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151. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author

Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, van der Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, O, Pankratz, VS, Wang, XS, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, Ans, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C (Conxi), Mai, PL, Benitez, J, Southey, MC, Schmidt, Marjanka K, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q (Qing), Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Dork, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, Maartje, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Alonso, MR, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Offit, K, Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, van der Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, O, Pankratz, VS, Wang, XS, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, Ans, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C (Conxi), Mai, PL, Benitez, J, Southey, MC, Schmidt, Marjanka K, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q (Qing), Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Dork, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, Maartje, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Alonso, MR, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Offit, K

Published
2013

152. Genome-wide association study for ovarian cancer susceptibility using pooled DNA.

Author

Lu, Y., Chen, X., Beesley, J., Johnatty, S.E., Defazio, A., Lambrechts, S., Lambrechts, D., Despierre, E., Vergotes, I., Chang-Claude, J., Hein, R., Nickels, S., Wang-Gohrke, S., Dork, T., Durst, M., Antonenkova, N., Bogdanova, N., Goodman, M.T., Lurie, G., Wilkens, L.R., Carney, M.E., Butzow, R., Nevanlinna, H., Heikkinen, T., Leminen, A., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Aben, K.K.H., Kjaer, S.K., Hogdall, E., Jensen, A., Brooks-Wilson, A., Le, N., Cook, L., Earp, M., Kelemen, L., Easton, D., Pharoah, P., Song, H., Tyrer, J., Ramus, S., Menon, U., Gentry-Maharaj, A., Gayther, S.A., Bandera, E.V., Olson, S.H., Orlow, I., Rodriguez-Rodriguez, L., MacGregor, S., Chenevix-Trench, G., Lu, Y., Chen, X., Beesley, J., Johnatty, S.E., Defazio, A., Lambrechts, S., Lambrechts, D., Despierre, E., Vergotes, I., Chang-Claude, J., Hein, R., Nickels, S., Wang-Gohrke, S., Dork, T., Durst, M., Antonenkova, N., Bogdanova, N., Goodman, M.T., Lurie, G., Wilkens, L.R., Carney, M.E., Butzow, R., Nevanlinna, H., Heikkinen, T., Leminen, A., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Aben, K.K.H., Kjaer, S.K., Hogdall, E., Jensen, A., Brooks-Wilson, A., Le, N., Cook, L., Earp, M., Kelemen, L., Easton, D., Pharoah, P., Song, H., Tyrer, J., Ramus, S., Menon, U., Gentry-Maharaj, A., Gayther, S.A., Bandera, E.V., Olson, S.H., Orlow, I., Rodriguez-Rodriguez, L., MacGregor, S., and Chenevix-Trench, G.

Abstract

1 oktober 2012, Contains fulltext : 108021.pdf (publisher's version ) (Open Access), Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.

Published
2012

153. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author

Ghoussaini, M., Fletcher, O., Michailidou, K., Turnbull, C., Schmidt, M.K., Dicks, E., Dennis, J., Wang, Q., Humphreys, M.K., Luccarini, C., Baynes, C., Conroy, D., Maranian, M., Ahmed, S., Driver, K., Johnson, N., Orr, N., dos Santos Silva, I., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A.G., Rivadeneira, F., Netherlands Collaborative Group on Hereditary, B., Ovarian, C., Hall, P., Czene, K., Irwanto, A., Liu, J., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Meindl, A., Schmutzler, R.K., Muller-Myhsok, B., Lichtner, P., Chang-Claude, J., Hein, R., Nickels, S., Flesch-Janys, D., Tsimiklis, H., Makalic, E., Schmidt, D., Bui, M., Hopper, J.L., Apicella, C., Park, D.J., Southey, M., Hunter, D.J., Chanock, S.J., Broeks, A., Verhoef, S., Hogervorst, F.B., Fasching, P.A., Lux, M.P., Beckmann, M.W., Ekici, A.B., Sawyer, E., Tomlinson, I., Kerin, M., Marme, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Guenel, P., Truong, T., Cordina-Duverger, E., Menegaux, F., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Milne, R.L., Alonso, M.R., Gonzalez-Neira, A., Benitez, J., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C.C., Brenner, H., Muller, H., Arndt, V., Stegmaier, C., Familial Breast Cancer, S., Justenhoven, C., Brauch, H., Bruning, T., Gene Environment Interaction of Breast Cancer in Germany, N., Wang-Gohrke, S., Eilber, U., Dork, T., Schurmann, P., Bremer, M., Hillemanns, P., Bogdanova, N.V., Antonenkova, N.N., Rogov, Y.I., Karstens, J.H., Bermisheva, M., Prokofieva, D., Ligtenberg, M.J., et al., Ghoussaini, M., Fletcher, O., Michailidou, K., Turnbull, C., Schmidt, M.K., Dicks, E., Dennis, J., Wang, Q., Humphreys, M.K., Luccarini, C., Baynes, C., Conroy, D., Maranian, M., Ahmed, S., Driver, K., Johnson, N., Orr, N., dos Santos Silva, I., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A.G., Rivadeneira, F., Netherlands Collaborative Group on Hereditary, B., Ovarian, C., Hall, P., Czene, K., Irwanto, A., Liu, J., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Meindl, A., Schmutzler, R.K., Muller-Myhsok, B., Lichtner, P., Chang-Claude, J., Hein, R., Nickels, S., Flesch-Janys, D., Tsimiklis, H., Makalic, E., Schmidt, D., Bui, M., Hopper, J.L., Apicella, C., Park, D.J., Southey, M., Hunter, D.J., Chanock, S.J., Broeks, A., Verhoef, S., Hogervorst, F.B., Fasching, P.A., Lux, M.P., Beckmann, M.W., Ekici, A.B., Sawyer, E., Tomlinson, I., Kerin, M., Marme, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Guenel, P., Truong, T., Cordina-Duverger, E., Menegaux, F., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Milne, R.L., Alonso, M.R., Gonzalez-Neira, A., Benitez, J., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C.C., Brenner, H., Muller, H., Arndt, V., Stegmaier, C., Familial Breast Cancer, S., Justenhoven, C., Brauch, H., Bruning, T., Gene Environment Interaction of Breast Cancer in Germany, N., Wang-Gohrke, S., Eilber, U., Dork, T., Schurmann, P., Bremer, M., Hillemanns, P., Bogdanova, N.V., Antonenkova, N.N., Rogov, Y.I., Karstens, J.H., Bermisheva, M., Prokofieva, D., Ligtenberg, M.J., and et al.

Abstract

Item does not contain fulltext, Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in approximately 70,000 cases and approximately 68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 x 10(-35)), 12q24 (rs1292011; P = 4.3 x 10(-19)) and 21q21 (rs2823093; P = 1.1 x 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Published
2012

154. Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

Author

Prokunina-Olsson, L, Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, K-Y, Noh, D-Y, Ahn, S-H, Dork, T, Schuermann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, X, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, Y-D, Broeks, A, Schmidt, MK, Van 't Veer, LJ, Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, P-E, Yu, J-C, Hsiung, C-N, Shen, C-Y, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, A-S, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, MJ, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Ignacio Arias, J, Pilar Zamora, M, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, X, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, V-M, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, C, Oldenburg, RA, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, K-R, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, Easton, DF, Prokunina-Olsson, L, Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, K-Y, Noh, D-Y, Ahn, S-H, Dork, T, Schuermann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, X, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, Y-D, Broeks, A, Schmidt, MK, Van 't Veer, LJ, Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, P-E, Yu, J-C, Hsiung, C-N, Shen, C-Y, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, A-S, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, MJ, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Ignacio Arias, J, Pilar Zamora, M, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, X, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, V-M, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, C, Oldenburg, RA, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, K-R, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, and Easton, DF

Abstract

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Published
2012

155. Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

Author

Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, KY, Noh, DY, Ahn, SH, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, XS, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, YD, Broeks, A, Schmidt, Marjanka K, van 't Veer, LJ (Laura), Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, PE, Yu, JC, Hsiung, CN, Shen, CY, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, AS, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, Maartje, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Arias, JI, Zamora, MP, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, XQ, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, VM, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, Caroline, Oldenburg, Rogier, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, KR, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, Easton, DF, Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, KY, Noh, DY, Ahn, SH, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, XS, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, YD, Broeks, A, Schmidt, Marjanka K, van 't Veer, LJ (Laura), Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, PE, Yu, JC, Hsiung, CN, Shen, CY, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, AS, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, Maartje, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Arias, JI, Zamora, MP, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, XQ, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, VM, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, Caroline, Oldenburg, Rogier, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, KR, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, and Easton, DF

Abstract

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I-2 = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95% CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Published
2012

156. Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Author

Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, Marjanka K, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, ID, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Perez, JIA, Zamora, MP, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, YD, Wang-Gohrke, S, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, J, Chen, XQ, Beesley, J, Lambrechts, D, Zhao, H (Hui), Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, AL, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, John, Seynaeve, Caroline, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, JJ, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S (Shahana), Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, KY, Noh, DY, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Shen, CY, Yu, JC, Hsu, HM, Hou, MF, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, Truong, T, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, Marjanka K, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, ID, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Perez, JIA, Zamora, MP, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, YD, Wang-Gohrke, S, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, J, Chen, XQ, Beesley, J, Lambrechts, D, Zhao, H (Hui), Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, AL, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, John, Seynaeve, Caroline, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, JJ, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S (Shahana), Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, KY, Noh, DY, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Shen, CY, Yu, JC, Hsu, HM, Hou, MF, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, and Truong, T

Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

Published
2012

157. Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe

Author

Dork, T Macek, M Mekus, F Tummler, B Tzountzouris, J and Casals, T Krebsova, A Koudova, M Sakmaryova, I Macek, M and Vavrova, V Zemkova, D Ginter, E Petrova, NV and Ivaschenko, T Baranov, V Witt, M Pogorzelski, A Bal, J and Zekanowsky, C Wagner, K Stuhrmann, M Bauer, I and Seydewitz, HH Neumann, T Jakubiczka, S Kraus, C Thamm, B and Nechiporenko, M Livshits, L Mosse, N Tsukerman, G and Kadasi, L Ravnik-Glavac, M Glavac, D Komel, R Vouk, K and Kucinskas, V Krumina, A Teder, M Kocheva, S Efremov, GD Onay, T Kirdar, B Malone, G Schwarz, M Zhou, ZQ and Friedman, KJ Carles, S Claustres, M Bozon, D and Verlingue, C Ferec, C Tzetis, M Kanavakis, E Cuppens, H and Bombieri, C Pignatti, PF Sangiuolo, F Jordanova, A and Kusic, J Radojkovic, D Sertic, J Richter, D Rukavina, AS and Bjorck, E Strandvik, B Cardoso, H Montgomery, M and Nakielna, B Hughes, D Estivill, X Aznarez, I Tullis, E and Tsui, LC Zielenski, J

Abstract

We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz.. a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2.3(21 kb), deletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2.3(21 kb) homozygotes and a comparison of compound heterozygotes for Delta F508/CFTRdele2,3(21 kb) with pairwise-matched Delta F508 homozygotes indicate that this deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%). Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype: XV-2c/KM. 19 “A” and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVSI7bCA) in all examined CFTRdele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.

Published
2000

158. The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing

Author

Pharoah, P.D., 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, M.J., 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, D.W, Cunningham, J.M., Despierre, E., Doherty, J.A., Dork, T., Durst, M., Eccles, D.M., Ekici, A.B., Easton, D., Fasching, P.A., Fazio, A. de, 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., 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.L.M., 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.A.G., 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., et al., Pharoah, P.D., 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, M.J., 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, D.W, Cunningham, J.M., Despierre, E., Doherty, J.A., Dork, T., Durst, M., Eccles, D.M., Ekici, A.B., Easton, D., Fasching, P.A., Fazio, A. de, 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., 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.L.M., 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.A.G., 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., and et al.

Abstract

Contains fulltext : 98456.pdf (publisher's version ) (Closed access), 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 article, 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 19 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 (PFS) data and 18 studies with all-cause mortality data. RESULTS: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% 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 (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS 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, seems unwarranted.

Published
2011

159. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium

Author

Amankwah, E.K., Wang, Q., Schildkraut, J.M., Tsai, Y.Y., Ramus, S.J., Fridley, B.L., Beesley, J., Johnatty, S.E., Webb, P.M., Chenevix-Trench, G., Dale, L.C., Lambrechts, D., Amant, F., Despierre, E., Vergote, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Chang-Claude, J., Wang-Gohrke, S., Anton-Culver, H., Ziogas, A., Dork, T., Durst, M., Antonenkova, N., Bogdanova, N., Brown, R., Flanagan, J.M., Kaye, S.B., Paul, J., Butzow, R., Nevanlinna, H., Campbell, I., Eccles, D.M., Karlan, B.Y., Gross, J., Walsh, C., Pharoah, P.D., Song, H., Kruger Kjaer, S., Hogdall, E., Hogdall, C., Lundvall, L., Nedergaard, L., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Vermeulen, H.H.M., Le, N.D., Brooks-Wilson, A., Cook, L.S., Phelan, C.M., Cunningham, J.M., Vachon, C.M., Vierkant, R.A., Iversen, E.S., Berchuck, A., Goode, E.L., Sellers, T.A., Kelemen, L.E., Amankwah, E.K., Wang, Q., Schildkraut, J.M., Tsai, Y.Y., Ramus, S.J., Fridley, B.L., Beesley, J., Johnatty, S.E., Webb, P.M., Chenevix-Trench, G., Dale, L.C., Lambrechts, D., Amant, F., Despierre, E., Vergote, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Chang-Claude, J., Wang-Gohrke, S., Anton-Culver, H., Ziogas, A., Dork, T., Durst, M., Antonenkova, N., Bogdanova, N., Brown, R., Flanagan, J.M., Kaye, S.B., Paul, J., Butzow, R., Nevanlinna, H., Campbell, I., Eccles, D.M., Karlan, B.Y., Gross, J., Walsh, C., Pharoah, P.D., Song, H., Kruger Kjaer, S., Hogdall, E., Hogdall, C., Lundvall, L., Nedergaard, L., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Vermeulen, H.H.M., Le, N.D., Brooks-Wilson, A., Cook, L.S., Phelan, C.M., Cunningham, J.M., Vachon, C.M., Vierkant, R.A., Iversen, E.S., Berchuck, A., Goode, E.L., Sellers, T.A., and Kelemen, L.E.

Abstract

Contains fulltext : 97229.pdf (publisher's version ) (Open Access), Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)>/=0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)>/=0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)

Published
2011

160. Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers

Author

Beesley, J., Pickett, H.A., Johnatty, S.E., Dunning, A.M., Chen, X., Li, J., Michailidou, K., Lu, Y., Rider, D.N., Palmieri, R.T., Stutz, M.D., Lambrechts, D., Despierre, E., Lambrechts, S., Vergote, I., Chang-Claude, J., Nickels, S., Vrieling, A., Flesch-Janys, D., Wang-Gohrke, S., Eilber, U., Bogdanova, N., Antonenkova, N., Runnebaum, I.B., Dork, T., Goodman, M.T., Lurie, G., Wilkens, L.R., Matsuno, R.K., Kiemeney, L.A.L.M., Aben, K.K.H., Marees, T., Massuger, L.F.A.G., Fridley, B.L., Vierkant, R.A., Bandera, E.V., Olson, S.H., Orlow, I., Rodriguez-Rodriguez, L., Cook, L.S., Le, N.D., Brooks-Wilson, A., Kelemen, L.E., Campbell, I., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Menon, U., Ahmed, S., Baynes, C., Pharoah, P.D., Muir, K., Lophatananon, A., Chaiwerawattana, A., Wiangnon, S., MacGregor, S., Easton, D.F., Reddel, R.R., Goode, E.L., Chenevix-Trench, G., Beesley, J., Pickett, H.A., Johnatty, S.E., Dunning, A.M., Chen, X., Li, J., Michailidou, K., Lu, Y., Rider, D.N., Palmieri, R.T., Stutz, M.D., Lambrechts, D., Despierre, E., Lambrechts, S., Vergote, I., Chang-Claude, J., Nickels, S., Vrieling, A., Flesch-Janys, D., Wang-Gohrke, S., Eilber, U., Bogdanova, N., Antonenkova, N., Runnebaum, I.B., Dork, T., Goodman, M.T., Lurie, G., Wilkens, L.R., Matsuno, R.K., Kiemeney, L.A.L.M., Aben, K.K.H., Marees, T., Massuger, L.F.A.G., Fridley, B.L., Vierkant, R.A., Bandera, E.V., Olson, S.H., Orlow, I., Rodriguez-Rodriguez, L., Cook, L.S., Le, N.D., Brooks-Wilson, A., Kelemen, L.E., Campbell, I., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Menon, U., Ahmed, S., Baynes, C., Pharoah, P.D., Muir, K., Lophatananon, A., Chaiwerawattana, A., Wiangnon, S., MacGregor, S., Easton, D.F., Reddel, R.R., Goode, E.L., and Chenevix-Trench, G.

Abstract

Contains fulltext : 96941.pdf (publisher's version ) (Open Access), Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.

Published
2011

161. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

Author

Broeks, A., Schmidt, M.K., Sherman, M.E., Couch, F.J., Hopper, J.L., Dite, G.S., Apicella, C., Smith, L.D., Hammet, F., Southey, M.C., Veer, L.J. van 't, Groot, R. de, Smit, V.T., Fasching, P.A., Beckmann, M.W., Jud, S., Ekici, A.B., Hartmann, A., Hein, A., Schulz-Wendtland, R., Burwinkel, B., Marme, F., Schneeweiss, A., Sinn, H.P., Sohn, C., Tchatchou, S., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Orsted, D.D., Kaur-Knudsen, D., Milne, R.L., Perez, J.I., Zamora, P., Rodriguez, P.M., Benitez, J., Brauch, H., Justenhoven, C., Ko, Y.D., Hamann, U., Fischer, H.P., Bruning, T., Pesch, B., Chang-Claude, J., Wang-Gohrke, S., Bremer, M., Karstens, J.H., Hillemanns, P., Dork, T., Nevanlinna, H.A., Heikkinen, T., Heikkila, P., Blomqvist, C., Aittomaki, K., Aaltonen, K., Lindblom, A., Margolin, S., Mannermaa, A., Kosma, V.M., Kauppinen, J.M., Kataja, V., Auvinen, P., Eskelinen, M., Soini, Y., Chenevix-Trench, G., Spurdle, A.B., Beesley, J., Chen, X., Holland, H., Lambrechts, D., Claes, B., Vandorpe, T., Neven, P., Wildiers, H., Flesch-Janys, D., Hein, R., Loning, T., Kosel, M., Fredericksen, Z.S., Wang, X., Giles, G.G., Baglietto, L., Severi, G., McLean, C., Haiman, C.A., Henderson, B.E., Marchand, L. le, Kolonel, L.N., Alnaes, G.G., Kristensen, V., Borresen-Dale, A.L., Hunter, D.J., Hankinson, S.E., Andrulis, I.L., Mulligan, A.M., O'Malley, F.P., Devilee, P., Huijts, P.E., Tollenaar, R.A.E.M., Asperen, C.J. van, Broeks, A., Schmidt, M.K., Sherman, M.E., Couch, F.J., Hopper, J.L., Dite, G.S., Apicella, C., Smith, L.D., Hammet, F., Southey, M.C., Veer, L.J. van 't, Groot, R. de, Smit, V.T., Fasching, P.A., Beckmann, M.W., Jud, S., Ekici, A.B., Hartmann, A., Hein, A., Schulz-Wendtland, R., Burwinkel, B., Marme, F., Schneeweiss, A., Sinn, H.P., Sohn, C., Tchatchou, S., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Orsted, D.D., Kaur-Knudsen, D., Milne, R.L., Perez, J.I., Zamora, P., Rodriguez, P.M., Benitez, J., Brauch, H., Justenhoven, C., Ko, Y.D., Hamann, U., Fischer, H.P., Bruning, T., Pesch, B., Chang-Claude, J., Wang-Gohrke, S., Bremer, M., Karstens, J.H., Hillemanns, P., Dork, T., Nevanlinna, H.A., Heikkinen, T., Heikkila, P., Blomqvist, C., Aittomaki, K., Aaltonen, K., Lindblom, A., Margolin, S., Mannermaa, A., Kosma, V.M., Kauppinen, J.M., Kataja, V., Auvinen, P., Eskelinen, M., Soini, Y., Chenevix-Trench, G., Spurdle, A.B., Beesley, J., Chen, X., Holland, H., Lambrechts, D., Claes, B., Vandorpe, T., Neven, P., Wildiers, H., Flesch-Janys, D., Hein, R., Loning, T., Kosel, M., Fredericksen, Z.S., Wang, X., Giles, G.G., Baglietto, L., Severi, G., McLean, C., Haiman, C.A., Henderson, B.E., Marchand, L. le, Kolonel, L.N., Alnaes, G.G., Kristensen, V., Borresen-Dale, A.L., Hunter, D.J., Hankinson, S.E., Andrulis, I.L., Mulligan, A.M., O'Malley, F.P., Devilee, P., Huijts, P.E., Tollenaar, R.A.E.M., and Asperen, C.J. van

Abstract

Contains fulltext : 96071.pdf (publisher's version ) (Closed access), Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P

Published
2011

163. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.

Author

Goode, E.L., Chenevix-Trench, G., Song, H., Ramus, S.J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R.A., Larson, M.C., Kjaer, S.K., Birrer, M.J., Berchuck, A., Schildkraut, J., Tomlinson, I.P., Kiemeney, L.A.L.M., Cook, L.S., Gronwald, J., Garcia-Closas, M., Gore, M.E., Campbell, I., Whittemore, A.S., Sutphen, R., Phelan, C.M., Anton-Culver, H., Pearce, C.L., Lambrechts, D., Rossing, M.A., Chang-Claude, J., Moysich, K.B., Goodman, M.T., Dork, T., Nevanlinna, H., Ness, R.B., Rafnar, T., Hogdall, E., Fridley, B.L., Cunningham, J.M., Sieh, W., McGuire, V., Godwin, A.K., Cramer, D.W, Hernandez, D., Levine, D., Lu, K., Iversen, E.S., Palmieri, R.T., Houlston, R.S., Altena, A.M. van, Aben, K.K.H., Massuger, L.F.A.G., Brooks-Wilson, A., Kelemen, L.E., Le, N.D., Jakubowska, A., Lubinski, J., Medrek, K., Stafford, A., Easton, D.F., Tyrer, J.P., Bolton, K.L., Harrington, P., Eccles, D., Chen, A., Molina, A.N., Davila, B.N., Arango, H., Tsai, Y.Y., Chen, Z., Risch, H.A., McLaughlin, J., Narod, S., Ziogas, A., Brewster, W., Gentry-Maharaj, A., Menon, U., Wu, A.H., Stram, D.O., Pike, M.C., Beesley, J., Webb, P.M., Chen, X., Ekici, A.B., Thiel, F.C., Beckmann, M.W., Yang, H., Wentzensen, N., Lissowska, J., Fasching, P.A., Despierre, E., Amant, F., Vergote, I., Doherty, J., Hein, R., Wang-Gohrke, S., Lurie, G., Carney, M.E., Thompson, P., Goode, E.L., Chenevix-Trench, G., Song, H., Ramus, S.J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R.A., Larson, M.C., Kjaer, S.K., Birrer, M.J., Berchuck, A., Schildkraut, J., Tomlinson, I.P., Kiemeney, L.A.L.M., Cook, L.S., Gronwald, J., Garcia-Closas, M., Gore, M.E., Campbell, I., Whittemore, A.S., Sutphen, R., Phelan, C.M., Anton-Culver, H., Pearce, C.L., Lambrechts, D., Rossing, M.A., Chang-Claude, J., Moysich, K.B., Goodman, M.T., Dork, T., Nevanlinna, H., Ness, R.B., Rafnar, T., Hogdall, E., Fridley, B.L., Cunningham, J.M., Sieh, W., McGuire, V., Godwin, A.K., Cramer, D.W, Hernandez, D., Levine, D., Lu, K., Iversen, E.S., Palmieri, R.T., Houlston, R.S., Altena, A.M. van, Aben, K.K.H., Massuger, L.F.A.G., Brooks-Wilson, A., Kelemen, L.E., Le, N.D., Jakubowska, A., Lubinski, J., Medrek, K., Stafford, A., Easton, D.F., Tyrer, J.P., Bolton, K.L., Harrington, P., Eccles, D., Chen, A., Molina, A.N., Davila, B.N., Arango, H., Tsai, Y.Y., Chen, Z., Risch, H.A., McLaughlin, J., Narod, S., Ziogas, A., Brewster, W., Gentry-Maharaj, A., Menon, U., Wu, A.H., Stram, D.O., Pike, M.C., Beesley, J., Webb, P.M., Chen, X., Ekici, A.B., Thiel, F.C., Beckmann, M.W., Yang, H., Wentzensen, N., Lissowska, J., Fasching, P.A., Despierre, E., Amant, F., Vergote, I., Doherty, J., Hein, R., Wang-Gohrke, S., Lurie, G., Carney, M.E., and Thompson, P.

Abstract

Contains fulltext : 89180.pdf (publisher's version ) (Closed access)

Published
2010

164. Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

Author

Fletcher, O., Johnson, N., Silva, Andreá Lema Da, Orr, N., Ashworth, A., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Burwinkel, B., Bartram, C.R., Meindl, A., Schmutzler, R.K., Cox, A., Brock, I., Elliott, George Arthur, Travis, Brandon Reed, Southey, M.C., Smith, L., Spurdle, A.B., Hopper, J.L., Couch, F.J., Olson, J.E., Wang, X.S., Fredericksen, Z., Schurmann, P., Waltes, R., Bremer, M., Dork, T., Devilee, P., van Asperen, C.J., Tollenaar, R.A.E.M., Seynaeve, C., Hall, Katrine Blædel Pinholt, Czene, K., Humphreys, K., Liu, J.J., Ahmed, S., Dunning, A.M., Maranian, M., Pharoah, P.D.P., Chenevix-Trench, G., Beesley, J., Bogdanova, N.V., Antonenkova, N.N., Zalutsky, I.V., Anton-Culver, H., Ziogas, A., Brauch, H., Ko, Y.D., Hamann, U., Fasching, P.A., Strick, R., Ekici, A.B., Beckmann, M.W., Gaubert, Giles, Severi, G., Baglietto, L., English, D.R., Milne, R.L., Benitez, J., Arias, J.I., Pita, G., Nordestgaard, B.G., Bojesen, S.E., Flyger, H., Kang, D., Larsen, Marie Sofie Yoo, Noh, D.Y., Mannermaa, A., Kataja, V., Kosma, V.M., Garcia-Closas, M., Chanock, S., Lissowska, J., Brinton, L.A., Chang-Claude, J., Wang-Gohrke, S., Broeks, A., Schmidt, M.K., van Leeuwen, F.E., Van't Veer, L.J., Margolin, S., Hansen, Anne Lindblom, Humphreys, M.K., Morrison, Ann Judith, Platte, R., Easton, D.F., Peto, J., Fletcher, O., Johnson, N., Silva, Andreá Lema Da, Orr, N., Ashworth, A., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Burwinkel, B., Bartram, C.R., Meindl, A., Schmutzler, R.K., Cox, A., Brock, I., Elliott, George Arthur, Travis, Brandon Reed, Southey, M.C., Smith, L., Spurdle, A.B., Hopper, J.L., Couch, F.J., Olson, J.E., Wang, X.S., Fredericksen, Z., Schurmann, P., Waltes, R., Bremer, M., Dork, T., Devilee, P., van Asperen, C.J., Tollenaar, R.A.E.M., Seynaeve, C., Hall, Katrine Blædel Pinholt, Czene, K., Humphreys, K., Liu, J.J., Ahmed, S., Dunning, A.M., Maranian, M., Pharoah, P.D.P., Chenevix-Trench, G., Beesley, J., Bogdanova, N.V., Antonenkova, N.N., Zalutsky, I.V., Anton-Culver, H., Ziogas, A., Brauch, H., Ko, Y.D., Hamann, U., Fasching, P.A., Strick, R., Ekici, A.B., Beckmann, M.W., Gaubert, Giles, Severi, G., Baglietto, L., English, D.R., Milne, R.L., Benitez, J., Arias, J.I., Pita, G., Nordestgaard, B.G., Bojesen, S.E., Flyger, H., Kang, D., Larsen, Marie Sofie Yoo, Noh, D.Y., Mannermaa, A., Kataja, V., Kosma, V.M., Garcia-Closas, M., Chanock, S., Lissowska, J., Brinton, L.A., Chang-Claude, J., Wang-Gohrke, S., Broeks, A., Schmidt, M.K., van Leeuwen, F.E., Van't Veer, L.J., Margolin, S., Hansen, Anne Lindblom, Humphreys, M.K., Morrison, Ann Judith, Platte, R., Easton, D.F., and Peto, J.

Abstract

Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P-trend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P-trend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 19(9); 2143-51. (C) 2010 AACR

Published
2010

165. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

Author

Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, KA, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, YD, Bruening, T, Haas, S, Dork, T, Schurmann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, VM, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beeslev, J, Chen, X, Devilee, P, van Asperen, CJ, Jacobi, CE, Tollenaar, RA, Huijts, PE, Klijn, Jan, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, M, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, van Kraft, PJA (Peter), Sherman, M, Chanock, S, Lissowska, J, Brinton, L, Peplonska, B, Hooning, Maartje, Meijers-Heijboer, EJ, Collee, Margriet, van den Ouweland, Ans, Uitterlinden, André, Liu, Jun, Lin, L, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, AJ, Tyrer, J, Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, KA, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, YD, Bruening, T, Haas, S, Dork, T, Schurmann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, VM, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beeslev, J, Chen, X, Devilee, P, van Asperen, CJ, Jacobi, CE, Tollenaar, RA, Huijts, PE, Klijn, Jan, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, M, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, van Kraft, PJA (Peter), Sherman, M, Chanock, S, Lissowska, J, Brinton, L, Peplonska, B, Hooning, Maartje, Meijers-Heijboer, EJ, Collee, Margriet, van den Ouweland, Ans, Uitterlinden, André, Liu, Jun, Lin, L, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, AJ, and Tyrer, J

Published
2008

166. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

Author

Garcia-Closas, M., Hall, P., Nevanlinna, H., Pooley, K., Morrison, J., Richesson, D.A., Bojesen, S.E., Axelsson, C.K., Arias, J.I., Milne, R.L., Ribas, G., Gonzalez-Neira, A., Benitez, J., Zamora, P., Brauch, H., Justenhoven, C., Hamann, U., Ko, Y.D., Bruening, T., Haas, S., Dork, T., Schurmann, P., Hillemanns, P., Bogdanova, N., Bremer, M., Karstens, J.H., Fagerholm, R., Aaltonen, K., Aittomaki, K., Smitten, K. Von, Blomqvist, C., Mannermaa, A., Uusitupa, M., Eskelinen, M., Tengstrom, M., Kosma, V.M., Kataja, V., Chenevix-Trench, G., Spurdle, A.B., Beesley, J., Chen, X., Devilee, P., Asperen, C.J. Van, Jacobi, C.E., Tollenaar, R.A.E.M., Huijts, P.E.A., Klijn, J.G.M., Chang-Claude, J., Kropp, S., Slanger, T., Flesch-Janys, D., Mutschelknauss, E., Salazar, R., Wang-Gohrke, S., Couch, F., Goode, E.L., Olson, J.E., Vachon, C., Fredericksen, Z.S., Giles, G.G., Baglietto, L., Severi, G., Hopper, J.L., English, D.R., Southey, M.C., Haiman, C.A., Henderson, B.E., Kolonel, L.N., Marchand, L. Le, Stram, D.O., Hunter, D.J., Hankinson, S.E., Cox, D.G., Tamimi, R., Kraft, P., Sherman, M.E., Chanock, S.J., Lissowska, J., Brinton, L.A., Peplonska, B., Hooning, M.J., Meijers-Heijboer, H., Collee, J.M., Ouweland, A. Van den, Uitterlinden, A.G., Liu, J., Lin, L.Y., Yuqing, L., Humphreys, K., Czene, K., Cox, A., Balasubramanian, S.P., Cross, S.S., Reed, M.W.R., Blows, F., Driver, K., Dunning, A., Tyrer, J., Ponder, B.A.J., Sangrajrang, S., Brennan, P., Mckay, J., Odefrey, F., Gabrieau, V., Sigurdson, A., Doody, M., Struewing, J.P., Alexander, B., Easton, D.F., Pharoah, P.D., Nordestgaard, Børge, Garcia-Closas, M., Hall, P., Nevanlinna, H., Pooley, K., Morrison, J., Richesson, D.A., Bojesen, S.E., Axelsson, C.K., Arias, J.I., Milne, R.L., Ribas, G., Gonzalez-Neira, A., Benitez, J., Zamora, P., Brauch, H., Justenhoven, C., Hamann, U., Ko, Y.D., Bruening, T., Haas, S., Dork, T., Schurmann, P., Hillemanns, P., Bogdanova, N., Bremer, M., Karstens, J.H., Fagerholm, R., Aaltonen, K., Aittomaki, K., Smitten, K. Von, Blomqvist, C., Mannermaa, A., Uusitupa, M., Eskelinen, M., Tengstrom, M., Kosma, V.M., Kataja, V., Chenevix-Trench, G., Spurdle, A.B., Beesley, J., Chen, X., Devilee, P., Asperen, C.J. Van, Jacobi, C.E., Tollenaar, R.A.E.M., Huijts, P.E.A., Klijn, J.G.M., Chang-Claude, J., Kropp, S., Slanger, T., Flesch-Janys, D., Mutschelknauss, E., Salazar, R., Wang-Gohrke, S., Couch, F., Goode, E.L., Olson, J.E., Vachon, C., Fredericksen, Z.S., Giles, G.G., Baglietto, L., Severi, G., Hopper, J.L., English, D.R., Southey, M.C., Haiman, C.A., Henderson, B.E., Kolonel, L.N., Marchand, L. Le, Stram, D.O., Hunter, D.J., Hankinson, S.E., Cox, D.G., Tamimi, R., Kraft, P., Sherman, M.E., Chanock, S.J., Lissowska, J., Brinton, L.A., Peplonska, B., Hooning, M.J., Meijers-Heijboer, H., Collee, J.M., Ouweland, A. Van den, Uitterlinden, A.G., Liu, J., Lin, L.Y., Yuqing, L., Humphreys, K., Czene, K., Cox, A., Balasubramanian, S.P., Cross, S.S., Reed, M.W.R., Blows, F., Driver, K., Dunning, A., Tyrer, J., Ponder, B.A.J., Sangrajrang, S., Brennan, P., Mckay, J., Odefrey, F., Gabrieau, V., Sigurdson, A., Doody, M., Struewing, J.P., Alexander, B., Easton, D.F., Pharoah, P.D., and Nordestgaard, Børge

Abstract

A three-stage genome-wide association study recently identified single nucleotide polymorphisms ( SNPs) in five loci ( fibroblast growth receptor 2 ( FGFR2), trinucleotide repeat containing 9 ( TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte- specific protein 1 ( LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER- positive ( per- allele OR ( 95%CI) = 1.31 (1.27-1.36)) than ER- negative (1.08 (1.03- 1.14)) disease ( P for heterogeneity = 10-(13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER- positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs ( rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER- negative disease, the strongest association being for rs3803662 in TNRC9 ( 1.14 ( 1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis ( per- allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER- positive and ER- negative disease are biologically d

Published
2008

168. Genome-wide association study identifies novel breast cancer susceptibility loci.

Author

Cox A., Farshid G., Fawcett S., Field M., Firgaira F., Fleming J., Forbes J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Haan E., Hart S., Humphrey E., Jenkins M., Kefford R., Kirk J., Kollias J., Kovalenko S., Lakhani S., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Maclurcan M., Marsh D., McKay M., Anne McLachlan S., Mitchell G., Newman B., O'Loughlin I., Osborne R., Peters L., Price M., Reeve J., Reeve T., Richards R., Rinehart G., Robinson B., Rudzki B., Salisbury E., Saunders C., Scott E., Seshadri R., Shelling A., Suthers G., Taylor D., Tennant C., Townshend S., Tyler J., Venter D., Visvader J., Walpole I., Ward R., Warner B., Warren G., Watson E., Williams R., Winship I., Bowtell D., Green A., DeFazio A., Gertig D., Webb P., Milne R., Young M.A., Harris M., Wilson J., Easton D.F., Pooley K.A., Dunning A.M., Pharoah P.D.P., Thompson D., Ballinger D.G., Struewing J.P., Morrison J., Field H., Luben R., Wareham N., Ahmed S., Healey C.S., Bowman R., Meyer K.B., Haiman C.A., Kolonel L.K., Henderson B.E., Le Marchand L., Brennan P., Sangrajrang S., Gaborieau V., Odefrey F., Shen C.-Y., Wu P.-E., Wang H.-C., Eccles D., Evans D.G., Peto J., Fletcher O., Johnson N., Seal S., Stratton M.R., Rahman N., Chenevix-Trench G., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Garcia-Closas M., Brinton L., Chanock S., Lissowska J., Peplonska B., Nevanlinna H., Fagerholm R., Eerola H., Kang D., Yoo K.-Y., Noh D.-Y., Ahn S.-H., Hunter D.J., Hankinson S.E., Cox D.G., Hall P., Wedren S., Liu J., Low Y.-L., Bogdanova N., Schurmann P., Dork T., Tollenaar R.A.E.M., Jacobi C.E., Devilee P., Klijn J.G.M., Sigurdson A.J., Doody M.M., Alexander B.H., Zhang J., Brock I.W., MacPherson G., Reed M.W.R., Couch F.J., Goode E.L., Olson J.E., Meijers-Heijboer H., Van Den Ouweland A., Uitterlinden A., Rivadeneira F., Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Hopper J., McCredie M., Southey M., Giles G., Schroen C., Justenhoven C., Brauch H., Hamann U., Ko Y.-D., Spurdle A.B., Beesley J., Chen X., Mannermaa A., Kosma V.-M., Kataja V., Hartikainen J., Day N.E., Cox D.R., Ponder B.A.J., Luccarini C., Conroy D., Shah M., Munday H., Jordan C., Perkins B., West J., Redman K., Driver K., Aghmesheh M., Amor D., Andrews L., Antill Y., Armes J., Armitage S., Arnold L., Balleine R., Begley G., Beilby J., Bennett I., Bennett B., Berry G., Blackburn A., Brennan M., Brown M., Buckley M., Burke J., Butow P., Byron K., Callen D., Campbell I., Clarke C., Colley A., Cotton D., Cui J., Culling B., Cummings M., Dawson S.-J., Dixon J., Dobrovic A., Dudding T., Edkins T., Eisenbruch M., Cox A., Farshid G., Fawcett S., Field M., Firgaira F., Fleming J., Forbes J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Haan E., Hart S., Humphrey E., Jenkins M., Kefford R., Kirk J., Kollias J., Kovalenko S., Lakhani S., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Maclurcan M., Marsh D., McKay M., Anne McLachlan S., Mitchell G., Newman B., O'Loughlin I., Osborne R., Peters L., Price M., Reeve J., Reeve T., Richards R., Rinehart G., Robinson B., Rudzki B., Salisbury E., Saunders C., Scott E., Seshadri R., Shelling A., Suthers G., Taylor D., Tennant C., Townshend S., Tyler J., Venter D., Visvader J., Walpole I., Ward R., Warner B., Warren G., Watson E., Williams R., Winship I., Bowtell D., Green A., DeFazio A., Gertig D., Webb P., Milne R., Young M.A., Harris M., Wilson J., Easton D.F., Pooley K.A., Dunning A.M., Pharoah P.D.P., Thompson D., Ballinger D.G., Struewing J.P., Morrison J., Field H., Luben R., Wareham N., Ahmed S., Healey C.S., Bowman R., Meyer K.B., Haiman C.A., Kolonel L.K., Henderson B.E., Le Marchand L., Brennan P., Sangrajrang S., Gaborieau V., Odefrey F., Shen C.-Y., Wu P.-E., Wang H.-C., Eccles D., Evans D.G., Peto J., Fletcher O., Johnson N., Seal S., Stratton M.R., Rahman N., Chenevix-Trench G., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Garcia-Closas M., Brinton L., Chanock S., Lissowska J., Peplonska B., Nevanlinna H., Fagerholm R., Eerola H., Kang D., Yoo K.-Y., Noh D.-Y., Ahn S.-H., Hunter D.J., Hankinson S.E., Cox D.G., Hall P., Wedren S., Liu J., Low Y.-L., Bogdanova N., Schurmann P., Dork T., Tollenaar R.A.E.M., Jacobi C.E., Devilee P., Klijn J.G.M., Sigurdson A.J., Doody M.M., Alexander B.H., Zhang J., Brock I.W., MacPherson G., Reed M.W.R., Couch F.J., Goode E.L., Olson J.E., Meijers-Heijboer H., Van Den Ouweland A., Uitterlinden A., Rivadeneira F., Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Hopper J., McCredie M., Southey M., Giles G., Schroen C., Justenhoven C., Brauch H., Hamann U., Ko Y.-D., Spurdle A.B., Beesley J., Chen X., Mannermaa A., Kosma V.-M., Kataja V., Hartikainen J., Day N.E., Cox D.R., Ponder B.A.J., Luccarini C., Conroy D., Shah M., Munday H., Jordan C., Perkins B., West J., Redman K., Driver K., Aghmesheh M., Amor D., Andrews L., Antill Y., Armes J., Armitage S., Arnold L., Balleine R., Begley G., Beilby J., Bennett I., Bennett B., Berry G., Blackburn A., Brennan M., Brown M., Buckley M., Burke J., Butow P., Byron K., Callen D., Campbell I., Clarke C., Colley A., Cotton D., Cui J., Culling B., Cummings M., Dawson S.-J., Dixon J., Dobrovic A., Dudding T., Edkins T., and Eisenbruch M.

Abstract

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2> 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. ©2007 Nature Publishing Group.

Published
2007

169. A role for XRCC2 gene polymorphisms in breast cancer risk and survival

Author

Lin, W.-Y., primary, Camp, N. J., additional, Cannon-Albright, L. A., additional, Allen-Brady, K., additional, Balasubramanian, S., additional, Reed, M. W. R., additional, Hopper, J. L., additional, Apicella, C., additional, Giles, G. G., additional, Southey, M. C., additional, Milne, R. L., additional, Arias-Perez, J. I., additional, Menendez-Rodriguez, P., additional, Benitez, J., additional, Grundmann, M., additional, Dubrowinskaja, N., additional, Park-Simon, T.-W., additional, Dork, T., additional, Garcia-Closas, M., additional, Figueroa, J., additional, Sherman, M., additional, Lissowska, J., additional, Easton, D. F., additional, Dunning, A. M., additional, Rajaraman, P., additional, Sigurdson, A. J., additional, Doody, M. M., additional, Linet, M. S., additional, Pharoah, P. D., additional, Schmidt, M. K., additional, and Cox, A., additional

Published
2011
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170. A polymorphism in the coding sequence of WT1 is an independent prognostic marker in 1,101 patients with lobular breast cancer.

Author

Heuser, M., primary, Damm, F., additional, Schuermann, P., additional, Zucknick, M., additional, Shah, M., additional, Harrington, P., additional, Pharoah, P., additional, Schmidt, M., additional, Broeks, A., additional, van Hien, R., additional, Tollenaar, R. A., additional, Nevanlinna, H., additional, Heikkinen, T., additional, Aittomaki, K., additional, Blomqvist, C., additional, Krauter, J., additional, Hillemanns, P., additional, Ganser, A., additional, Park-Simon, T., additional, and Dork, T., additional

Published
2011
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172. Dominant negative ATM mutations in breast cancer families

Author

Chenevix-Trench, G., Spurdle, A. B., Gatei, M., Kelly, H., Marsh, A., Chen, X., Donn, K., Cummings, M., Nyholt, D.R., Jenkins, M. A., Scott, C., Pupo, G. M., Dork, T., Bendix, R., Kirk, J., Tucker, K., McCredie, M. R., Hopper, J. L., Sambrook, J., Mann, G. J., Khanna, K. K., Chenevix-Trench, G., Spurdle, A. B., Gatei, M., Kelly, H., Marsh, A., Chen, X., Donn, K., Cummings, M., Nyholt, D.R., Jenkins, M. A., Scott, C., Pupo, G. M., Dork, T., Bendix, R., Kirk, J., Tucker, K., McCredie, M. R., Hopper, J. L., Sambrook, J., Mann, G. J., and Khanna, K. K.

Abstract

Free to read at publisher's site. BACKGROUND: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. METHODS: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. RESULTS: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. CONCLUSION: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene i

Published
2002

175. 'Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene'

Author

Osborne, L., G:santis, Schwarz, M., Klinger, K., Dork, T., Mcintosh, I., Schwartz, M., Nunes, V., MACEK JR, M., Reiss, J., Highsmith, W., Gasparini, Paolo, L., Osborne, G:santis, M., Schwarz, K., Klinger, T., Dork, I., Mcintosh, M., Schwartz, V., Nune, M., MACEK JR, J., Rei, W., Highsmith, and Gasparini, Paolo

Published
1992

176. INCIDENCE AND EXPRESSION OF THE N1303K MUTATION OF THE CYSTIC-FIBROSIS (CFTR) GENE

Author

OSBORNE, L SANTIS, G SCHWARZ, M KLINGER, K DORK, T and MCINTOSH, I SCHWARTZ, M NUNES, V MACEK, M REISS, J and HIGHSMITH, WE MCMAHON, R NOVELLI, G MALIK, N BURGER, J and ANVRET, M WALLACE, A WILLIAMS, C MATHEW, C ROZEN, R and GRAHAM, C GASPARINI, P BAL, J CASSIMAN, JJ and BALASSOPOULOU, A DAVIDOW, L RASKIN, S KALAYDJIEVA, L and KEREM, B RICHARDS, S SIMONBOUY, B SUPER, M WULBRAND, U and KESTON, M ESTIVILL, X VAVROVA, V FRIEDMAN, KJ and BARTON, D DALLAPICCOLA, B STUHRMANN, M BEARDS, F HILL, AJM PIGNATTI, PF CUPPENS, H ANGELICHEVA, D TUMMLER, B and BROCK, DJH CASALS, T MACEK, M SCHMIDTKE, J MAGEE, AC and BONIZZATO, A DEBOECK, C KUFFARDJIEVA, A HODSON, M and KNIGHT, RA

Abstract

The N1303K mutation was identified in the second nucleotide binding fold of the cystic fibrosis (CF) gene last year. We have gathered data from laboratories throughout Europe and the United States of America in order to estimate its frequency and to attempt to characterise the clinical manifestations of this mutation. N1303K, identified on 216 of nearly 15000 CF chromosomes tested, accounts for 1.5% of all CF chromosomes. The frequency of the N1303K allele varies significantly between countries and ethnic groups, being more common in Southern than in Northern Europe. This variation is independent of the DELTA-F508 allele. It was not found on UK Asian, American Black or Australian chromosomes. N1303K is associated with four different linked marker haplotypes for the polymorphic markers XV-2c, KM.19 and pMP6d-9. Ten patients are homozygous for this mutation, whereas 106 of the remainder carry one of 12 known CF mutations in the other CF allele. We classify N1303K as a “severe” mutation with respect to the pancreas, but can find no correlation between this mutation, in either the homozygous or heterozygous state, and the severity of lung disease.

Published
1992

177. Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe

Author

Dork, T, Macek, M, Mekus, F, Tummler, B, Tzountzouris, J, Casals, T, Krebsova, A, Koudova, M, Sakmaryova, I, Vavrova, V, Zemkova, D, Ginter, E, Petrova, NV, Ivaschenko, T, Baranov, V, Witt, M, Pogorzelski, A, Bal, J, Zekanowsky, C, Wagner, K, Stuhrmann, M, Bauer, I, Seydewitz, HH, Neumann, T, Jakubiczka, S, Kraus, C, Thamm, B, Nechiporenko, M, Livshits, L, Mosse, N, Tsukerman, G, Kadasi, L, Ravnik-Glavac, M, Glavac, D, Komel, R, Vouk, K, Kucinskas, V, Krumina, A, Teder, M, Kocheva, S, Efremov, GD, Onay, T, Kirdar, B, Malone, G, Schwarz, M, Zhou, ZQ, Friedman, KJ, Carles, S, Claustres, M, Bozon, D, Verlingue, C, Ferec, C, Tzetis, M, Kanavakis, E, Cuppens, H, Bombieri, C, Pignatti, PF, Sangiuolo, F, Jordanova, A, Kušić-Tišma, Jelena, Radojković, Dragica, Sertić, J, Richter, D, Rukavina, AS, Bjorck, E, Strandvik, B, Cardoso, H, Montgomery, M, Nakielna, B, Hughes, D, Estivill, X, Aznarez, I, Tullis, E, Tsui, LC, Zielenski, J, Dork, T, Macek, M, Mekus, F, Tummler, B, Tzountzouris, J, Casals, T, Krebsova, A, Koudova, M, Sakmaryova, I, Vavrova, V, Zemkova, D, Ginter, E, Petrova, NV, Ivaschenko, T, Baranov, V, Witt, M, Pogorzelski, A, Bal, J, Zekanowsky, C, Wagner, K, Stuhrmann, M, Bauer, I, Seydewitz, HH, Neumann, T, Jakubiczka, S, Kraus, C, Thamm, B, Nechiporenko, M, Livshits, L, Mosse, N, Tsukerman, G, Kadasi, L, Ravnik-Glavac, M, Glavac, D, Komel, R, Vouk, K, Kucinskas, V, Krumina, A, Teder, M, Kocheva, S, Efremov, GD, Onay, T, Kirdar, B, Malone, G, Schwarz, M, Zhou, ZQ, Friedman, KJ, Carles, S, Claustres, M, Bozon, D, Verlingue, C, Ferec, C, Tzetis, M, Kanavakis, E, Cuppens, H, Bombieri, C, Pignatti, PF, Sangiuolo, F, Jordanova, A, Kušić-Tišma, Jelena, Radojković, Dragica, Sertić, J, Richter, D, Rukavina, AS, Bjorck, E, Strandvik, B, Cardoso, H, Montgomery, M, Nakielna, B, Hughes, D, Estivill, X, Aznarez, I, Tullis, E, Tsui, LC, and Zielenski, J

Abstract

We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz.. a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2.3(21 kb), deletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2.3(21 kb) homozygotes and a comparison of compound heterozygotes for Delta F508/CFTRdele2,3(21 kb) with pairwise-matched Delta F508 homozygotes indicate that this deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%). Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype: XV-2c/KM. 19 "A" and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVSI7bCA) in all examined CFTRdele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent

Published
2000

178. Diversity of the basic defect of homozygous CFTR mutation genotypes in humans

Author

Stanke, F, primary, Ballmann, M, additional, Bronsveld, I, additional, Dork, T, additional, Gallati, S, additional, Laabs, U, additional, Derichs, N, additional, Ritzka, M, additional, Posselt, H-G, additional, Harms, H K, additional, Griese, M, additional, Blau, H, additional, Mastella, G, additional, Bijman, J, additional, Veeze, H, additional, and Tummler, B, additional

Published
2007
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181. Mutagen sensitivity of human lymphoblastoid cells with a BRCA1 mutation in comparison to ataxia telangiectasia heterozygote cells.

Author

Speit, G., Trenz, K., Schutz, P., Bendix, R., and Dork, T.

Subjects
LYMPHOBLASTOID cell lines, MUTAGENESIS, GENETIC mutation, ATAXIA telangiectasia, HETEROZYGOSITY, GEL electrophoresis
Abstract

Our previous results indicated a close relationship between the presence of a BRCA1 mutation in lymphocytes and hypersensitivity for the induction of micronuclei by gamma irradiation and hydrogen peroxide (H[sub 2] O[sub 2] ). Comparative investigations with the comet assay (single-cell gel electrophoresis) suggested a normal rate of damage removal and pointed to a disturbed fidelity of DNA repair as a direct or indirect consequence of a BRCA1 mutation. We now wanted to see whether similar results could be obtained with lymphoblastoid cell lines (LCLs) and whether such permanent cells are suitable as a model for the investigation of mechanisms involved in mutagen sensitivity. Our results show that LCLs with a BRCA1 mutation are also hypersensitive to the chromosome-damaging effects of gamma irradiation or H[sub 2] O[sub 2] , as revealed by the micronucleus test. Interestingly, LCLs heterozygous for an ataxia telangiectasia (AT) mutation have similar characteristics as BRCA1 cells with respect to the induction and repair of DNA damage induced by either gamma irradiation or H[sub 2] O[sub 2] . However, caffeine enhanced the induction of micronuclei by gamma irradiation only in normal and heterozygous AT cells but not in BRCA1 cells, thus indicating a difference in the pathways leading to mutagen sensitivity in cells with a BRCA1 or an AT mutation. Our results suggest that caffeine could be useful in discriminating AT heterozygotes from carriers of a BRCA1 mutation, as well as BRCA1 mutation carriers from normal individuals. Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Published
2000
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182. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

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.

Subjects
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.

Published
2015
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183. Risk of Ovarian Cancer and the NF- B Pathway: Genetic Association with IL1A and TNFSF10

Author

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.

Subjects
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

Published
2013
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184. The Role of KRAS rs61764370 in Invasive Epithelial Ovarian Cancer: Implications for Clinical Testing

Author

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.

Abstract

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.

Published
2011
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185. Effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other CHEK2 or BRCA1 mutations.

Author

Cybulski, C., Górski, B., Huzarski, T., Byrski, T., Gronwald, J., Dbniak, T., Wokoorczyk, D., Jakubowska, A., Serrano-Fernández, P., Dork, T., Narod, S. A., and Lubiski, J.

Subjects
BREAST cancer, DISEASE risk factors, CARCINOGENS research, CANCER, WOMEN'S health
Abstract

Background: Carriers of heterozygous mutations in CHEK2 or BRCA1 are at increased risk of breast cancer. These mutations are rare and a very small number of women in a population will carry two mutations. However, it is of interest to estimate the breast cancer risks associated with carrying two mutations because this information may be informative for genetic counsellors and may provide clues to the carcinogenic process. Methods: We genotyped 7782 Polish breast cancer patients and 6233 controls for seven founder mutations in BRCA1 and CHEK2. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the mutations, singly and in combination. Results: Of the 7782 women with breast cancer, 1091 had one mutation (14.0%) and 37 had two mutations (0.5%). Compared to controls, the odds ratio for a BRCA1 mutation in isolation was 13.1 (95% CI 8.2 to 21). The odds ratio was smaller for BRCA1 mutation carriers who also carried a CHEK2 mutation (OR 6.6, 95% CI 1.5 to 29), but the difference was not statistically significant. In contrast, the odds ratio for women who carried two CHEK2 mutations (OR 3.9, 95% CI 1.5 to 10) was greater than that for women who carried one CHEK2 mutation (OR 1.9, 95% CI 1.6 to 2.1). The odds ratio for women who carried both a truncating mutation and the missense mutation in CHEK2 was 7.0 (95% CI 0.9 to 56) and was greater than for women who carried the truncating mutation alone (OR 3.3, 95% CI 2.4 to 4.3) or the missense mutation alone (OR 1.6, 95% CI 1.4 to 1.9), but the difference was not statistically significant. Conclusion: Our study suggests that the risk of breast cancer in carriers of a deleterious CHEK2 mutation is increased if the second allele is the I157T missense variant. However, the presence of a CHEK2 mutation in women with a BRCA1 mutation may not increase their risk beyond that of the BRCA1 mutation alone. These suggestive findings need to be verified in other studies. [ABSTRACT FROM AUTHOR]

Published
2009

189. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

Author

Levi H, Carmi S, Rosset S, Yerushalmi R, Zick A, Yablonski-Peretz T, Wang Q, Bolla MK, Dennis J, Michailidou K, Lush M, Ahearn T, Andrulis IL, Anton-Culver H, Antoniou AC, Arndt V, Augustinsson A, Auvinen P, Beane Freeman L, Beckmann M, Behrens S, Bermisheva M, Bodelon C, Bogdanova NV, Bojesen SE, Brenner H, Byers H, Camp N, Castelao J, Chang-Claude J, Chirlaque MD, Chung W, Clarke C, Collee MJ, Colonna S, Couch F, Cox A, Cross SS, Czene K, Daly M, Devilee P, Dork T, Dossus L, Eccles DM, Eliassen AH, Eriksson M, Evans G, Fasching P, Fletcher O, Flyger H, Fritschi L, Gabrielson M, Gago-Dominguez M, García-Closas M, Garcia-Saenz JA, Genkinger J, Giles GG, Goldberg M, Guénel P, Hall P, Hamann U, He W, Hillemanns P, Hollestelle A, Hoppe R, Hopper J, Jakovchevska S, Jakubowska A, Jernström H, John E, Johnson N, Jones M, Vijai J, Kaaks R, Khusnutdinova E, Kitahara C, Koutros S, Kristensen V, Kurian AW, Lacey J, Lambrechts D, Le Marchand L, Lejbkowicz F, Lindblom A, Loibl S, Lori A, Lubinski J, Mannermaa A, Manoochehri M, Mavroudis D, Menon U, Mulligan A, Murphy R, Nevelsteen I, Newman WG, Obi N, O'Brien K, Offit K, Olshan A, Plaseska-Karanfilska D, Olson J, Panico S, Park-Simon TW, Patel A, Peterlongo P, Rack B, Radice P, Rennert G, Rhenius V, Romero A, Saloustros E, Sandler D, Schmidt MK, Schwentner L, Shah M, Sharma P, Simard J, Southey M, Stone J, Tapper WJ, Taylor J, Teras L, Toland AE, Troester M, Truong T, van der Kolk LE, Weinberg C, Wendt C, Yang XR, Zheng W, Ziogas A, Dunning AM, Pharoah P, Easton DF, Ben-Sachar S, Elefant N, Shamir R, and Elkon R

Subjects
Humans, Female, Genome-Wide Association Study, Jews genetics, Israel epidemiology, Genetic Predisposition to Disease, Risk Factors, Multifactorial Inheritance genetics, Transcription Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics
Abstract

Background: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women., Methods: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel., Results: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28)., Conclusions: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women., Competing Interests: Competing interests: BCAC conflict of interest: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. JV is one ofthe inventors of diagnosis and treatment of ERCC3-mutant cancer. AWK has a research funding for his institution from Myriad Genetics for an unrelated project (funding dates 2017–2019). UM has research collaborations with Mercy BioAnalytics, RNA Guardian, Dana Farber and iLOF (Intelligent Lab on Fiber). RAM is a consultant for Pharmavite., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Published
2023
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190. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.

Author

Song H, Dicks EM, Tyrer J, Intermaggio M, Chenevix-Trench G, Bowtell DD, Traficante N, Group A, Brenton J, Goranova T, Hosking K, Piskorz A, van Oudenhove E, Doherty J, Harris HR, Rossing MA, Duerst M, Dork T, Bogdanova NV, Modugno F, Moysich K, Odunsi K, Ness R, Karlan BY, Lester J, Jensen A, Krüger Kjaer S, Høgdall E, Campbell IG, Lázaro C, Pujara MA, Cunningham J, Vierkant R, Winham SJ, Hildebrandt M, Huff C, Li D, Wu X, Yu Y, Permuth JB, Levine DA, Schildkraut JM, Riggan MJ, Berchuck A, Webb PM, Group OS, Cybulski C, Gronwald J, Jakubowska A, Lubinski J, Alsop J, Harrington P, Chan I, Menon U, Pearce CL, Wu AH, de Fazio A, Kennedy CJ, Goode E, Ramus S, Gayther S, and Pharoah P

Subjects
Case-Control Studies, Female, Genetic Variation, Humans, Risk Assessment, Fanconi Anemia Complementation Group N Protein genetics, Genetic Predisposition to Disease, Ovarian Neoplasms genetics
Abstract

Purpose: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes., Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics., Results: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive., Conclusions: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Published
2021
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191. Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.

Author

Shi J, Zhang Y, Zheng W, Michailidou K, Ghoussaini M, Bolla MK, Wang Q, Dennis J, Lush M, Milne RL, Shu XO, Beesley J, Kar S, Andrulis IL, Anton-Culver H, Arndt V, Beckmann MW, Zhao Z, Guo X, Benitez J, Beeghly-Fadiel A, Blot W, Bogdanova NV, Bojesen SE, Brauch H, Brenner H, Brinton L, Broeks A, Brüning T, Burwinkel B, Cai H, Canisius S, Chang-Claude J, Choi JY, Couch FJ, Cox A, Cross SS, Czene K, Darabi H, Devilee P, Droit A, Dork T, Fasching PA, Fletcher O, Flyger H, Fostira F, Gaborieau V, García-Closas M, Giles GG, Guenel P, Haiman CA, Hamann U, Hartman M, Miao H, Hollestelle A, Hopper JL, Hsiung CN, Ito H, Jakubowska A, Johnson N, Torres D, Kabisch M, Kang D, Khan S, Knight JA, Kosma VM, Lambrechts D, Li J, Lindblom A, Lophatananon A, Lubinski J, Mannermaa A, Manoukian S, Le Marchand L, Margolin S, Marme F, Matsuo K, McLean C, Meindl A, Muir K, Neuhausen SL, Nevanlinna H, Nord S, Børresen-Dale AL, Olson JE, Orr N, van den Ouweland AMW, Peterlongo P, Putti TC, Rudolph A, Sangrajrang S, Sawyer EJ, Schmidt MK, Schmutzler RK, Shen CY, Hou MF, Shrubsole MJ, Southey MC, Swerdlow A, Teo SH, Thienpont B, Toland AE, Tollenaar RAEM, Tomlinson I, Truong T, Tseng CC, Wen W, Winqvist R, Wu AH, Yip CH, Zamora PM, Zheng Y, Floris G, Cheng CY, Hooning MJ, Martens JWM, Seynaeve C, Kristensen VN, Hall P, Pharoah PDP, Simard J, Chenevix-Trench G, Dunning AM, Antoniou AC, Easton DF, Cai Q, and Long J

Subjects
Alleles, Case-Control Studies, Female, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide, Risk, White People genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Chromosome Mapping, Chromosomes, Human, Pair 8 genetics, Genetic Variation, Quantitative Trait Loci
Abstract

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry., (© 2016 UICC.)

Published
2016
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192. Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Author

Kirchhoff T, Gaudet MM, Antoniou AC, McGuffog L, Humphreys MK, Dunning AM, Bojesen SE, Nordestgaard BG, Flyger H, Kang D, Yoo KY, Noh DY, Ahn SH, Dork T, Schürmann P, Karstens JH, Hillemanns P, Couch FJ, Olson J, Vachon C, Wang X, Cox A, Brock I, Elliott G, Reed MW, Burwinkel B, Meindl A, Brauch H, Hamann U, Ko YD, Broeks A, Schmidt MK, Van 't Veer LJ, Braaf LM, Johnson N, Fletcher O, Gibson L, Peto J, Turnbull C, Seal S, Renwick A, Rahman N, Wu PE, Yu JC, Hsiung CN, Shen CY, Southey MC, Hopper JL, Hammet F, Van Dorpe T, Dieudonne AS, Hatse S, Lambrechts D, Andrulis IL, Bogdanova N, Antonenkova N, Rogov JI, Prokofieva D, Bermisheva M, Khusnutdinova E, van Asperen CJ, Tollenaar RA, Hooning MJ, Devilee P, Margolin S, Lindblom A, Milne RL, Arias JI, Zamora MP, Benítez J, Severi G, Baglietto L, Giles GG, Spurdle AB, Beesley J, Chen X, Holland H, Healey S, Wang-Gohrke S, Chang-Claude J, Mannermaa A, Kosma VM, Kauppinen J, Kataja V, Agnarsson BA, Caligo MA, Godwin AK, Nevanlinna H, Heikkinen T, Fredericksen Z, Lindor N, Nathanson KL, Domchek SM, Loman N, Karlsson P, Stenmark Askmalm M, Melin B, von Wachenfeldt A, Hogervorst FB, Verheus M, Rookus MA, Seynaeve C, Oldenburg RA, Ligtenberg MJ, Ausems MG, Aalfs CM, Gille HJ, Wijnen JT, Gómez García EB, Peock S, Cook M, Oliver CT, Frost D, Luccarini C, Pichert G, Davidson R, Chu C, Eccles D, Ong KR, Cook J, Douglas F, Hodgson S, Evans DG, Eeles R, Gold B, Pharoah PD, Offit K, Chenevix-Trench G, and Easton DF

Subjects
Alleles, Confidence Intervals, Female, Genetic Association Studies, Heterozygote, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide genetics, Proportional Hazards Models, Receptors, Estrogen genetics, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 6 genetics, Genetic Predisposition to Disease
Abstract

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Published
2012
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193. BRCA1 and BRCA2 mutations in breast cancer patients from Saudi Arabia.

Author

El-Harith el-HA, Abdel-Hadi MS, Steinmann D, and Dork T

Subjects
Adult, Asia ethnology, Breast Neoplasms epidemiology, Female, Humans, Saudi Arabia epidemiology, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation
Abstract

Objective: The aim of this pilot study was to screen the major segments of the BRCA1 and BRCA2 genes for disease-associated mutations in Arab and Asian women with breast cancer from the Kingdom of Saudi Arabia., Methods: Deoxyribonucleic acid samples from 29 Arab women and 11 Asian women, with unilateral breast cancer were investigated for BRCA1 and BRCA2 mutations. For this purpose single strand conformation polymorphism and direct nucleotide sequencing techniques were employed. This study was carried out at King Fahad Hospital of the University, Al-Khobar, Kingdom of Saudi Arabia, during the time frame March 2000 through to August 2001., Results: One novel BRCA2 truncating mutation, the frame-shift mutation 2482delGACT, was uncovered in an Arab patient of Palestinian descent. This mutation is a 4-nucleotide deletion that creates a stop signal at codon 770 of the BRCA2 transcript. The BRCA1 disease-associated mutation Arg841Trp was detected in another Arab patient from Egypt. The clinical presentation in the 2 heterozygous carriers of these 2 mutations is described here. In addition the unclassified BRCA1 variant Phe486Leu combined with Asn550His, and the unclassified BRCA2 variant Asp1420Tyr, were identified in Arab patients. Five BRCA1 polymorphisms and 6 BRCA2 polymorphisms were detected at different allele frequencies in both mutation carriers and patients with normal genotype., Conclusion: We conclude that BRCA1 and BRCA2 mutations are likely to contribute to the pathogenesis of familial breast cancer in female patients from the Kingdom of Saudi Arabia.

Published
2002

194. Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer.

Author

Scott SP, Bendix R, Chen P, Clark R, Dork T, and Lavin MF

Subjects
Alleles, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms physiopathology, Cell Cycle Proteins, Cell Line, DNA, Complementary genetics, DNA, Neoplasm genetics, DNA-Binding Proteins, Female, Genes, Dominant, Genetic Variation, Heterozygote, Humans, In Vitro Techniques, Mutagenesis, Site-Directed, Phenotype, Transfection, Tumor Suppressor Proteins, Breast Neoplasms genetics, Mutation, Missense, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases physiology
Abstract

The human genetic disorder ataxia-telangiectasia (A-T) is characterized by hypersensitivity to ionizing radiation and an elevated risk of malignancy. Epidemiological data support an increased risk for breast and other cancers in A-T heterozygotes. However, screening breast cancer cases for truncating mutations in the ATM (A-T mutated) gene has failed largely to reveal an increased incidence in these patients. It has been hypothesized that ATM missense mutations are implicated in breast cancer, and there is some evidence to support this. The presence of a large variety of rare missense variants in addition to common polymorphisms in ATM makes it difficult to establish such a relationship by association studies. To investigate the functional significance of these changes we have introduced missense substitutions, identified in either A-T or breast cancer patients, into ATM cDNA before establishing stable cell lines to determine their effect on ATM function. Pathogenic missense mutations and neutral missense variants were distinguished initially by their capacity to correct the radiosensitive phenotype in A-T cells. Furthermore missense mutations abolished the radiation-induced kinase activity of ATM in normal control cells, caused chromosome instability, and reduced cell viability in irradiated control cells, whereas neutral variants failed to do so. Mutant ATM was expressed at the same level as endogenous protein, and interference with normal ATM function seemed to be by multimerization. This approach represents a means of identifying genuine ATM mutations and addressing the significance of missense changes in the ATM gene in a variety of cancers including breast cancer.

Published
2002
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