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16. A role for cyclin-dependent kinase(s) in the modulation of fast anterograde axonal transport: effects defined by olomoucine and the APC tumor suppressor protein

Author

Ratner, N, Bloom, G. S, and Brady, S. T

Subjects
Life Sciences (General)
Abstract

Proteins that interact with both cytoskeletal and membrane components are candidates to modulate membrane trafficking. The tumor suppressor proteins neurofibromin (NF1) and adenomatous polyposis coli (APC) both bind to microtubules and interact with membrane-associated proteins. The effects of recombinant NF1 and APC fragments on vesicle motility were evaluated by measuring fast axonal transport along microtubules in axoplasm from squid giant axons. APC4 (amino acids 1034-2844) reduced only anterograde movements, whereas APC2 (aa 1034-2130) or APC3 (aa 2130-2844) reduced both anterograde and retrograde transport. NF1 had no effect on organelle movement in either direction. Because APC contains multiple cyclin-dependent kinase (CDK) consensus phosphorylation motifs, the kinase inhibitor olomoucine was examined. At concentrations in which olomoucine is specific for cyclin-dependent kinases (5 microM), it reduced only anterograde transport, whereas anterograde and retrograde movement were both affected at concentrations at which other kinases are inhibited as well (50 microM). Both anterograde and retrograde transport also were inhibited by histone H1 and KSPXK peptides, substrates for proline-directed kinases, including CDKs. Our data suggest that CDK-like axonal kinases modulate fast anterograde transport and that other axonal kinases may be involved in modulating retrograde transport. The specific effect of APC4 on anterograde transport suggests a model in which the binding of APC to microtubules may limit the activity of axonal CDK kinase or kinases in restricted domains, thereby affecting organelle transport.

Published
1998

22. Health policy processes in Asian transitional economies

Author

Bloom, G., Fang, L., Jönsson, K., Men, C. R., Phoummalaysith, B., Xeuatvongsa, A., Wang, Y., Zhao, H., Meessen, B., Pei, X., Criel, B., Bloom, G., Van Lerberghe, W., Kegels, G., and De Brouwere, V.

Subjects
China, Laos, Asia, East, Asia, Southeast, Cambodia, Health policy
Published
2008

23. Some final thoughts

Author

Bloom, G., Pei, X., Meessen, B., Pei, X., Criel, B., Bloom, G., Van Lerberghe, W., Kegels, G., and De Brouwere, V.

Subjects
China, Laos, Asia, East, Poverty reduction, Asia, Southeast, Cambodia, Health services, Health policy
Published
2008

26. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author

Permuth-Wey, J, Lawrenson, K, Shen, HC, Velkova, A, Tyrer, JP, Chen, Z, Lin, HY, Ann Chen, Y, Tsai, YY, Qu, X, Ramus, SJ, Karevan, R, Lee, J, Lee, N, Larson, MC, Aben, KK, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Armasu, SM, Bacot, F, Baglietto, L, Bandera, EV, Barnholtz-Sloan, J, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Cai, Q, Campbell, I, Chang-Claude, J, Chanock, S, Chenevix-Trench, G, Cheng, JQ, Cicek, MS, Coetzee, GA, Cook, LS, Couch, FJ, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Easton, DF, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, DA, Flanagan, JM, Garcia-Closas, M, Gentry-Maharaj, A, Giles, GG, Glasspool, RM, Gonzalez-Bosquet, J, Goodman, MT, Gore, M, Górski, B, Gronwald, J, Hall, P, Halle, MK, Harter, P, Heitz, F, Hillemanns, P, Hoatlin, M, Høgdall, CK, Høgdall, E, Hosono, S, Jakubowska, A, Jensen, A, Jim, H, Kalli, KR, Karlan, BY, Kaye, SB, Kelemen, LE, Kiemeney, LA, Kikkawa, F, and Konecny, GE

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10-8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10-10). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes. © 2013 Macmillan Publishers Limited. All rights reserved.

Published
2013

27. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Author

Pharoah, PDP, Tsai, YY, Ramus, SJ, Phelan, CM, Goode, EL, Lawrenson, K, Buckley, M, Fridley, BL, Tyrer, JP, Shen, H, Weber, R, Karevan, R, Larson, MC, Song, H, Tessier, DC, Bacot, F, Vincent, D, Cunningham, JM, Dennis, J, Dicks, E, Aben, KK, Anton-Culver, H, Antonenkova, N, Armasu, SM, Baglietto, L, Bandera, EV, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brenton, JD, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Campbell, I, Carney, ME, Carvalho, RS, Chang-Claude, J, Chen, YA, Chen, Z, Chow, WH, Cicek, MS, Coetzee, G, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, D, Flanagan, J, Gao, YT, Garcia-Closas, M, Gentry-Maharaj, A, Giles, G, Gjyshi, A, Gore, M, Gronwald, J, Guo, Q, Halle, MK, Harter, P, Hein, A, Heitz, F, Hillemanns, P, Hoatlin, M, Høgdall, E, Høgdall, CK, Hosono, S, Jakubowska, A, Jensen, A, Kalli, KR, and Karlan, BY

Subjects
endocrine system diseases
Abstract

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Published
2013

29. Eighth annual meeting of the European Association for the Study of Diabetes: Madrid, Spain September, 6–8, 1972

Author

Alberti, K. G. M. M., Darley, J., Emerson, Pauline M., Hockaday, T. D. R., Amherdt, M., Like, A. A., Blondel, B., Marliss, B., Wollheim, C., Orci, L., Andersen, O. Ortved, Andersson, Arne, Antonini, F. M., Fumagalli, C., Petruzzi, E., Bertini, G., Mori, S., Tinti, P., Ashcroft, S. J. H., Weerasinghe, L. C. C., Randle, P. J., Assan, R., Slusher, N., Guy-Grand, B., Girard, F., Soufflet, E., Attali, J. R., Ballerio, G., Boillot, J., Atkins, T., Matty, A. J., Bailey, C. J., Aynsley-Green, A., Bloom, S. R., Bacchus, R. A., Meade, L. G., London, D. R., Balant, L., Zahnd, G., Petitpierre, B., Fabre, J., Balasse, E. O., Neef, M. A., Barta, L., Brooser, G., Molnar, Maria, Bataille, D. P., Freychet, P., Kitabgi, P., Rosselin, G. E., Berne, Christian, Beyer, J., Cordes, U., Sell, G., Rosak, C., Schöffling, K., Birkner, B., Henner, J., Wagner, P., Erhardt, F., Dieterle, P., Bloom, S. R., Vaughan, N. J. A., Edwards, A. V., Boquist, L., Brand, I., Söling, H. D., Brandenburg, D., Gliemann, J., Ooms, H. A., Puls, W., Wollmer, A., Camerini-Davalos, R. A., Bloodworth, Jr., J. M. B., Limburg, B., Oppermann, W., Campbell, A. K., Siddle, K., Cañadell, J. M., Barraquer, J., Muiños, A., Heredia, C. D., Castillo-Olivares, J., Guijo, J., Pallardo, L. F., Cerasi, E., Efendić, S., Luft, R., Cerasi, E., Wahren, J., Luft, R., Felig, P., Christensen, Niels Juel, Christiansen, A. H., Vølund, A., Connon, J. J., Trimble, E., Copinschi, G., Leclercq, R., Bruno, O. D., Cordes, U., Sell, G., Beyer, J., Haupt, E., Schöffling, K., Creutzfeldt, C., Track, N. S., Cuendet, G. S., Wollheim, C. B., Cameron, D. P., Balant, L., Stauffacher, W., Marliss, E. B., Czyzyk, A., Lao, B., Bartosiewicz, W., Szczepanik, Z., De Nobel, E., Laar, A. Van't, Koene, R. A. P., Benraad, Th. J., Dietze, G., Hepp, K. D., Wickmayr, M., Mehnert, H., Dixon, K., Exon, P. D., Hughes, H. R., Jones, D. W., Elkeles, R. S., Exon, P. D., Dixon, K., FitzGerald, M. G., Malins, J. M., Falorni, A., Massi-Benedetti, F., Gallo, G., Maffei, S., Fedele, D., Tiengo, A., Muggeo, M., Fabris, P., Crepaldi, G., Federlin, K., Helmke, K., Slijepčević, M., Pfeiffer, E. F., Felber, J. P., Oulès, J., Schindler, Ch., Chabot, V., Fernandez-Cruz, Jr., A., Catalán, E., Otero, M. Luque, Hermida, O. Garcia, Otero, M. Luque, Catalán, E., Flatt, J. P., Blackburn, G., Randers, G., Förster, H., Hoos, I, Lerche, D., Förster, H., Hoos, I., Matthäus, M., Franckson, J. R. M., Ooms, H. A., Frerichs, H., Daweke, H., Gries, F., Grüneklee, D., Hessing, J., Jahnke, K., Keup, U., Miss, H., Otto, H., Puls, W., Schmidt, D., Zumfelde, C., Funcke, H. v., Löffler, G., Wieland, O., Galton, D. J., Guttman, R., Gazzola, G. C., Franchi, R., Ronchi, P., Saibene, V., Guidotti, G. G., Gligore, V., Hîncu, N., Tecuceanu, Rodica, Goberna, R., Garcia-Albertos, F., Tamarit-Rodriguez, J., del Rio, E., Roca, R., Gomez-Acebo, José, Creco, A. V., Fedeli, G., Ghirlanda, G., Fenici, R., Lucente, M., Gutman, A., Agam, G., Nahas, N., Cazalis, P., Gylfe, E., Hellman, B., Hadden, D. R., Connolly, J. H., Montgomery, D. A. D., Weaver, J. A., Hellerström, Claes, Howell, Simon, Andersson, Arne, Edwards, John, Sehlin, J., Täljedal, I. -B., Heptner, W., Neubauer, H. B., Herchuelz, A., Pipeleers, D. G., Malaisse, W. J., Herrera, E., Montoya, Eladio, Hommel, H., Fischer, IT., Schmid, B., Fiedler, H., Bibergeil, H., Iversen, J., Iynedjian, P. B., Peters, G., Jacquemin, C., Lambert, B., Sutter, B. Ch. J., Jakob, A., Zapf, J., Froesch, E. R., Jansen, F. K., Freytag, G., Herberg, L., Jarrett, R. J., Baker, I. A., Jarrousse, C., Rancon, F., Rosselin, G. E., Job, D., Tchobroutsky, G., Eschwege, E., Guyot-Argenton, C., Aubry, J. P., Déret, M., Karman, H., Mialhe, P., Kissebah, A., Tulloch, B., Fraser, Russell, Kissebah, A., Tulloch, B., Vydelingum, N., Fraser, Russell, Kissing, J., Raptis, S., Dollinger, H., Faulhaber, J., Rothenbuchner, G., Pfeiffer, E. F., Kleineke, J., Sauer, H., Söling, H. D., Kloeze, J., Kohner, Eva M., Sutcliffe, Barbara A., Tudball, M., Dollery, C. T., Korp, W., Neubert, J., Bruneder, H., Lenhardt, A., Levett, R. E., Koschinsky, T., Gries, F. A., Landgraf-Leurs, M. M. C., Landgraf, R., Hörl, R., Langslow, D. R., Laube, H., Fussgänger, R., Mayer, R., Pfeiffer, E. F., Laube, H., Fussgänger, R., Klör, H., Pfeiffer, E. F., Lázaro, E., Leclercq-Meyer, V., Marchand, J. J., Malaisse, W., Ledet, Thomas, Lefébvre, P. J., Luyckx, A. S., Le Marchand, Y., Assimacopoulos, F., Singh, A., Amherdt, M., Rouiller, Ch., Jeanrenaud, B., Lenti, G., Frezzotti, R., Angotzi, G., Bardelli, A. M., Pagano, G., Basetti-Sani, A., Galli, M., Lernmark, Å., Fex, G., Lindsay, D. G., Loge, O., Lopez-Quijada, C., Chiva, L., Rodriguez-Lopez, M., Loten, E. G., Loubatières, A. L., Loubatières-Mariani, M. M., Ribes, G., Chapal, J., Lubetzki, J., Duprey, J., Sambourg, Cl., Lefebvre, P. J., Maier, V., Hinz, M., Schatz, H., Nierle, C., Pfeiffer, E. F., Malaisse, W. J., Pipeleers, D. G., Malaisse-Lagae, F., Orci, L., Malaisse-Lagae, F., Amherdt, M., Ravazzola, M., Stauffacher, W., Orci, L., Renold, A. E., Manzano, P., Rojas-Hidalgo, E., Marco, J., Diaz-Fierros, D., Calle, C., Roman, D., Villanueva, M. L., Valverde, I., Marliss, E. B., Wollheim, C. B., Blondel, B., Orci, L., Like, A., Amherdt, M., Stauffacher, W., Massi-Benedetti, F., Luycks, A. L., Fracassini, F., Lefebvre, P. J., Falorni, A., Menzel, R., Michaelis, D., Neumann, I., Bibergeil, H., Schulz, B., Wilke, W., Wulfert, P., Krämer, K., Menzinger, G., Fallucca, F., Tamburrano, F., Carratu', R., Andreani, D., Metzger, P., Franken, P., Balasse, E. O., Michael, R., Hildmann, W., Jutzi, E., Michl, J., Fankhauser, S., Schlichtkrull, J., Mirouze, J., Orsetti, A., Vierne, Y., Arnoux, N., Mølsted-Pederson, L., Tygstrup, Inge, Villumsen, Åge L., Pedersen, Jørgen, Montague, W., Howell, S. L., Moody, A. J., Agerbak, G. S., Sundby, F., Muggeo, M., Crepaldi, G., Fedele, D., Baritussio, A., Naeser, Peter, Navalesi, R., Pilo, A., Lenzi, S., Cecchetti, P., Corsini, G., Donato, L., Nerup, J., Andersen, O. Ortved, Bendixen, G., Egeberg, J., Poulsen, J. E., Nielsen, J. Høiriis, Hansen, F. Mølgaard, Gliemann, J., Niki, A., Niki, H., Koide, T., Lin, B. J., Nikkels, R. E., Terpstra, J., Gay, A., Oakman, R. H., Lazarus, Norman R., Orci, L., Amherdt, M., Stauffacher, W., Like, A. A., Rouiller, C., Renold, A. E., Malaisse-Lagae, F., Ravazzola, M., Ostman, J., Backman, L., Cerasi, E., Luft, R., Hallberg, D., Ostrowski, K., Panten, U., Christians, J., Parving, H. -H., Rasmussen, S. Munkgaard, Marichal, M., Platilovà, H., Dufek, M., Konopàsek, E., Pozuelo, V., Tamarit, J., Suner, A., Castell, C., Pruett, E. D. R., Maehlum, S., Raptis, S., Grebe, B., Chrissiku, M., Rothenbuchner, G., Müller, R., Hinze, H. J., Pfeiffer, E. F., Reinauer, H., Müller-Ruchholtz, E. R., Rietzler, X., Passa, P., Canivet, J., Schatz, H., Otto, J., Hinz, M., Maier, V., Nierle, C., Behrens, G., Bücher, T., Pfeiffer, E. F., Schlumpf, U., Morell, B., Zingg, A., Schönborn, J., Westphal, P., Panten, U., Bloom, G. D., Idahl, L. -A., Lernmark, A., Söderberg, M., Rios, M. Serrano, Hawkins, F. G., Escobar, F., Mato, J. M., Larrodera, L., de Oya, M., Rodriguez-Miñon, J. L., Shafrir, E., Gutman, A., Sitbon, G., Mialhe, P., Skrabalo, Z., Panajatović, N., Papić, Z., Posinovec, J., Stavljenić, A., Lipovac, V., Aganović, I., Soler, N. G., Bennett, M. A., Söling, H. D., Peters, H., Janson, G., Sönksen, P. H., Srivastava, M. C., Tompkins, C. V., Nabarro, J. D. N., Sørensen, N. Schwartz, Ladefoged, K., Wildenhoff, K. E., Sorge, F., Diehl, H. -J., Hoffmann, H., Schwartzkopff, W., Standl, E., Kolb, H., Standl, A., Mehnert, H., Sutherland, H. W., Stowers, J. M., Whetham, J. C. G., Sutter, B. C. J., Billaudel, B., Sutter, B. Ch. J., Sutter-Dub, M. T., Leclercq, R., Jacquot, R., Täljedal, I. B., Tamarit, J., Tamarit-Rodriguez, J., Goberna, R., Gobema, R., Tamás, Jr., Gy., Baranyi, Éva, Baranyi, A., Radvanyi, A., Tatoń, J., Hinek, A., Wiśniewska, A., Tattersall, R. B., Pyke, D. A., Terpstra, J., Slot, J. Bruins, Sande, P. L. M. v. d., Radder, J. K., Waldeok, K. J. J., Muijden, R. C. P. A. v., Tiengo, A., Assan, R., Frerichs, H., Creutzfeldt, W., Turner, D. S., Baker, R. W., Gent, W. G. L., Shabaan, A., Marks, V., Young, D. A. B., Vague, Ph., Heim, H., Laval, C. Martin, Vegezzi, M., Campo, C.Di, Rahamandridona, G., Garron, D., Heyraud, B., Vague, J., Valverde, I., Villanueva, M. L., Lozano, I., Diaz-Fierros, M., Marco, J., Van Assche, F. A., Gepts, W., Van Obberghen, E., Somers, G., Devis, G., Vaughan, G. D., Malaisse-Lagae, F., Orci, L., Malaisse, W. J., Veleminsky, J., Spirova, E., Waldhäusl, W., Frisch, H., Haydl, H., Weiss, L., Löffler, G., Wieland, O., Willms, B., Deuticke, U., Wollheim, C. B., Marliss, E. B., Blondel, B., Orci, L., Like, A., Renold, A. E., Zrůstová, M., and Roštlapil, J.

Published
1973
Full Text
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30. Health and social protection: experiences from Cambodia, China and Lao

Author

Meessen, B., Pei, X., Criel, B., Bloom, G., Van Lerberghe, W., Kegels, G., and De Brouwere, V.

Subjects
Social security, China, Poverty reduction, Social health insurance, Disease burden, Health services, needs and demand, Equity, Accessibility, Catastrophic health expenditures, Health insurance, Health equity funds (HEF), Laos, Asia, East, Prevention strategies, Asia, Southeast, Health sector reform, National policies, Cambodia, User fees, Revolving drug funds
Published
2008

36. Iatrogenic poverty [editorial]

Author

Meessen, B., Zhenzhong, Z., Van Damme, W., Devadasan, N., Criel, B., and Bloom, G.

Subjects
China, Health care, Economic transition, India, Socioeconomic aspects, Accessibility, Catastrophic health expenditures, Impact, Health insurance, Iatrogenic, Asia, East, Market economy, Household expenditures, Willingness-to-pay, Asia, South, Asia, Southeast, Cambodia, Poverty, Illness
Abstract

The definitive version is available at www3.interscience.wiley.com

Published
2003

37. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author

Permuth-Wey, J., Lawrenson, K., Shen, H.C., Velkova, A., Tyrer, J.P., Chen, Z., Lin, H.Y., Ann Chen, Y., Tsai, Y.Y., Qu, X., Ramus, S.J., Karevan, R., Lee, J. van der, Lee, N., Larson, M.C., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Antoniou, A.C., Armasu, S.M., Bacot, F., Baglietto, L., Bandera, E.V., Barnholtz-Sloan, J., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Cai, Q., Campbell, I., Chang-Claude, J., Chanock, S., Chenevix-Trench, G., Cheng, J.Q., Cicek, M.S., Coetzee, G.A., Cook, L.S., Couch, F.J., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Easton, D.F., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D.A., Flanagan, J.M., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G.G., Glasspool, R.M., Gonzalez-Bosquet, J., Goodman, M.T., Gore, M., Gorski, B., Gronwald, J., Hall, P., Halle, M.K., Harter, P., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Jim, H., Kalli, K.R., Karlan, B.Y., Kaye, S.B., Kelemen, L.E., Kiemeney, L.A.L.M., Kikkawa, F., Konecny, G.E., Krakstad, C., Kruger Kjaer, S., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Lancaster, J.M., Le, N.D., Leminen, A., Levine, D.A., Liang, D., Kiong Lim, B., Lin, J., Massuger, L.F.A.G., Altena, A.M. van, et al., Permuth-Wey, J., Lawrenson, K., Shen, H.C., Velkova, A., Tyrer, J.P., Chen, Z., Lin, H.Y., Ann Chen, Y., Tsai, Y.Y., Qu, X., Ramus, S.J., Karevan, R., Lee, J. van der, Lee, N., Larson, M.C., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Antoniou, A.C., Armasu, S.M., Bacot, F., Baglietto, L., Bandera, E.V., Barnholtz-Sloan, J., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Cai, Q., Campbell, I., Chang-Claude, J., Chanock, S., Chenevix-Trench, G., Cheng, J.Q., Cicek, M.S., Coetzee, G.A., Cook, L.S., Couch, F.J., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Easton, D.F., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D.A., Flanagan, J.M., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G.G., Glasspool, R.M., Gonzalez-Bosquet, J., Goodman, M.T., Gore, M., Gorski, B., Gronwald, J., Hall, P., Halle, M.K., Harter, P., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Jim, H., Kalli, K.R., Karlan, B.Y., Kaye, S.B., Kelemen, L.E., Kiemeney, L.A.L.M., Kikkawa, F., Konecny, G.E., Krakstad, C., Kruger Kjaer, S., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Lancaster, J.M., Le, N.D., Leminen, A., Levine, D.A., Liang, D., Kiong Lim, B., Lin, J., Massuger, L.F.A.G., Altena, A.M. van, and et al.

Abstract

Contains fulltext : 118576.pdf (publisher's version ) (Open Access), Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

Published
2013

38. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Author

Pharoah, P.D., Tsai, Y.Y., Ramus, S.J., Phelan, C.M., Goode, E.L., Lawrenson, K., Buckley, M., Fridley, B.L., Tyrer, J.P., Shen, H., Weber, R., Karevan, R., Larson, M.C., Song, H., Tessier, D.C., Bacot, F., Vincent, D., Cunningham, J.M., Dennis, J., Dicks, E., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Armasu, S.M., Baglietto, L., Bandera, E.V., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brenton, J.D., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Campbell, I., Carney, M.E., Carvalho, R.S., Chang-Claude, J., Chen, Y.A., Chen, Z., Chow, W.H., Cicek, M.S., Coetzee, G., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D., Flanagan, J., Gao, Y.T., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G., Gjyshi, A., Gore, M., Gronwald, J., Guo, Q., Halle, M.K., Harter, P., Hein, A., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, E., Hogdall, C.K., Hosono, S., Jakubowska, A., Jensen, A., Kalli, K.R., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Konecny, G.E., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, N., Lee, J. van der, Leminen, A., Lim, B.K., Lissowska, J., Lubinski, J., Lundvall, L., Lurie, G., Massuger, L.F.A.G., Altena, A.M. van, Pharoah, P.D., Tsai, Y.Y., Ramus, S.J., Phelan, C.M., Goode, E.L., Lawrenson, K., Buckley, M., Fridley, B.L., Tyrer, J.P., Shen, H., Weber, R., Karevan, R., Larson, M.C., Song, H., Tessier, D.C., Bacot, F., Vincent, D., Cunningham, J.M., Dennis, J., Dicks, E., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Armasu, S.M., Baglietto, L., Bandera, E.V., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brenton, J.D., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Campbell, I., Carney, M.E., Carvalho, R.S., Chang-Claude, J., Chen, Y.A., Chen, Z., Chow, W.H., Cicek, M.S., Coetzee, G., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D., Flanagan, J., Gao, Y.T., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G., Gjyshi, A., Gore, M., Gronwald, J., Guo, Q., Halle, M.K., Harter, P., Hein, A., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, E., Hogdall, C.K., Hosono, S., Jakubowska, A., Jensen, A., Kalli, K.R., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Konecny, G.E., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, N., Lee, J. van der, Leminen, A., Lim, B.K., Lissowska, J., Lubinski, J., Lundvall, L., Lurie, G., Massuger, L.F.A.G., and Altena, A.M. van

Abstract

Contains fulltext : 118459.pdf (publisher's version ) (Closed access), Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 x 10(-9)) and 10p12 (rs1243180, P = 1.8 x 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 x 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Published
2013

39. A gene expression model of intrinsic tumor radiosensitivity: prediction of response and prognosis after chemoradiation.

Author

Eschrich, S.A., Pramana, J., Zhang, H., Zhao, H., Boulware, D., Lee, J.H., Bloom, G., Rocha-Lima, C., Kelley, S., Calvin, D.P., Yeatman, T.J., Begg, A.C., Torres-Roca, J.F., Eschrich, S.A., Pramana, J., Zhang, H., Zhao, H., Boulware, D., Lee, J.H., Bloom, G., Rocha-Lima, C., Kelley, S., Calvin, D.P., Yeatman, T.J., Begg, A.C., and Torres-Roca, J.F.

Abstract

Contains fulltext : 81391.pdf (publisher's version ) (Closed access), PURPOSE: Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients. METHODS AND MATERIALS: Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12). RESULTS: Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05). CONCLUSIONS: We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.

Published
2009

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