuomas), Nevanlinna, H. (Heli), Hopper, J. L. (John L.), Doerk, T. (Thilo), Claes, K. B. (Kathleen B. M.), Reis-Filho, J. (Jorge), Teo, Z. L. (Zhi Ling), Radice, P. (Paolo), Catucci, I. (Irene), Peterlongo, P. (Paolo), Tsimiklis, H. (Helen), Odefrey, F. A. (Fabrice A.), Dowty, J. G. (James G.), Schmidt, M. K. (Marjanka K.), Broeks, A. (Annegien), Hogervorst, F. B. (Frans B.), Verhoef, S. (Senno), Carpenter, J. (Jane), Clarke, C. (Christine), Scott, R. J. (Rodney J.), Fasching, P. A. (Peter A.), Haeberle, L. (Lothar), Ekici, A. B. (Arif B.), Beckmann, M. W. (Matthias W.), Peto, J. (Julian), dos-Santos-Silva, I. (Isabel), Fletcher, O. (Olivia), Johnson, N. (Nichola), Bolla, M. K. (Manjeet K.), Sawyer, E. J. (Elinor J.), Tomlinson, I. (Ian), Kerin, M. J. (Michael J.), Miller, N. (Nicola), Marme, F. (Federik), Burwinkel, B. (Barbara), Yang, R. (Rongxi), Guenel, P. (Pascal), Menegaux, F. (Florence), Sanchez, M. (Marie), Bojesen, S. (Stig), Nielsen, S. F. (Sune F.), Flyger, H. (Henrik), Benitez, J. (Javier), Pilar Zamora, M. (M.), Arias Perez, J. I. (Jose Ignacio), Menendez, P. (Primitiva), Anton-Culver, H. (Hoda), Neuhausen, S. (Susan), Ziogas, A. (Argyrios), Clarke, C. A. (Christina A.), Brenner, H. (Hermann), Arndt, V. (Volker), Stegmaier, C. (Christa), Brauch, H. (Hiltrud), Bruening, T. (Thomas), Ko, Y.-D. (Yon-Dschun), Muranen, T. A. (Taru A.), Aittomaki, K. (Kristiina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Antonenkova, N. N. (Natalia N.), Lindblom, A. (Annika), Margolin, S. (Sara), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V.-M. (Veli-Matti), Hartikainen, J. M. (Jaana M.), Spurdle, A. B. (Amanda B.), Wauters, E. (Els), Smeets, D. (Dominiek), Beuselinck, B. (Benoit), Floris, G. (Giuseppe), Chang-Claude, J. (Jenny), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Olson, J. E. (Janet E.), Vachon, C. (Celine), Pankratz, V. S. (Vernon S.), McLean, C. (Catriona), Haiman, C. A. (Christopher A.), Henderson, B. E. (Brian E.), Schumacher, F. (Fredrick), Le Marchand, L. (Loic), Kristensen, V. (Vessela), Alnaes, G. G. (Grethe Grenaker), Zheng, W. (Wei), Hunter, D. J. (David J.), Lindstrom, S. (Sara), Hankinson, S. E. (Susan E.), Kraft, P. (Peter), Andrulis, I. (Irene), Knight, J. A. (Julia A.), Glendon, G. (Gord), Mulligan, A. M. (Anna Marie), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Kauppila, S. (Saila), Devilee, P. (Peter), Tollenaar, R. A. (Robert A. E. M.), Seynaeve, C. (Caroline), Hollestelle, A. (Antoinette), Garcia-Closas, M. (Montserrat), Figueroa, J. (Jonine), Chanock, S. J. (Stephen J.), Lissowska, J. (Jolanta), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mikael), Eccles, D. M. (Diana M.), Rafiq, S. (Sajjad), Tapper, W. J. (William J.), Gerty, S. M. (Sue M.), Hooning, M. J. (Maartje J.), Martens, J. W. (John W. M.), Collee, J. M. (J. Margriet), Tilanus-Linthorst, M. (Madeleine), Hall, P. (Per), Li, J. (Jingmei), Brand, J. S. (Judith S.), Humphreys, K. (Keith), Cox, A. (Angela), Reed, M. W. (Malcolm W. R.), Luccarini, C. (Craig), Baynes, C. (Caroline), Dunning, A. M. (Alison M.), Hamann, U. (Ute), Torres, D. (Diana), Ulmer, H. U. (Hans Ulrich), Ruediger, T. (Thomas), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Slager, S. (Susan), Toland, A. E. (Amanda E.), Ambrosone, C. B. (Christine B.), Yannoukakos, D. (Drakoulis), Swerdlow, A. (Anthony), Ashworth, A. (Alan), Orr, N. (Nick), Jones, M. (Michael), Gonzalez-Neira, A. (Anna), Pita, G. (Guillermo), Rosario Alonso, M. (M.), Alvarez, N. (Nuria), Herrero, D. (Daniel), Tessier, D. C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Simard, J. (Jacques), Dumont, M. (Martine), Soucy, P. (Penny), Eeles, R. (Rosalind), Muir, K. (Kenneth), Wiklund, F. (Fredrik), Gronberg, H. (Henrik), Schleutker, J. (Johanna), Nordestgaard, B. G. (Borge G.), Weischer, M. (Maren), Travis, R. C. (Ruth C.), Neal, D. (David), Donovan, J. L. (Jenny L.), Hamdy, F. C. (Freddie C.), Khaw, K.-T. (Kay-Tee), Stanford, J. L. (Janet L.), Blot, W. J. (William J.), Thibodeau, S. (Stephen), Schaid, D. J. (Daniel J.), Kelley, J. L. (Joseph L.), Maier, C. (Christiane), Kibel, A. S. (Adam S.), Cybulski, C. (Cezary), Cannon-Albright, L. (Lisa), Butterbach, K. (Katja), Park, J. (Jong), Kaneva, R. (Radka), Batra, J. (Jyotsna), Teixeira, M. R. (Manuel R.), Kote-Jarai, Z. (Zsofia), Al Olama, A. A. (Ali Amin), Benlloch, S. (Sara), Renner, S. P. (Stefan P.), Hartmann, A. (Arndt), Hein, A. (Alexander), Ruebner, M. (Matthias), Lambrechts, D. (Diether), Van Nieuwenhuysen, E. (Els), Vergote, I. (Ignace), Lambretchs, S. (Sandrina), Doherty, J. A. (Jennifer A.), Rossing, M. A. (Mary Anne), Nickels, S. (Stefan), Eilber, U. (Ursula), Wang-Gohrke, S. (Shan), Odunsi, K. (Kunle), Sucheston-Campbell, L. E. (Lara E.), Friel, G. (Grace), Lurie, G. (Galina), Killeen, J. L. (Jeffrey L.), Wilkens, L. R. (Lynne R.), Goodman, M. T. (Marc T.), Runnebaum, I. (Ingo), Hillemanns, P. A. (Peter A.), Pelttari, L. M. (Liisa M.), Butzow, R. (Ralf), Modugno, F. (Francesmary), Edwards, R. P. (Robert P.), Ness, R. B. (Roberta B.), Moysich, K. B. (Kirsten B.), du Bois, A. (Andreas), Heitz, F. (Florian), Harter, P. (Philipp), Kommoss, S. (Stefan), Karlan, B. Y. (Beth Y.), Walsh, C. (Christine), Lester, J. (Jenny), Jensen, A. (Allan), Kjaer, S. K. (Susanne Kruger), Hogdall, E. (Estrid), Peissel, B. (Bernard), Bonanni, B. (Bernardo), Bernard, L. (Loris), Goode, E. L. (Ellen L.), Fridley, B. L. (Brooke L.), Vierkant, R. A. (Robert A.), Cunningham, J. M. (Julie M.), Larson, M. C. (Melissa C.), Fogarty, Z. C. (Zachary C.), Kalli, K. R. (Kimberly R.), Liang, D. (Dong), Lu, K. H. (Karen H.), Hildebrandt, M. A. (Michelle A. T.), Wu, X. (Xifeng), Levine, D. A. (Douglas A.), Dao, F. (Fanny), Bisogna, M. (Maria), Berchuck, A. (Andrew), Iversen, E. S. (Edwin S.), Marks, J. R. (Jeffrey R.), Akushevich, L. (Lucy), Cramer, D. W. (Daniel W.), Schildkraut, J. (Joellen), Terry, K. L. (Kathryn L.), Poole, E. M. (Elizabeth M.), Stampfer, M. (Meir), Tworoger, S. S. (Shelley S.), Bandera, E. V. (Elisa V.), Orlow, I. (Irene), Olson, S. H. (Sara H.), Bjorge, L. (Line), Salvesen, H. B. (Helga B.), van Altena, A. M. (Anne M.), Aben, K. K. (Katja K. H.), Kiemeney, L. A. (Lambertus A.), Massuger, L. F. (Leon F. A. G.), Pejovic, T. (Tanja), Bean, Y. (Yukie), Brooks-Wilson, A. (Angela), Kelemen, L. E. (Linda E.), Cook, L. S. (Linda S.), Le, N. D. (Nhu D.), Grski, B. (Bohdan), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Hogdall, C. K. (Claus K.), Lundvall, L. (Lene), Nedergaard, L. (Lotte), Engelholm, S. A. (Svend Aage), Dicks, E. (Ed), Tyrer, J. (Jonathan), Campbell, I. (Ian), McNeish, I. (Iain), Paul, J. (James), Siddiqui, N. (Nadeem), Glasspool, R. (Rosalind), Whittemore, A. S. (Alice S.), Rothstein, J. H. (Joseph H.), McGuire, V. (Valerie), Sieh, W. (Weiva), Cai, H. (Hui), Shu, X.-O. (Xiao-Ou), Teten, R. T. (Rachel T.), Sutphen, R. (Rebecca), McLaughlin, J. R. (John R.), Narod, S. A. (Steven A.), Phelan, C. M. (Catherine M.), Monteiro, A. N. (Alvaro N.), Fenstermacher, D. (David), Lin, H.-Y. (Hui-Yi), Permuth, J. B. (Jennifer B.), Sellers, T. A. (Thomas A.), Chen, Y. A. (Y. Ann), Tsai, Y.-Y. (Ya-Yu), Chen, Z. (Zhihua), Gentry-Maharaj, A. (Aleksandra), Gayther, S. A. (Simon A.), Ramus, S. J. (Susan J.), Menon, U. (Usha), Wu, A. H. (Anna H.), Pearce, C. L. (Celeste L.), Van den Berg, D. (David), Pike, M. C. (Malcolm C.), Dansonka-Mieszkowska, A. (Agnieszka), Plisiecka-Halasa, J. (Joanna), Moes-Sosnowska, J. (Joanna), Kupryjanczyk, J. (Jolanta), Pharoah, P. D. (Paul D. P.), Song, H. (Honglin), Winship, I. (Ingrid), Chenevix-Trench, G. (Georgia), Giles, G. G. (Graham G.), Tavtigian, S. V. (Sean V.), Easton, D. F. (Doug F.), and Milne, R. L. (Roger L.)
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skin and connective tissue diseases - Abstract
Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p = 7.1 × 10⁻⁵), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p = 6.9 × 10⁻⁸) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p = 0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p ≤ 0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p = 0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p = 0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
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- 2016
10. Chemoprevention of Breast Cancer by Mimicking the Protective Effect of Early First Birth
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UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, Pike, Malcolm C, Wu, Anna H, Pearce, C L, Chodosh, Lewis, UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, Pike, Malcolm C, Wu, Anna H, Pearce, C L, and Chodosh, Lewis
- Abstract
We have shown in the rat that pregnancy, and also estradiol, estradiol plus progesterone, and beta-HCG are protective against mammary cancer; associated RNA expression changes have been identified. No definitive evidence was obtained of parity or hormonal prevention of mammary cancer in mice. Breast gene expression in parous and nulliparous women showed marked between-women differences but failed to distinguish parous from nulliparous women. ER and PR expression, and cell proliferation in the breast epithelium has been studied by immunohistochemistry in four protocols relating to chemoprevention: (1) parous and nulliparous women; (2) women in the first trimester of pregnancy; (3) women briefly exposed to high estrogen levels; and (4) women using oral contraceptives with markedly different progestin doses. Further studies are ongoing. Pregnancy reduced PRA expression and lower PRA distinguished parous from nulliparous women. Analysis of the results of women exposed to high estrogen levels and women using oral contraceptives with markedly different progestin doses is ongoing. Pregnancy reduces mammographic density and breast cancer risk. How these are related has been studied in a large autopsy series; results suggest that part of the protection may be the result of a reduction in breast epithelium; further studies of these samples are ongoing., The original document contains color images.
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- 2010
11. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium
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Pearce, C L, Near, A M, Van Den Berg, D J, Ramus, S J, Gentry-Maharaj, A, Menon, U, Gayther, S A, Anderson, A R, Edlund, C K, Wu, A H, Chen, X, Beesley, J, Webb, P M, Holt, S K, Chen, C, Doherty, J A, Rossing, M A, Whittemore, A S, McGuire, V, DiCioccio, R A, Goodman, M T, Lurie, G, Carney, M E, Wilkens, L R, Ness, R B, Moysich, K B, Edwards, R, Jennison, E, Kjær, Susanne Krüger, Hogdall, E, Hogdall, C K, Goode, E L, Sellers, T A, Vierkant, R A, Cunningham, J M, Cunningham, J C, Schildkraut, J M, Berchuck, A, Moorman, P G, Iversen, E S, Cramer, D W, Terry, K L, Vitonis, A F, Titus-Ernstoff, L, Song, H, Pharoah, P D P, Spurdle, A B, Anton-Culver, H, Ziogas, A, Brewster, W, Pearce, C L, Near, A M, Van Den Berg, D J, Ramus, S J, Gentry-Maharaj, A, Menon, U, Gayther, S A, Anderson, A R, Edlund, C K, Wu, A H, Chen, X, Beesley, J, Webb, P M, Holt, S K, Chen, C, Doherty, J A, Rossing, M A, Whittemore, A S, McGuire, V, DiCioccio, R A, Goodman, M T, Lurie, G, Carney, M E, Wilkens, L R, Ness, R B, Moysich, K B, Edwards, R, Jennison, E, Kjær, Susanne Krüger, Hogdall, E, Hogdall, C K, Goode, E L, Sellers, T A, Vierkant, R A, Cunningham, J M, Cunningham, J C, Schildkraut, J M, Berchuck, A, Moorman, P G, Iversen, E S, Cramer, D W, Terry, K L, Vitonis, A F, Titus-Ernstoff, L, Song, H, Pharoah, P D P, Spurdle, A B, Anton-Culver, H, Ziogas, A, and Brewster, W
- Abstract
Udgivelsesdato: 2009-Jan-27, The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.
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- 2009
12. Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer
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Quaye, L, Song, H, Ramus, S J, Gentry-Maharaj, A, Høgdall, E, DiCioccio, R A, McGuire, V, Wu, A H, Van Den Berg, D J, Pike, M C, Wozniak, E, Doherty, J A, Rossing, M A, Ness, R B, Moysich, K B, Høgdall, C, Blaakaer, J, Easton, D F, Ponder, B A J, Jacobs, I J, Menon, U, Whittemore, A S, Krüger-Kjaer, S, Pearce, C L, Pharoah, P D P, Gayther, S A, Quaye, L, Song, H, Ramus, S J, Gentry-Maharaj, A, Høgdall, E, DiCioccio, R A, McGuire, V, Wu, A H, Van Den Berg, D J, Pike, M C, Wozniak, E, Doherty, J A, Rossing, M A, Ness, R B, Moysich, K B, Høgdall, C, Blaakaer, J, Easton, D F, Ponder, B A J, Jacobs, I J, Menon, U, Whittemore, A S, Krüger-Kjaer, S, Pearce, C L, Pharoah, P D P, and Gayther, S A
- Abstract
Udgivelsesdato: 2009-Mar-24, Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.
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- 2009
13. No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned
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Pearce, C. L., primary, Van Den Berg, D. J., additional, Makridakis, N., additional, Reichardt, J. K.V., additional, Ross, R. K., additional, Pike, M. C., additional, Kolonel, L. N., additional, and Henderson, B. E., additional
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- 2008
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14. Clarifying the PROGINS Allele Association in Ovarian and Breast Cancer Risk: A Haplotype-Based Analysis
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Pearce, C. L., primary, Hirschhorn, J. N., additional, Wu, A. H., additional, Burtt, N. P., additional, Stram, D. O., additional, Young, S., additional, Kolonel, L. N., additional, Henderson, B. E., additional, Altshuler, D., additional, and Pike, M. C., additional
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- 2005
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15. Estrogens, Progestins, and Risk of Breast Cancer.
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Conneely, O., Otto, C., Pike, M. C., Wu, A. H., Spicer, D. V., Lee, S., and Pearce, C. L.
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Obesity is associated with a decreased risk of breast cancer in premenopausal women but an increased risk in postmenopausal women, an effect that increases with time since menopause. Analysis of these effects of obesity shows that there is a ceiling to the carcinogenic effect of estrogen on the breast; increases in nonsex hormone-binding globulin-bound estradiol (non-SHBG bound E2) exceeding approximately 10.2 pg/ml have no further effect on breast cancer risk; this ceiling is lower than the lowest level seen during the menstrual cycle. This suggests that the effects of menopausal estrogen therapy (ET) and menopausal estrogen-progestin therapy (EPT) on a woman's breast cancer risk will greatly depend on her body mass index (BMI; weight in kilograms/height in meters squared, kg/m2) with the largest effects being in slender women. Epidemiological studies confirm this prediction. Our best estimates, per 5 years of use, of the effects of ET on breast cancer risk is a 30% increase in a woman with a BMI of 20 kg/m2 decreasing to an 8% increase in a woman with a BMI of 30 kg/m2; the equivalent figures for EPT are 50% and 26%. The analysis of the effects of estrogen also shows that even reducing the dose of estrogen in ET and EPT by as much as a half will have little or no effect on these risks. Reducing the progestin dose is likely to significantly reduce the risk of EPT: this is possible with an endometrial route of administration. [ABSTRACT FROM AUTHOR]
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- 2008
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16. Evidence for an Association between the SRD5A2 (Type II Steroid 5α-Reductase) Locus and Prostate Cancer in Italian Patients
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Margiotti, K., primary, Sangiuolo, F., additional, De Luca, A., additional, Froio, F., additional, Pearce, C. L., additional, Ricci-Barbini, V., additional, Micali, F., additional, Bonafè, M., additional, Franceschi, C., additional, Dallapiccola, B., additional, Novelli, G., additional, and Reichardt, J. K. V., additional
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- 2000
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17. Safety and efficacy of long-term use of rimantadine for prophylaxis of type A influenza in nursing homes
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Monto, A S, primary, Ohmit, S E, additional, Hornbuckle, K, additional, and Pearce, C L, additional
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- 1995
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18. Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer
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Winham, S. J., Pirie, A., Chen, Y. A., Larson, M. C., Fogarty, Z. C., Earp, M. A., Anton-Culver, H., Bandera, E. V., Cramer, Daniel William, Doherty, J. A., Goodman, M. T., Gronwald, J., Karlan, B. Y., Kjaer, S. K., Levine, D. A., Menon, U., Ness, R. B., Pearce, C. L., Pejovic, T., Rossing, M. A., Wentzensen, N., Bean, Y. T., Bisogna, M., Brinton, L. A., Carney, M. E., Cunningham, J. M., Cybulski, C., deFazio, A., Dicks, E. M., Edwards, R. P., Gayther, S. A., Gentry-Maharaj, A., Gore, M., Iversen, E. S., Jensen, A., Johnatty, S. E., Lester, J., Lin, H.-Y., Lissowska, J., Lubinski, J., Menkiszak, J., Modugno, F., Moysich, K. B., Orlow, I., Pike, M. C., Ramus, S. J., Song, H., Terry, Kathryn Lynne, Thompson, P. J., Tyrer, J. P., van den Berg, D. J., Vierkant, R. A., Vitonis, A. F., Walsh, C., Wilkens, L. R., Wu, A. H., Yang, H., Ziogas, A., Berchuck, A., Schildkraut, J. M., Permuth-Wey, J., Phelan, C. M., Pharoah, P. D. P., Fridley, B. L., Sellers, T. A., and Goode, E. L.
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epithelial ovarian cancer ,overall survival ,exome - Abstract
While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). METHODS: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). RESULTS: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). CONCLUSIONS: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. IMPACT: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study., Other Research Unit
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- 2016
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19. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types
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Kar, S. P., Beesley, J., Amin Al Olama, A., Michailidou, K., Tyrer, J., Kote-Jarai, Z., Lawrenson, K., Lindstrom, S., Ramus, S. J., Thompson, D. J., Kibel, Adam Stuart, Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A. K., Gentry-Maharaj, A., Whittemore, A. S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A., Rudolph, A., Gonzalez-Neira, A., Wu, A. H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A. B., Burwinkel, B., Karlan, B. Y., Nordestgaard, B. G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C. L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C. B., Hogdall, C. K., Teerlink, C. C., Kang, D., Tessier, D. C., Schaid, D. J., Stram, D. O., Cramer, Daniel William, Neal, D. E., Eccles, D., Flesch-Janys, D., Edwards, D. R. V., Wokozorczyk, D., Levine, D. A., Yannoukakos, D., Sawyer, E. J., Bandera, E. V., Poole, Elizabeth M., Goode, E. L., Khusnutdinova, E., Hogdall, E., Song, F, Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F. C., Wiklund, F., Giles, G. G., Olsson, H., Wildiers, H., Ulmer, H.-U., Pandha, H., Risch, H. A., Darabi, H., Salvesen, H. B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H.-Y., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J. L., Benitez, J., Doherty, J. A., Permuth, J. B., Chang-Claude, J., Donovan, J. L., Dennis, J., Schildkraut, J. M., Schleutker, J., Hopper, J. L., Kupryjanczyk, J., Park, J. Y., Figueroa, J., Clements, J. A., Knight, J. A., Peto, J., Cunningham, J. M., Pow-Sang, J., Batra, J., Czene, K., Lu, K. H., Herkommer, K., Khaw, K.-T., Matsuo, K., Muir, K., Offitt, K., Chen, K., Moysich, K. B., Aittoma ki, K., Odunsi, K., Kiemeney, L. A., Massuger, L. F. A. G., Fitzgerald, L. M., Cook, L. S., Cannon-Albright, L., Hooning, M. J., Pike, M. C., Bolla, M. K., Luedeke, M., Teixeira, M. R., Goodman, M. T., Schmidt, M. K., Riggan, M., Aly, M., Rossing, M. A., Beckmann, M. W., Moisse, M., Sanderson, M., Southey, M. C., Jones, M., Lush, M., Hildebrandt, M. A. T., Hou, M.-F., Schoemaker, M. J., Garcia-Closas, M., Bogdanova, N., Rahman, N., Le, N. D., Orr, N., Wentzensen, N., Pashayan, N., Peterlongo, P., Guenel, P., Brennan, P., Paulo, P., Webb, P. M., Broberg, P., Fasching, P. A., Devilee, P., Wang, Q., Cai, Q., Li, Q., Kaneva, R., Butzow, R., Kopperud, R. K., Schmutzler, R. K., Stephenson, R. A., MacInnis, R. J., Hoover, R. N., Winqvist, R., Ness, R., Milne, R. L., Travis, R. C., Benlloch, S., Olson, S. H., McDonnell, S. K., Tworoger, Shelley Slate, Maia, S., Berndt, S., Lee, S. C., Teo, S.-H., Thibodeau, S. N., Bojesen, S. E., Gapstur, S. M., Kjaer, S. K., Pejovic, T., Tammela, T. L. J., Do rk, T., Bru ning, T., Wahlfors, T., Key, T. J., Edwards, T. L., Menon, U., Hamann, U., Mitev, V., Kosma, V.-M., Setiawan, V. W., Kristensen, V., Arndt, V., Vogel, W., Zheng, W., Sieh, W., Blot, W. J., Kluzniak, W., Shu, X.-O., Gao, Y.-T., Schumacher, F., Freedman, M. L., Berchuck, A., Dunning, A. M., Simard, J., Haiman, C. A., Spurdle, A., Sellers, T. A., Hunter, David J., Henderson, B. E., Kraft, Peter Elias, Chanock, S. J., Couch, F. J., Hall, P., Gayther, S. A., Easton, D. F., Chenevix-Trench, G., Eeles, R., Pharoah, P. D. P., Lambrechts, D., and undefined, undefined
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breast cancer ,ovarian cancer ,prostate cancer ,genome-wide association studies ,pleiotropy - Abstract
Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Other Research Unit
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- 2016
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20. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.
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Pearce, C. L., Near, A. M., Van Den Berg, D. J., Ramus, S. J., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Anderson, A. R., Edlund, C. K., Wu, A. H., Chen, X., Beesley, J., Webb, P. M., Holt, S. K., Chen, C., Doherty, J. A., Rossing, M. A., Whittemore, A. S., McGuire, V., and DiCioccio, R. A.
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OVARIAN tumors , *CANCER genetics , *STEROID hormones , *SEX hormones , *DNA repair , *CELL cycle , *TUMOR risk factors , *CANCER invasiveness , *COMPARATIVE studies , *DISEASE susceptibility , *ENZYMES , *GENETIC polymorphisms , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *OXIDOREDUCTASES , *RESEARCH , *DNA-binding proteins , *EVALUATION research , *CASE-control method , *GENETIC carriers , *GENOTYPES - Abstract
The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted. [ABSTRACT FROM AUTHOR]
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- 2009
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21. Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis.
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Pearce, C. L., Wu, A. H., Gayther, S. A., Bale, A. E., Beck, P. A., Beesley, J., Chanock, S., Cramer, D. W., DiCioccio, R., Edwards, R., Fredericksen, Z. S., Garcia-Closas, M., Goode, E. L., Green, A. C., Hartmann, L. C., Hogdall, E., Kjær, S. K., Lissowska, J., McGuire, V., and Modugno, F.
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PROGESTERONE receptors , *OVARIAN cancer , *ETIOLOGY of diseases , *HISTOPATHOLOGY , *HUMAN genetic variation , *HORMONE receptors , *CANCER invasiveness , *CELL receptors , *COMPARATIVE studies , *DISEASE susceptibility , *GENETIC polymorphisms , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *META-analysis , *GENETIC mutation , *OVARIAN tumors , *RESEARCH , *ENDOMETRIAL tumors , *EVALUATION research , *CASE-control method - Abstract
There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer. [ABSTRACT FROM AUTHOR]
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- 2008
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22. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk
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Kar, S. P., Tyrer, J. P., Li, Qiyuan, Lawrenson, K., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y. A., Chen, Z., Cook, L. S., Cramer, Daniel William, Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J. A., Dork, T., du Bois, A., Durst, M., Eccles, D., Easton, D. F., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y.-T., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goode, E. L., Goodman, M. T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A. T., Hillemanns, P., Hogdall, E., Hogdall, C. K., Hosono, S., Iversen, E. S., Jakubowska, A., Paul, J., Jensen, A., Ji, B.-T., Karlan, B. Y., Kjaer, S. K., Kelemen, L. E., Kellar, M., Kelley, J., Kiemeney, L. A., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I. A., Menon, U., Modugno, F., Moysich, K. B., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Pearce, C. L., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Phelan, C. M., Pike, M. C., Poole, Elizabeth M., Ramus, S. J., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schildkraut, J. M., Schwaab, I., Shu, X.-O., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Sucheston-Campbell, L. E., Tangen, I. L., Teo, S.-H., Terry, Kathryn Lynne, Thompson, P. J., Timorek, A., Tsai, Y.-Y., Tworoger, Shelley Slate, van Altena, A. M., Van Nieuwenhuysen, E., Vergote, I., Vierkant, R. A., Wang-Gohrke, S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Woo, Y.-L., Wu, X., Wu, A., Yang, H., Zheng, W., Ziogas, A., Sellers, T. A., Monteiro, A. N. A., Freedman, M. L., Gayther, S. A., and Pharoah, P. D. P.
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ovarian cancer ,network analysis ,GWAS ,gene expression ,transcription factors - Abstract
BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
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- 2015
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23. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium
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Johnatty, S. E., Tyrer, J. P., Kar, S., Beesley, J., Lu, Y., Gao, B., Fasching, P. A., Hein, A., Ekici, A. B., Beckmann, M. W., Lambrechts, D., Van Nieuwenhuysen, E., Vergote, I., Lambrechts, S., Rossing, M. A., Doherty, J. A., Chang-Claude, J., Modugno, F., Ness, R. B., Moysich, K. B., Levine, D. A., Kiemeney, L. A., Massuger, L. F. A. G., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Brinton, L., Lissowska, J., Wentzensen, N., Song, H., Rhenius, V., Campbell, I., Eccles, D., Sieh, W., Whittemore, A. S., McGuire, V., Rothstein, J. H., Sutphen, R., Anton-Culver, H., Ziogas, A., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Pearce, C. L., Pike, M. C., Stram, D. O., Wu, A. H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Rzepecka, I. K., Spiewankiewicz, B., Goodman, M. T., Wilkens, L. R., Carney, M. E., Thompson, P. J., Heitz, F., du Bois, A., Schwaab, I., Harter, P., Pisterer, J., Hillemanns, P., Karlan, B. Y., Walsh, C., Lester, J., Orsulic, S., Winham, S. J., Earp, M., Larson, M. C., Fogarty, Z. C., Hogdall, E., Jensen, A., Kjaer, S. K., Fridley, B. L., Cunningham, J. M., Vierkant, R. A., Schildkraut, J. M., Iversen, E. S., Terry, Kathryn Lynne, Cramer, Daniel William, Bandera, E. V., Orlow, I., Pejovic, T., Bean, Y., Hogdall, C., Lundvall, L., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Sellers, T., Kennedy, C., Chiew, Y.-E., Berchuck, A., MacGregor, S., Pharoah, P. D. P., Goode, E. L., deFazio, A., Webb, P. M., and Chenevix-Trench, G.
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progression-free survival ,overall survival ,epithelial ovarian cancer ,lncRNA ,chemotherapy - Abstract
PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. RESULTS: Five SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)). CONCLUSIONS: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies., Other Research Unit
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- 2015
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24. Variation in NF- B Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer
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Block, M. S., Charbonneau, B., Vierkant, R. A., Fogarty, Z., Bamlet, W. R., Pharoah, P. D. P., Rossing, M. A., Cramer, Daniel William, Pearce, C. L., Schildkraut, J., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y. T., Hays, L. E., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L. A., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C. S., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubi ski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van Den Berg, D., Terry, Kathryn Lynne, Vitonis, A. F., Ramirez, S. M., Rider, D. N., Knutson, K. L., Sellers, T. A., Phelan, C. M., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Kalli, K. R., Fridley, B. L., Cunningham, J. M., and Goode, E. L.
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single nucleotide polymorphism ,recurrence ,survival ,ovarian neoplasms - Abstract
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (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 CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41–2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) 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 TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77–0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) 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.
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- 2014
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25. Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies
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Sieh, W., Salvador, S., McGuire, V., Weber, R. P., Terry, Kathryn Lynne, Rossing, M. A., Risch, H., Wu, A. H., Webb, P. M., Moysich, K., Doherty, J. A., Felberg, A., Miller, D., Jordan, S. J., Goodman, M. T., Lurie, G., Chang-Claude, J., Rudolph, A., Kjaer, S. K., Jensen, A., Hogdall, E., Bandera, E. V., Olson, S. H., King, M. G., Rodriguez-Rodriguez, L., Kiemeney, L. A., Marees, T., Massuger, L. F., van Altena, A. M., Ness, R. B., Cramer, Daniel William, Pike, M. C., Pearce, C. L., Berchuck, A., Schildkraut, J. M., and Whittemore, A. S.
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Ovarian cancer ,tubal ligation ,sterilization - Abstract
Background Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes. Methods We pooled primary data from 13 population-based case-control studies, including 10 157 patients with ovarian cancer (7942 invasive; 2215 borderline) and 13 904 control women. Invasive cases were analysed by histological type, grade and stage, and borderline cases were analysed by histological type. Pooled odds ratios were estimated using conditional logistic regression to match on site, race/ethnicity and age categories, and to adjust for age, oral contraceptive use duration and number of full-term births. Results Tubal ligation was associated with significantly reduced risks of invasive serous (OR, 0.81; 95% CI, 0.74-0.89; P < 0.001), endometrioid (OR, 0.48; 95% CI, 0.40-0.59; P < 0.001), clear cell (OR, 0.52; 95% CI, 0.40-0.67; P < 0.001) and mucinous (OR, 0.68; 95% CI, 0.52-0.89; P = 0.005) cancers. The magnitude of risk reduction was significantly greater for invasive endometrioid (P < 0.0001) and clear cell (P = 0.0018) than for serous cancer. No significant associations were found with borderline serous or mucinous tumours. Conclusions We found that the protective effects of tubal ligation on ovarian cancer risk were subtype-specific. These findings provide insights into distinct aetiologies of ovarian cancer subtypes and mechanisms underlying the protective effects of tubal ligation.
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- 2013
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26. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome
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White, K. L., Vierkant, R. A., Fogarty, Z. C., Charbonneau, B., Block, M. S., Pharoah, P. D. P., Chenevix-Trench, G., Rossing, M. A., Cramer, Daniel William, Pearce, C. L., Schildkraut, J. M., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van DenBerg, D., Terry, Kathryn Lynne, Vitonis, A. F., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Sellers, T. A., Phelan, C. M., Kalli, K. R., Cunningham, J. M., Fridley, B. L., and Goode, E. L.
- Abstract
Background Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNPs) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000 observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.
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- 2013
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27. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium
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Olsen, C. M., Nagle, C. M., Whiteman, D. C., Ness, R., Pearce, C. L., Pike, M. C., Rossing, M. A., Terry, Kathryn Lynne, Wu, A. H., Risch, H. A., Yu, H., Doherty, J. A., Chang-Claude, J., Hein, R., Nickels, S., Wang-Gohrke, S., Goodman, M. T., Carney, M. E., Matsuno, R. K., Lurie, G., Moysich, K., Kjaer, S. K., Jensen, A., Hogdall, E., Goode, E. L., Fridley, B. L., Vierkant, R. A., Larson, M. C., Schildkraut, J., Hoyo, C., Moorman, P., Weber, R. P., Cramer, Daniel William, Vitonis, A. F., Bandera, E. V., Olson, S. H., Rodriguez-Rodriguez, L., King, M., Brinton, L. A., Yang, H., Garcia-Closas, M., Lissowska, J., Anton-Culver, H., Ziogas, A., Gayther, S. A., Ramus, S. J., Menon, U., Gentry-Maharaj, A., and Webb, P. M.
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ovarian cancer ,obesity ,body mass index - Abstract
Whilst previous studies have reported that higher body-mass index (BMI) increases a woman’s risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum, and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13,548 cases, 17,913 controls). We combined study-specific adjusted odds ratios (ORs) using a random–effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5kg/m2; 95%CI 1.18–1.30), invasive endometrioid (1.17; 1.11–1.23) and invasive mucinous (1.19; 1.06–1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94–1.02), but increased risks for low grade serous invasive tumours (1.13, 1.03–1.25) and in pre-menopausal women (1.11; 1.04–1.18). Among post–menopausal women, the associations did not differ between HRT users and non–users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.
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- 2013
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28. Risk of Ovarian Cancer and the NF- B Pathway: Genetic Association with IL1A and TNFSF10
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Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, Shelley Slate, 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 Lynne, 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 William, 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 R, 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., and Goode, E. L.
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clear cell ,endometrioid ,case-control ,single nucleotide polymorphism ,IL-1α - Abstract
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., Other Research Unit
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- 2013
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29. The Role of KRAS rs61764370 in Invasive Epithelial Ovarian Cancer: Implications for Clinical Testing
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Pharoah, P. D. P., Palmieri, R. T., Ramus, S. J., Gayther, S. A., Andrulis, I. L., Anton-Culver, H., Antonenkova, N., Antoniou, A. C., Goldgar, D., Beattie, M. S., Beckmann, M. W., Birrer, Michael James, Bogdanova, N., Bolton, K. L., Brewster, W., Brooks-Wilson, A., Brown, R., Butzow, R., Caldes, T., Caligo, M. A., Campbell, I., Chang-Claude, J., Chen, Y. A., Cook, L. S., Couch, F. J., Cramer, Daniel William, Cunningham, J. M., Despierre, E., Doherty, J. A., Dork, T., Durst, M., Eccles, D. M., Ekici, A. B., Easton, D., Fasching, P. A., de Fazio, A., Fenstermacher, D. A., Flanagan, J. M., Fridley, B. L., Friedman, E., Gao, B., Sinilnikova, O., Gentry-Maharaj, A., Godwin, A. K., Goode, E. L., Goodman, M. T., Gross, J., Hansen, T. V. O., Harnett, P., Rookus, M., Heikkinen, T., Hein, R., Hogdall, C., Hogdall, E., Iversen, E. S., Jakubowska, A., Johnatty, S. E., Karlan, B. Y., Kauff, N. D., Kaye, S. B., Chenevix-Trench, G., Kelemen, L. E., Kiemeney, L. A., Kjaer, S. K., Lambrechts, D., LaPolla, J. P., Lazaro, C., Le, N. D., Leminen, A., Leunen, K., Levine, D. A., Lu, Y., Lundvall, L., Macgregor, S., Marees, T., Massuger, L. F., McLaughlin, J. R., Menon, U., Montagna, M., Moysich, K. B., Narod, S. A., Nathanson, K. L., Nedergaard, L., Ness, R. B., Nevanlinna, H., Nickels, S., Osorio, A., Paul, J., Pearce, C. L., Phelan, C. M., Pike, M. C., Radice, P., Rossing, M. A., Schildkraut, J. M., Sellers, T. A., Singer, C. F., Song, H., Stram, D. O., Sutphen, R., Lindblom, A., Terry, Kathryn Lynne, Tsai, Y.-Y., van Altena, A. M., Vergote, I., Vierkant, R. A., Vitonis, A. F., Walsh, C., Wang-Gohrke, S., Wappenschmidt, B., Wu, A. H., Ziogas, A., Berchuck, A., and Risch, H. A.
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Purpose An assay for the single nucleotide polymorphism (SNP) rs61764370 has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′UTR miRNA binding site of the KRAS oncogene, and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published paper, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from nineteen studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival data and eighteen studies with all-cause mortality data. Results No evidence of association was observed between genotype and risk of unselected EOC (odds ratio (OR)=1.02, 95% confidence interval (CI)=0.95–1.10), serous EOC (OR=1.08, 95%CI=0.98–1.18), familial EOC (OR=1.09, 95%CI=0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR=1.09, 95%CI=0.88–1.36). There was little evidence for association with survival time among unselected cases (hazard ratio (HR)=1.10, 95%CI=0.99–1.22), among serous cases (HR=1.12, 95%CI=0.99–1.28), or with progression-free survival in 540 cases treated with carboplatin and paclitaxel (HR=1.18, 95%CI=0.93–1.52). Conclusions These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction therefore appears unwarranted.
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- 2011
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30. Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer
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Amankwah, E. K., Kelemen, L. E., Wang, Q., Song, H., Chenevix-Trench, G., Beesley, J., Webb, P. M., Pearce, C. L., Wu, A. H., Pike, M. C., Stram, D. O., Chang-Claude, J., Wang-Gohrke, S., Ness, R. B., Goode, E. L., Cunningham, J. M., Fridley, B. L., Vierkant, R. A., Tworoger, Shelley Slate, Whittemore, A. S., McGuire, V., Sieh, W., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Rossing, M. A., Doherty, J. A., Goodman, M. T., Carney, M. E., Lurie, G., Wilkens, L. R., Kruger Kjaer, S., Hogdall, E., Cramer, Daniel William, Terry, Kathryn Lynne, Garcia-Closas, M., Yang, H., Lissowska, J., Anton-Culver, H., Ziogas, A., Schildkraut, J. M., Berchuck, A., and Pharoah, P. D. P.
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chromosome 3p ,SNP ,ovarian cancer ,risk factors - Abstract
Background We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC) [odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4, Ptrend=0.01] that showed a stronger association with the serous histological subtype (OR=1.3, 95% CI=1.1-1.5, Ptrend=0.003). Methods We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium. Results No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.61; serous: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.85) or from the combined analysis of discovery and replication studies (all: OR=1.0, 95% CI=1.0-1.1, Ptrend= 0.28; serous: OR=1.1, 95% CI=1.0-1.2, Ptrend=0.11). There was no evidence for statistical heterogeneity in ORs across the studies. Conclusions Although rs2660753 is a strong a prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study. Impact Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.
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- 2011
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31. Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium
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Kelemen, L. E., Goodman, M. T., McGuire, V., Rossing, M. A., Webb, P. M., Kobel, M., Anton-Culver, H., Beesley, J., Berchuck, A., Brar, S., Carney, M. E., Chang-Claude, J., Chenevix-Trench, G., Cramer, Daniel William, Cunningham, J. M., DiCioccio, R. A., Doherty, J. A., Easton, D. F., Fredericksen, Z. S., Fridley, B. L., Gates, M. A., Gayther, S. A., Gentry-Maharaj, A., Hogdall, E., Kjaer, S. K., Lurie, G., Menon, U., Moorman, P. G., Moysich, K., Ness, R. B., Palmieri, R. T., Pearce, C. L., Pharoah, P. D. P., Ramus, S. J., Song, H., Stram, D. O., Tworoger, Shelley Slate, Van Den Berg, D., Vierkant, R. A., Wang-Gohrke, S., Whittemore, A. S., Wilkens, L. R., Wu, A. H., Schildkraut, J. M., Sellers, T. A., and Goode, E. L.
- Abstract
Background We previously reported risks of ovarian carcinoma for common polymorphisms in one-carbon (1-C) transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990 and TYMS rs495139 with risk of ovarian carcinoma overall, and to utilize the large sample of assembled cases to investigate associations by histological type. Methods Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site. Results The five polymorphisms were not associated with ovarian carcinoma overall (P trend > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04) and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04) (P heterogeneity = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05). Conclusions TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathological classification. Impact Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology. Additional genotyping in a larger sample with increased gene coverage is underway.
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- 2010
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32. Humoral immunity to commensal oral bacteria in human infants: salivary secretory immunoglobulin A antibodies reactive with Streptococcus mitis biovar 1, Streptococcus oralis, Streptococcus mutans, and Enterococcus faecalis during the first two years of life.
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Cole, M F, Bryan, S, Evans, M K, Pearce, C L, Sheridan, M J, Sura, P A, Wientzen, R L, and Bowden, G H
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Secretory immunoglobulin A (SIgA) antibodies reactive with the pioneer oral streptococci Streptococcus mitis biovar 1 and Streptococcus oralis, the late oral colonizer Streptococcus mutans, and the pioneer enteric bacterium Enterococcus faecalis in saliva samples from 10 human infants from birth to age 2 years were analyzed. Low levels of salivary SIgA1 and SIgA2 antibodies reactive with whole cells of all four species were detected within the first month after birth, even though S. mutans and E. faecalis were not recovered from the mouths of the infants during the study period. Although there was a fivefold increase in the concentration of SIgA between birth and age 2 years, there were no differences between the concentrations of SIgA1 and SIgA2 antibodies reactive with the four species over this time period. When the concentrations of SIgA1 and SIgA2 antibodies reactive with all four species were normalized to the concentrations of SIgA1 and SIgA2 in saliva, SIgA1 and SIgA2 antibodies reactive with these bacteria showed a significant decrease from birth to 2 years of age. Adsorption of each infant's saliva with cells of one species produced a dramatic reduction of antibodies recognizing the other three species. Sequential adsorption of saliva samples removed all SIgA antibody to the bacteria, indicating that the SIgA antibodies were directed to antigens shared by all four species. The induction by the host of a limited immune response to common antigens that are likely not involved in adherence may be among the mechanisms that commensal streptococci employ to persist in the oral cavity.
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- 1999
33. Humoral immunity to commensal oral bacteria in human infants: salivary antibodies reactive with Actinomyces naeslundii genospecies 1 and 2 during colonization.
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Cole, M F, Bryan, S, Evans, M K, Pearce, C L, Sheridan, M J, Sura, P A, Wientzen, R, and Bowden, G H
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The secretory immune response in saliva to colonization by Actinomyces naeslundii genospecies 1 and 2 was studied in 10 human infants from birth to 2 years of age. Actinomyces species were not recovered from the mouths of the infants until approximately 4 months after the eruption of teeth. However, low levels of secretory immunoglobulin A1 (SIgA1) and SIgA2 antibodies reactive with whole cells of A. naeslundii genospecies 1 and 2 were detected within the first month after birth. Although there was a fivefold increase in the concentration of SIgA between birth and age 2 years, there were no differences between the concentrations of SIgA1 and SIgA2 antibodies reactive with A. naeslundii genospecies 1 and 2 over this period. When the concentrations of SIgA1 and SIgA2 antibodies reactive with whole cells of A. naeslundii genospecies 1 and 2 were normalized to the concentrations of SIgA1 and SIgA2 in saliva, the A. naeslundii genospecies 1- and 2-reactive SIgA1 and SIgA2 antibodies showed a significant decrease from birth to 2 years of age. The fine specificities of A. naeslundii genospecies 1- and 2-reactive SIgA1 and SIgA2 antibodies were examined by Western blotting of envelope proteins. Similarities in the molecular masses of proteins recognized by SIgA1 and SIgA2 antibodies, both within and between subjects over time, were examined by cluster analysis and showed considerable variability. Taken overall, our data suggest that among the mechanisms Actinomyces species employ to persist in the oral cavity are the induction of a limited immune response and clonal replacement with strains differing in their antigen profiles.
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- 1998
34. Explaining Disparities in Ovarian Cancer Incidence Rates between Women of African and European Ancestry: The Role of Genetic Factors.
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Mullins, M., Mukherjee, B., Wu, A. H., Pike, M., Pharoah, P. D. P., Berchuck, A., and Pearce, C. L.
- Abstract
Non-Hispanic White (NHW) women are at higher risk of ovarian cancer than African-American (AA) women. Approximately 30% of the difference in age-adjusted invasive epithelial ovarian cancer incidence rates (AAIR) between the two groups can be explained by differing oophorectomy rates and the prevalence of non-genetic risk and protective factors. Our purpose was to determine how much of the remaining difference in AAIRs could be explained by varying allele frequencies between NHWs and AAs for 18 genome-wide significant common susceptibility variants for ovarian cancer. Using data on 13,385 cases and 24,875 controls from the Ovarian Cancer Association Consortium, a genetic risk score (GRS) was created from 18 single nucleotide polymorphisms (SNPs) associated with ovarian cancer risk following the Collaborative Oncological Gene-environment Study (COGS) effort. Relative risks for each GRS quintile were estimated using conditional logistic regression, adjusting for genetic ancestry and conditioning on study site, age, and race. The population attributable risk percent (PAR) for GRS above the lowest quintile was calculated using the Bruzzi method. Previously reported oophorectomy and non-genetic risk factor (talc, oral contraceptive use, family history of ovarian cancer, endometriosis, parity and tubal ligation) adjusted incidence rates for ovarian cancer in NHWs and AA's were 7.2 and 5.8 per 100,000 respectively. These incidence rates were further adjusted for the contribution of the GRS from this analysis. The subsequent genetic PAR adjusted rate was 5.1 per 100,000 for the European ancestry group and 4.9 for the African ancestry group, after taking into account the different oophorectomy rates and prevalence of non-genetic risk factors. These incidence rates show the unexplained difference in incidence rates between NHWs and AAs is only 3.9%. Future efforts should focus on incorporating novel non-genetic and genetic factors into this analysis to determine whether essentially all of the difference in incidence between these groups can be explained. [ABSTRACT FROM AUTHOR]
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- 2017
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35. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility 'hot-spot'
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Johnatty, S. E., Beesley, J., Chen, X., Macgregor, S., Duffy, D. L., Spurdle, A. B., Defazio, A., Gava, N., Penelope Webb, Rossing, M. A., Doherty, J. A., Goodman, M. T., Lurie, G., Thompson, P. J., Wilkens, L. R., Ness, R. B., Moysich, K. B., Chang-Claude, J., Wang-Gohrke, S., Cramer, D. W., Terry, K. L., Hankinson, S. E., Tworoger, S. S., Garcia-Closas, M., Yang, H., Lissowska, J., Chanock, S. J., Pharoah, P. D., Song, H., Whitemore, A. S., Pearce, C. L., Stram, D. O., Wu, A. H., Pike, M. C., Gayther, S. A., Ramus, S. J., Menon, U., Gentry-Maharaj, A., Anton-Culver, H., Ziogas, A., Hogdall, E., Kjaer, S. K., Hogdall, C., Berchuck, A., Schildkraut, J. M., Iversen, E. S., Moorman, P. G., Phelan, C. M., Sellers, T. A., Cunningham, J. M., Vierkant, R. A., Rider, D. N., Goode, E. L., Haviv, I., Chenevix-Trench, G., Ovarian Cancer Association Consortium, Australian Ovarian Cancer Study Group, and Australian Cancer Study (Ovarian Cancer)
- Subjects
Cancer Research ,Genotype ,lcsh:QH426-470 ,Colorectal cancer ,Locus (genetics) ,Genome-wide association study ,Single-nucleotide polymorphism ,Genetics and Genomics/Complex Traits ,Biology ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Telomerase reverse transcriptase ,Genetics and Genomics/Cancer Genetics ,Telomerase ,Molecular Biology ,Genetics and Genomics/Genetics of Disease ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,Epithelial Cells ,medicine.disease ,3. Good health ,lcsh:Genetics ,Serous fluid ,Case-Control Studies ,030220 oncology & carcinogenesis ,Cancer research ,Chromosomes, Human, Pair 5 ,Female ,Public Health and Epidemiology/Epidemiology ,Stromal Cells ,Ovarian cancer ,Research Article - Abstract
We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with P per-allele, Author Summary In this article, we report the findings from a large-scale analysis of common variation in genes that are expressed as a consequence of interactions between ovarian cancer cells and their host micro-environment that could influence serous ovarian cancer risk. We evaluated 1,302 common variants within or near 173 genes in two large case-control studies from the Ovarian Cancer Association Consortium (OCAC) and selected three variants for further evaluation in sixteen OCAC studies and an additional 18 for evaluation in five OCAC studies. We observed a significantly increased risk of serous ovarian cancer associated with a variant in the telomerase reverse transcriptase (TERT) gene. Although TERT variants have not been previously shown to contribute to ovarian cancer risk, several studies have recently reported associations between TERT variants and other forms of cancer, including gliomas, lung cancer, adenocarcinoma, basal cell carcinoma, prostate cancer, and multiple other cancers. TERT encodes a protein that is essential for the replication and maintenance of chromosomal integrity during cell division. In cancer cells, TERT has been linked to genomic instability and tumour cell proliferation. Further studies are necessary to confirm our findings and to investigate the mechanisms for the observed association.
36. Men and Women in Organizations: Are Future Managers Exposed To the Issues?
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Rosener, J. B., primary and Pearce, C. L., additional
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- 1989
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37. Prognostic gene expression signature for high-grade serous ovarian cancer.
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Millstein J, Budden T, Goode EL, Anglesio MS, Talhouk A, Intermaggio MP, Leong HS, Chen S, Elatre W, Gilks B, Nazeran T, Volchek M, Bentley RC, Wang C, Chiu DS, Kommoss S, Leung SCY, Senz J, Lum A, Chow V, Sudderuddin H, Mackenzie R, George J, Fereday S, Hendley J, Traficante N, Steed H, Koziak JM, Köbel M, McNeish IA, Goranova T, Ennis D, Macintyre G, Silva De Silva D, Ramón Y Cajal T, García-Donas J, Hernando Polo S, Rodriguez GC, Cushing-Haugen KL, Harris HR, Greene CS, Zelaya RA, Behrens S, Fortner RT, Sinn P, Herpel E, Lester J, Lubiński J, Oszurek O, Tołoczko A, Cybulski C, Menkiszak J, Pearce CL, Pike MC, Tseng C, Alsop J, Rhenius V, Song H, Jimenez-Linan M, Piskorz AM, Gentry-Maharaj A, Karpinskyj C, Widschwendter M, Singh N, Kennedy CJ, Sharma R, Harnett PR, Gao B, Johnatty SE, Sayer R, Boros J, Winham SJ, Keeney GL, Kaufmann SH, Larson MC, Luk H, Hernandez BY, Thompson PJ, Wilkens LR, Carney ME, Trabert B, Lissowska J, Brinton L, Sherman ME, Bodelon C, Hinsley S, Lewsley LA, Glasspool R, Banerjee SN, Stronach EA, Haluska P, Ray-Coquard I, Mahner S, Winterhoff B, Slamon D, Levine DA, Kelemen LE, Benitez J, Chang-Claude J, Gronwald J, Wu AH, Menon U, Goodman MT, Schildkraut JM, Wentzensen N, Brown R, Berchuck A, Chenevix-Trench G, deFazio A, Gayther SA, García MJ, Henderson MJ, Rossing MA, Beeghly-Fadiel A, Fasching PA, Orsulic S, Karlan BY, Konecny GE, Huntsman DG, Bowtell DD, Brenton JD, Doherty JA, Pharoah PDP, and Ramus SJ
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- Female, Humans, Prognosis, Proportional Hazards Models, Survival Analysis, Transcriptome, Cystadenocarcinoma, Serous genetics, Ovarian Neoplasms genetics
- Abstract
Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC., Patients and Methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies., Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years., Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches., Competing Interests: Disclosure BYK served on Invitae Corporation's Advisory Board from 2017 to 2018. IAM has acted on the Advisory Boards for AstraZeneca, Clovis Oncology, Tesaro, Carrick Therapeutics and Takeda. His institution receives funding from AstraZeneca. RG is on the Advisory Boards for AstraZeneca, Tesaro, Clovis and Immunogen and does consultancy work for SOTIO. She has received support to attend conferences from AstraZeneca, Roche and Tesaro. Her institution has received research funding from Boehringer Ingelheim and Lilly/Ignyta and she is the national co-ordinating investigator for the UK for trials sponsored by AstraZeneca and Tesaro and site principal investigator for trials sponsored by AstraZeneca, Tesaro, Immunogen, Pfizer, Lilly and Clovis. PAF has received grants from Novartis, BioNtech and Cepheid as well as personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi-Sankyo, TEVA, Astra Zeneca, Merck Sharp & Dohme, Myelo Therapeutics, MacroGenics, Eisai and Puma during the conduct of the study. JDB has acted on Advisory Boards for AstraZeneca and has received support from GSK to attend conferences. His institution receives funding from AstraZeneca and Aprea. UM has shares in Abcodia Ltd. Sandra Orsulic and Beth Y. Karlan have patents on predictive gene signatures in ovarian cancer (US010253368 and EU2908913). All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
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38. Pharmacogenetic Associations with ADME Variants and Virologic Response to an Initial HAART Regimen in HIV-Infected Women.
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Pearce CL, Stram D, Wiensch A, Frasco MA, Kono N, Den Berg DV, Anastos K, Cohen MH, DeHovitz J, Golub ET, Tamraz B, Liu C, and Mack WJ
- Abstract
Background: Clinical response to highly active antiretroviral therapy (HAART) varies among different populations. A portion of this variability may be due to variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of HAART., Design: To identify genetic factors involved in virologic responses to HAART, 13 genes in ADME pathways were analyzed in a cohort of HIV-infected women on HAART. A total of 569 HIV-positive participants from the Women's Interagency HIV Study who initiated HAART from 1994-2012 and had genotype data were included in these analyses., Methods: Admixture maximum likelihood burden testing was used to evaluate gene-level associations between common genetic variation and virologic response (achieving <80 viral copies/mL) to HAART overall and with specific drug classes. Results: Six statistically significant (P<0.05) gene-level burden tests were observed with response to specific regimen types. CYP2B6, CYP2C19 and CYP2C9 were significantly associated with response to protease inhibitor (PI)-based regimens. CYP2C9, ADH1A and UGT1A1 were significantly associated with response to triple nucleoside reverse transcriptase inhibitor (NRTI) treatment., Conclusions: Although no genome-wide associations with virologic response to HAART overall were detected in this cohort of HIV-infected women, more statistically significant gene-level burden tests were observed than would be expected by chance (two and a half expected, six observed). It is likely that variation in one of the significant genes is associated with virologic response to certain HAART regimens. Further characterization of the genes associated with response to PI-based treatment is warranted.
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- 2017
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39. Expression of Wnt signaling pathway genes in human endometriosis tissue: a pilot study.
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Brueggmann D, Jaque JM, Lee AW, Pearce CL, and Templeman C
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- Adult, Endometriosis metabolism, Endometriosis pathology, Female, Humans, Middle Aged, Pilot Projects, Young Adult, Endometriosis genetics, Endometrium metabolism, Wnt Signaling Pathway genetics
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- 2016
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40. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.
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Nagle CM, Dixon SC, Jensen A, Kjaer SK, Modugno F, deFazio A, Fereday S, Hung J, Johnatty SE, Fasching PA, Beckmann MW, Lambrechts D, Vergote I, Van Nieuwenhuysen E, Lambrechts S, Risch HA, Rossing MA, Doherty JA, Wicklund KG, Chang-Claude J, Goodman MT, Ness RB, Moysich K, Heitz F, du Bois A, Harter P, Schwaab I, Matsuo K, Hosono S, Goode EL, Vierkant RA, Larson MC, Fridley BL, Høgdall C, Schildkraut JM, Weber RP, Cramer DW, Terry KL, Bandera EV, Paddock L, Rodriguez-Rodriguez L, Wentzensen N, Yang HP, Brinton LA, Lissowska J, Høgdall E, Lundvall L, Whittemore A, McGuire V, Sieh W, Rothstein J, Sutphen R, Anton-Culver H, Ziogas A, Pearce CL, Wu AH, and Webb PM
- Subjects
- Body Mass Index, Carcinoma, Ovarian Epithelial, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Neoplasms, Glandular and Epithelial mortality, Obesity mortality, Ovarian Neoplasms mortality, Neoplasms, Glandular and Epithelial pathology, Obesity pathology, Ovarian Neoplasms pathology
- Abstract
Background: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer., Methods: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype., Results: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant., Conclusions: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.
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- 2015
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41. Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.
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Quaye L, Song H, Ramus SJ, Gentry-Maharaj A, Høgdall E, DiCioccio RA, McGuire V, Wu AH, Van Den Berg DJ, Pike MC, Wozniak E, Doherty JA, Rossing MA, Ness RB, Moysich KB, Høgdall C, Blaakaer J, Easton DF, Ponder BA, Jacobs IJ, Menon U, Whittemore AS, Krüger-Kjaer S, Pearce CL, Pharoah PD, and Gayther SA
- Subjects
- Adult, Aged, Class I Phosphatidylinositol 3-Kinases, Female, Genes, erbB-2, Genotype, Haplotypes, Humans, Intracellular Signaling Peptides and Proteins genetics, Middle Aged, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras), ras Proteins genetics, Genetic Predisposition to Disease, Oncogenes, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.
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- 2009
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42. Evidence for an association between the SRD5A2 (type II steroid 5 alpha-reductase) locus and prostate cancer in Italian patients.
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Margiotti K, Sangiuolo F, De Luca A, Froio F, Pearce CL, Ricci-Barbini V, Micali F, Bonafe M, Franceschi C, Dallapiccola B, Novelli G, and Reichardt JK
- Subjects
- Adenocarcinoma enzymology, Aged, Aged, 80 and over, Amino Acid Substitution, Androstane-3,17-diol analogs & derivatives, Androstane-3,17-diol blood, Codon genetics, Dinucleotide Repeats, Ethnicity genetics, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genotype, Humans, Italy epidemiology, Male, Middle Aged, Mutation, Missense, Neoplasm Proteins genetics, Polymorphism, Genetic, Prostatic Neoplasms enzymology, Risk, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase genetics, Adenocarcinoma genetics, Prostatic Neoplasms genetics
- Abstract
We have investigated the contributions of three polymorphic markers in the SRD5A2 gene to prostate cancer in a group of Italian patients. We have genotyped cases and controls for a polymorphic (TA)n dinucleotide repeat and two functional substitutions, A49T and V89L, substituting respectively alanine with threonine at codon 49, and valine to leucine at codon 89. We found a substantially increased but not significant risk associated with the 49T mutation and a reduction of risk for the V89L substitution. In conclusion, we report on preliminary evidence for both increased and decreased risk associated with separate markers at this locus.
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- 2000
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43. Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA.
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Makridakis NM, Ross RK, Pike MC, Crocitto LE, Kolonel LN, Pearce CL, Henderson BE, and Reichardt JK
- Subjects
- Black or African American statistics & numerical data, Aged, Androgens metabolism, Case-Control Studies, Genetic Predisposition to Disease genetics, Genetic Variation, Hispanic or Latino statistics & numerical data, Humans, Incidence, Los Angeles epidemiology, Male, Middle Aged, Polymorphism, Genetic, Risk Factors, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase genetics, Mutation, Missense, Prostatic Neoplasms ethnology, Prostatic Neoplasms genetics
- Abstract
Background: Prostate cancer is a very common disease in more-developed countries, but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predisposition to the disease. Thus, variations in androgen metabolism genes may affect risk of this disease., Methods: We screened 216 African-American and 172 Hispanic men with prostate cancer, and 261 African-American and 200 Hispanic healthy men (controls), from a large prospective cohort study (the Hawaii-Los Angeles Multiethnic Cohort Study) for a mis-sense substitution in the human prostatic (or type II) steroid 5alpha-reductase (SRD5A2) gene, the product of which controls metabolic activation of testosterone to dihydrotestosterone. This mis-sense substitution results in an alanine residue at codon 49 being replaced with threonine (A49T). We also reconstructed this mutation in the SRD5A2 cDNA, and overexpressed the enzyme in mammalian tissue culture cells., Findings: The A49T aminoacid substitution in the SRD5A2 gene increased the risk of clinically significant disease 7.2-fold in African-American men (95% CI=2.17-27.91; p=0.001) and 3.6-fold in Hispanic men (1.09-12.27; p=0.04). The mutant enzyme had a higher in-vitro Vmax than the normal enzyme (9.9 vs 1.9 nmol min(-1) mg(-1))., Interpretation: The A49T variant of the SRD5A2 gene may be a significant contributor to the incidence of prostate cancer in African-American and Hispanic men in Los Angeles. We estimate that the population attributable risk due to this aminoacid substitution for clinically significant disease is about 8% in both populations. Increased conversion of testosterone to dihydrotestosterone catalysed by this variant steroid 5alpha-reductase enzyme may be the cause of the increased risk.
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- 1999
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44. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility.
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Ross RK, Coetzee GA, Pearce CL, Reichardt JK, Bretsky P, Kolonel LN, Henderson BE, Lander E, Altshuler D, and Daley G
- Subjects
- Androgens genetics, Germ-Line Mutation, Humans, Incidence, Male, Models, Genetic, Prostatic Neoplasms epidemiology, Prostatic Neoplasms metabolism, Risk Assessment, Androgens metabolism, Genetic Predisposition to Disease, Prostatic Neoplasms genetics
- Abstract
The prostate is an androgen-regulated organ, which has led to longstanding interest in the role of androgens in prostate carcinogenesis. Although evidence of a hormonal etiology for prostate cancer is strong, it is almost entirely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormones. The international and racial-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that genetic factors play a central role in determining prostate cancer risk. We are developing a polygenic model of prostate carcinogenesis, focused around a series of genes involved in androgen biosynthesis, transport and metabolism. We have begun to develop this model by utilizing sequence variants to study how polymorphic markers in two genes (SRD5A2 and AR) are related to prostate cancer risk within and between racial-ethnic groups. We are now collaborating with the Whitehead Institute/MIT, Center for Genome Research, to screen for single nucleotide polymorphisms in additional genes relevant to the androgen pathway and prostate cell growth. The model when fully developed can potentially provide a basis for targeting populations for screening interventions and for implementing primary preventive strategies.
- Published
- 1999
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45. Clonal diversity of vancomycin-resistant enterococci from an outbreak in a tertiary care university hospital.
- Author
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Pearce CL, Evans MK, Peters SM, and Cole MF
- Subjects
- Clone Cells, Cluster Analysis, Cross Infection transmission, District of Columbia, Drug Resistance, Microbial, Enterococcus faecalis genetics, Enterococcus faecium genetics, Gram-Positive Bacterial Infections transmission, Hospitals, University, Humans, Infection Control, Phylogeny, Risk Factors, Serotyping, Anti-Bacterial Agents, Cross Infection microbiology, DNA, Bacterial analysis, Disease Outbreaks statistics & numerical data, Enterococcus faecalis classification, Enterococcus faecium classification, Gram-Positive Bacterial Infections microbiology, Vancomycin
- Abstract
Background: Enterococci have become important nosocomial pathogens and now account for approximately 12% of nosocomial infections. Enterococci can be transferred from patient to patient and from health care personnel to patient. We investigated the clonal diversity of vancomycinresistant enterococci (VRE) causing an outbreak of infections and attempted to determine the patterns of spread of these bacteria in a university hospital., Methods: Ribotyping was used to examine the clonal diversity of 50 VRE isolates, including 23 from wounds, 14 from urine, 8 from blood, 3 from the rectum, 1 from drainage, and 1 from the cornea., Results: Nine patients were infected with Enterococcus faecalis, 10 with Enterococcus faecium, 3 with both E faecalis and E faecium, and 1 with Enterococcus avium. The results suggest that the sources of the VRE infections included endogenous strains and strains acquired by transmission from attending staff or from the environment. Three patients were infected by both nosocomial and endogenous strains., Conclusions: These data suggest that the collection and analysis of several isolates from repeated specimens is necessary to obtain a fuller understanding of the epidemiology and population structure of antibiotic-resistant enterococci.
- Published
- 1998
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46. Immunoglobulin A subclasses in infants' saliva and in saliva and milk from their mothers.
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Fitzsimmons SP, Evans MK, Pearce CL, Sheridan MJ, Wientzen R, and Cole MF
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- Breast Feeding, Female, Humans, Infant, Infant Food, Infant, Newborn, Male, Milk, Human chemistry, Prospective Studies, Proteins analysis, Saliva chemistry, Immunoglobulin A, Secretory analysis, Milk, Human immunology, Saliva immunology
- Abstract
We sought to determine (1) the ontogeny of secretory IgA subclasses in saliva of breast- and formula-fed infants and (2) the influence of breast-feeding on the maturation of secretory salivary IgA subclasses. Secretory IgA and subclasses 1 and 2 concentrations were determined in saliva from 40 healthy, term infants from birth to age 18 months, and in parallel milk samples from the infants' mothers who were breast-feeding during the first 6 months after birth. Secretory IgA was detected in the neonates' saliva as early as 3 days after birth, increased rapidly during the next 6 months, but then stabilized at a level approximately one-sixth that of the mothers' salivary secretory IgA. Secretory IgA2 represented less than 15% of secretory IgA in saliva collected 2 weeks after birth but by 6 months represented 24.4% of secretory IgA, a value approaching that of the mothers' salivary secretory IgA2 (30.4%). This increase in the proportion of secretory IgA2 was temporally related to a reduction in the proportion of secretory IgA2 in milk throughout lactation. The secretory IgA concentration increased more rapidly during the first 6 months after birth in infants exclusively breast fed than in those exclusively bottle fed. We conclude that although secretory immunity is immature in infants, breast-feeding may aid in protection against pathogenic microorganisms by increasing the rate of mucosal IgA maturation.
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- 1994
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47. Prevention of developmental disabilities: a model for organizing clinical activities.
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Dumars KW, Gawron TW, Pearce CL, and Foster CA
- Subjects
- Attitude, Counseling, Ethics, Health Education, Humans, Neural Tube Defects prevention & control, Phenylketonurias diet therapy, alpha-Fetoproteins blood, Developmental Disabilities prevention & control, Models, Theoretical
- Abstract
Prevention of developmental disabilities receives widespread support, however, a comprehensive approach involving federal and local governments, major professional groups, and the general public has yet to be defined and implemented. Three major issues appear to impede a coordinated approach: (a) prevention's image problem; (b) the complexity surrounding prevention efforts; and (c) the absence of consistent evaluation methods. The University of California, Irvine-University Affiliated Program has developed a model for prevention activities in response to these issues. This model is interdisciplinary, promotes reasoned cooperative efforts, and provides a basis for evaluation and research. This paradigm can be helpful to policy makers in prioritizing prevention activities. The model is composed of five major and functional approaches to prevention with a central core devoted to ethical considerations. The model emphasizes the variety, scope and interdisciplinary nature of prevention/intervention activities, as well as the necessity for a longitudinal approach.
- Published
- 1987
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