11 results on '"Ligtenberg, MJ"'
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2. Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88
- Author
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Ligtenberg, Mj, van der Post, R, de Voer, Rm, Kets, Cm, Jansen, Tj, Jacobs, L, Schreibelt, G, International Gastric Cancer Genetics Group (Lubinski, J, Jakubowska, A, Teodorczyk, U, Schackert, Hk, Aalfs, Cm, Genuardi, Maurizio, Gómez García, Eb, Ranzani, Gn, Molinaro, V, van Hest, Lp, Hes, Fj, Holinski-Feder, E, Ausems, Mg, Sijmons, Rh, Wagner, A, van der Kolk, Le, Pinheiro, H, Oliveira, C, Bjørnevoll, I, Vetti, Hh, van Krieken, J, ), De, Vrie, Ij, Netea, Mg, Hoogerbrugge, N, Genuardi M. (ORCID:0000-0002-7410-8351), Ligtenberg, Mj, van der Post, R, de Voer, Rm, Kets, Cm, Jansen, Tj, Jacobs, L, Schreibelt, G, International Gastric Cancer Genetics Group (Lubinski, J, Jakubowska, A, Teodorczyk, U, Schackert, Hk, Aalfs, Cm, Genuardi, Maurizio, Gómez García, Eb, Ranzani, Gn, Molinaro, V, van Hest, Lp, Hes, Fj, Holinski-Feder, E, Ausems, Mg, Sijmons, Rh, Wagner, A, van der Kolk, Le, Pinheiro, H, Oliveira, C, Bjørnevoll, I, Vetti, Hh, van Krieken, J, ), De, Vrie, Ij, Netea, Mg, Hoogerbrugge, N, and Genuardi M. (ORCID:0000-0002-7410-8351)
- Abstract
Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk.
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- 2017
3. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
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Antoniou, AC, Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, Piedmonte, M, Antoniou, AC, Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, and Piedmonte, M
- Published
- 2012
4. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
- Author
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Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, Piedmonte, M, Kirk, J, Cohn, D, Hurteau, J, Byron, J, Fiorica, J, Toland, AE, Montagna, M, Oliani, C, Imyanitov, E, Isaacs, C, Tihomirova, L, Blanco, I, Lazaro, C, Teule, A, Del Valle, J, Gayther, SA, Odunsi, K, Gross, J, Karlan, BY, Olah, E, Teo, S-H, Ganz, PA, Beattie, MS, Dorfling, CM, van Rensburg, EJ, Diez, O, Kwong, A, Schmutzler, RK, Wappenschmidt, B, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Heidemann, S, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Fiebig, B, Schaefer, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Muranen, TA, Lesperance, B, Spurdle, AB, Neuhausen, SL, Ding, YC, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Bonanni, B, Bernard, L, Dolcetti, R, Papi, L, Ottini, L, Radice, P, Greene, MH, Loud, JT, Andrulis, IL, Ozcelik, H, Mulligan, AM, Glendon, G, Thomassen, M, Gerdes, A-M, Jensen, UB, Skytte, A-B, Kruse, TA, Chenevix-Trench, G, Couch, FJ, Simard, J, Easton, DF, Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, Piedmonte, M, Kirk, J, Cohn, D, Hurteau, J, Byron, J, Fiorica, J, Toland, AE, Montagna, M, Oliani, C, Imyanitov, E, Isaacs, C, Tihomirova, L, Blanco, I, Lazaro, C, Teule, A, Del Valle, J, Gayther, SA, Odunsi, K, Gross, J, Karlan, BY, Olah, E, Teo, S-H, Ganz, PA, Beattie, MS, Dorfling, CM, van Rensburg, EJ, Diez, O, Kwong, A, Schmutzler, RK, Wappenschmidt, B, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Heidemann, S, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Fiebig, B, Schaefer, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Muranen, TA, Lesperance, B, Spurdle, AB, Neuhausen, SL, Ding, YC, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Bonanni, B, Bernard, L, Dolcetti, R, Papi, L, Ottini, L, Radice, P, Greene, MH, Loud, JT, Andrulis, IL, Ozcelik, H, Mulligan, AM, Glendon, G, Thomassen, M, Gerdes, A-M, Jensen, UB, Skytte, A-B, Kruse, TA, Chenevix-Trench, G, Couch, FJ, Simard, J, and Easton, DF
- Abstract
INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
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- 2012
5. Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
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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
6. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
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Antoniou, AC, Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, Piedmonte, M, Antoniou, AC, Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, and Piedmonte, M
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- 2012
7. Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
- Author
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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
8. Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- Author
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Ashworth, A, Maxwell, CA, Benitez, J, Gomez-Baldo, L, Osorio, A, Bonifaci, N, Fernandez-Ramires, R, Costes, SV, Guino, E, Chen, H, Evans, GJR, Mohan, P, Catala, I, Petit, A, Aguilar, H, Villanueva, A, Aytes, A, Serra-Musach, J, Rennert, G, Lejbkowicz, F, Peterlongo, P, Manoukian, S, Peissel, B, Ripamonti, CB, Bonanni, B, Viel, A, Allavena, A, Bernard, L, Radice, P, Friedman, E, Kaufman, B, Laitman, Y, Dubrovsky, M, Milgrom, R, Jakubowska, A, Cybulski, C, Gorski, B, Jaworska, K, Durda, K, Sukiennicki, G, Lubinski, J, Shugart, YY, Domchek, SM, Letrero, R, Weber, BL, Hogervorst, FBL, Rookus, MA, Collee, JM, Devilee, P, Ligtenberg, MJ, van der Luijt, RB, Aalfs, CM, Waisfisz, Q, Wijnen, J, van Roozendaal, CEP, Easton, DF, Peock, S, Cook, M, Oliver, C, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Eccles, D, Douglas, F, Brewer, C, Nevanlinna, H, Heikkinen, T, Couch, FJ, Lindor, NM, Wang, X, Godwin, AK, Caligo, MA, Lombardi, G, Loman, N, Karlsson, P, Ehrencrona, H, von Wachenfeldt, A, Barkardottir, RB, Hamann, U, Rashid, MU, Lasa, A, Caldes, T, Andres, R, Schmitt, M, Assmann, V, Stevens, K, Offit, K, Curado, J, Tilgner, H, Guigo, R, Aiza, G, Brunet, J, Castellsague, J, Martrat, G, Urruticoechea, A, Blanco, I, Tihomirova, L, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Deissler, H, Varon-Mateeva, R, Sutter, C, Niederacher, D, Imyamitov, E, Sinilnikova, OM, Stoppa-Lyonne, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, Y-J, Uhrhammer, N, Peyrat, J-P, Vennin, P, Ferrer, SF, Collonge-Rame, M-A, Mortemousque, I, Spurdle, AB, Beesley, J, Chen, X, Healey, S, Barcellos-Hoff, MH, Vidal, M, Gruber, SB, Lazaro, C, Capella, G, McGuffog, L, Nathanson, KL, Antoniou, AC, Chenevix-Trench, G, Fleisch, MC, Moreno, V, Angel Pujana, M, Ashworth, A, Maxwell, CA, Benitez, J, Gomez-Baldo, L, Osorio, A, Bonifaci, N, Fernandez-Ramires, R, Costes, SV, Guino, E, Chen, H, Evans, GJR, Mohan, P, Catala, I, Petit, A, Aguilar, H, Villanueva, A, Aytes, A, Serra-Musach, J, Rennert, G, Lejbkowicz, F, Peterlongo, P, Manoukian, S, Peissel, B, Ripamonti, CB, Bonanni, B, Viel, A, Allavena, A, Bernard, L, Radice, P, Friedman, E, Kaufman, B, Laitman, Y, Dubrovsky, M, Milgrom, R, Jakubowska, A, Cybulski, C, Gorski, B, Jaworska, K, Durda, K, Sukiennicki, G, Lubinski, J, Shugart, YY, Domchek, SM, Letrero, R, Weber, BL, Hogervorst, FBL, Rookus, MA, Collee, JM, Devilee, P, Ligtenberg, MJ, van der Luijt, RB, Aalfs, CM, Waisfisz, Q, Wijnen, J, van Roozendaal, CEP, Easton, DF, Peock, S, Cook, M, Oliver, C, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Eccles, D, Douglas, F, Brewer, C, Nevanlinna, H, Heikkinen, T, Couch, FJ, Lindor, NM, Wang, X, Godwin, AK, Caligo, MA, Lombardi, G, Loman, N, Karlsson, P, Ehrencrona, H, von Wachenfeldt, A, Barkardottir, RB, Hamann, U, Rashid, MU, Lasa, A, Caldes, T, Andres, R, Schmitt, M, Assmann, V, Stevens, K, Offit, K, Curado, J, Tilgner, H, Guigo, R, Aiza, G, Brunet, J, Castellsague, J, Martrat, G, Urruticoechea, A, Blanco, I, Tihomirova, L, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Deissler, H, Varon-Mateeva, R, Sutter, C, Niederacher, D, Imyamitov, E, Sinilnikova, OM, Stoppa-Lyonne, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, Y-J, Uhrhammer, N, Peyrat, J-P, Vennin, P, Ferrer, SF, Collonge-Rame, M-A, Mortemousque, I, Spurdle, AB, Beesley, J, Chen, X, Healey, S, Barcellos-Hoff, MH, Vidal, M, Gruber, SB, Lazaro, C, Capella, G, McGuffog, L, Nathanson, KL, Antoniou, AC, Chenevix-Trench, G, Fleisch, MC, Moreno, V, and Angel Pujana, M
- Abstract
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
- Published
- 2011
9. Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2
- Author
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Osorio, A, Milne, RL, Alonso, R, Pita, G, Peterlongo, P, Teule, A, Nathanson, KL, Domchek, SM, Rebbeck, T, Lasa, A, Konstantopoulou, I, Hogervorst, FB, Verhoef, S, van Dooren, MF, Jager, A, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Vreeswijk, M, Waisfisz, Q, Van Roozendaal, CE, Ligtenberg, MJ, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Curzon, B, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Davidson, R, Adlard, J, Eccles, D, Ong, K-R, Douglas, F, Downing, S, Brewer, C, Walker, L, Nevanlinna, H, Aittomaki, K, Couch, FJ, Fredericksen, Z, Lindor, NM, Godwin, A, Isaacs, C, Caligo, MA, Loman, N, Jernstrom, H, Barbany-Bustinza, G, Liljegren, A, Ehrencrona, H, Stenmark-Askmalm, M, Feliubadalo, L, Manoukian, S, Peissel, B, Zaffaroni, D, Bonanni, B, Fortuzzi, S, Johannsson, OT, Chenevix-Trench, G, Chen, X-C, Beesley, J, Spurdle, AB, Sinilnikova, OM, Healey, S, McGuffog, L, Antoniou, AC, Brunet, J, Radice, P, Benitez, J, Osorio, A, Milne, RL, Alonso, R, Pita, G, Peterlongo, P, Teule, A, Nathanson, KL, Domchek, SM, Rebbeck, T, Lasa, A, Konstantopoulou, I, Hogervorst, FB, Verhoef, S, van Dooren, MF, Jager, A, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Vreeswijk, M, Waisfisz, Q, Van Roozendaal, CE, Ligtenberg, MJ, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Curzon, B, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Davidson, R, Adlard, J, Eccles, D, Ong, K-R, Douglas, F, Downing, S, Brewer, C, Walker, L, Nevanlinna, H, Aittomaki, K, Couch, FJ, Fredericksen, Z, Lindor, NM, Godwin, A, Isaacs, C, Caligo, MA, Loman, N, Jernstrom, H, Barbany-Bustinza, G, Liljegren, A, Ehrencrona, H, Stenmark-Askmalm, M, Feliubadalo, L, Manoukian, S, Peissel, B, Zaffaroni, D, Bonanni, B, Fortuzzi, S, Johannsson, OT, Chenevix-Trench, G, Chen, X-C, Beesley, J, Spurdle, AB, Sinilnikova, OM, Healey, S, McGuffog, L, Antoniou, AC, Brunet, J, Radice, P, and Benitez, J
- Abstract
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.
- Published
- 2011
10. Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- Author
-
Maxwell, CA, Benitez, J, Gomez-Baldo, L, Osorio, A, Bonifaci, N, Fernandez-Ramires, R, Costes, SV, Guino, E, Chen, H, Evans, GJR, Mohan, P, Catala, I, Petit, A, Aguilar, H, Villanueva, A, Aytes, A, Serra-Musach, J, Rennert, G, Lejbkowicz, F, Peterlongo, P, Manoukian, S, Peissel, B, Ripamonti, CB, Bonanni, B, Viel, A, Allavena, A, Bernard, L, Radice, P, Friedman, E, Kaufman, B, Laitman, Y, Dubrovsky, M, Milgrom, R, Jakubowska, A, Cybulski, C, Gorski, B, Jaworska, K, Durda, K, Sukiennicki, G, Lubinski, J, Shugart, YY, Domchek, SM, Letrero, R, Weber, BL, Hogervorst, FBL, Rookus, MA, Collee, Margriet, Devilee, P, Ligtenberg, MJ, van der Luijt, RB, Aalfs, CM, Waisfisz, Q, van Wijnen, J (Juul), Roozendaal, CEP, Easton, DF, Peock, S, Cook, M, Oliver, C, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Eccles, D, Douglas, F, Brewer, C, Nevanlinna, H, Heikkinen, T, Couch, FJ, Lindor, NM, Wang, XS, Godwin, AK, Caligo, MA, Lombardi, G, Loman, N, Karlsson, P, Ehrencrona, H, von Wachenfeldt, A, Barkardottir, RB, Hamann, U, Rashid, MU, Lasa, A, Caldes, T, Andres, R, Schmitt, M, Assmann, V, Stevens, K, Offit, K, Curado, J, Tilgner, H, Guigo, R, Aiza, G, Brunet, J, Castellsague, J, Martrat, G, Urruticoechea, A, Blanco, I, Tihomirova, L, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Deissler, H, Varon-Mateeva, R, Sutter, C, Niederacher, D, Imyamitov, E, Sinilnikova, OM, Stoppa-Lyonne, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, YJ, Uhrhammer, N, Peyrat, JP, Vennin, P, Ferrer, SF, Collonge-Rame, MA, Mortemousque, I, Spurdle, AB, Beesley, J, Chen, XQ, Healey, S, Barcellos-Hoff, MH, Vidal, M, Gruber, SB, Lazaro, C (Conxi), Capella, G, McGuffog, L, Nathanson, KL, Antoniou, AC, Chenevix-Trench, G, Fleisch, MC, Moreno, V, Pujana, MA, Maxwell, CA, Benitez, J, Gomez-Baldo, L, Osorio, A, Bonifaci, N, Fernandez-Ramires, R, Costes, SV, Guino, E, Chen, H, Evans, GJR, Mohan, P, Catala, I, Petit, A, Aguilar, H, Villanueva, A, Aytes, A, Serra-Musach, J, Rennert, G, Lejbkowicz, F, Peterlongo, P, Manoukian, S, Peissel, B, Ripamonti, CB, Bonanni, B, Viel, A, Allavena, A, Bernard, L, Radice, P, Friedman, E, Kaufman, B, Laitman, Y, Dubrovsky, M, Milgrom, R, Jakubowska, A, Cybulski, C, Gorski, B, Jaworska, K, Durda, K, Sukiennicki, G, Lubinski, J, Shugart, YY, Domchek, SM, Letrero, R, Weber, BL, Hogervorst, FBL, Rookus, MA, Collee, Margriet, Devilee, P, Ligtenberg, MJ, van der Luijt, RB, Aalfs, CM, Waisfisz, Q, van Wijnen, J (Juul), Roozendaal, CEP, Easton, DF, Peock, S, Cook, M, Oliver, C, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Eccles, D, Douglas, F, Brewer, C, Nevanlinna, H, Heikkinen, T, Couch, FJ, Lindor, NM, Wang, XS, Godwin, AK, Caligo, MA, Lombardi, G, Loman, N, Karlsson, P, Ehrencrona, H, von Wachenfeldt, A, Barkardottir, RB, Hamann, U, Rashid, MU, Lasa, A, Caldes, T, Andres, R, Schmitt, M, Assmann, V, Stevens, K, Offit, K, Curado, J, Tilgner, H, Guigo, R, Aiza, G, Brunet, J, Castellsague, J, Martrat, G, Urruticoechea, A, Blanco, I, Tihomirova, L, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Deissler, H, Varon-Mateeva, R, Sutter, C, Niederacher, D, Imyamitov, E, Sinilnikova, OM, Stoppa-Lyonne, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, YJ, Uhrhammer, N, Peyrat, JP, Vennin, P, Ferrer, SF, Collonge-Rame, MA, Mortemousque, I, Spurdle, AB, Beesley, J, Chen, XQ, Healey, S, Barcellos-Hoff, MH, Vidal, M, Gruber, SB, Lazaro, C (Conxi), Capella, G, McGuffog, L, Nathanson, KL, Antoniou, AC, Chenevix-Trench, G, Fleisch, MC, Moreno, V, and Pujana, MA
- Abstract
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
- Published
- 2011
11. Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2
- Author
-
Osorio, A, Milne, RL, Alonso, R, Pita, G, Peterlongo, P, Teule, A, Nathanson, KL, Domchek, SM, Rebbeck, T, Lasa, A, Konstantopoulou, I, Hogervorst, FB, Verhoef, S, van Dooren, Marieke, Jager, Agnes, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Vreeswijk, M (Marlies), Waisfisz, Q, Van Roozendaal, CE, Ligtenberg, MJ, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Curzon, B, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Davidson, R, Adlard, J, Eccles, D, Ong, KR, Douglas, F, Downing, S, Brewer, C, Walker, L, Nevanlinna, H, Aittomaki, K, Couch, FJ, Fredericksen, Z, Lindor, NM, Godwin, A, Isaacs, C, Caligo, MA, Loman, N, Jernstrom, H, Barbany-Bustinza, G, Liljegren, A, Ehrencrona, H, Stenmark-Askmalm, M, Feliubadalo, L, Manoukian, S, Peissel, B, Zaffaroni, D, Bonanni, B, Fortuzzi, S, Johannsson, OT, Chenevix-Trench, G, Chen, XC, Beesley, J, Spurdle, AB, Sinilnikova, OM, Healey, S, McGuffog, L, Antoniou, AC, Brunet, J, Radice, P, Benitez, J, Osorio, A, Milne, RL, Alonso, R, Pita, G, Peterlongo, P, Teule, A, Nathanson, KL, Domchek, SM, Rebbeck, T, Lasa, A, Konstantopoulou, I, Hogervorst, FB, Verhoef, S, van Dooren, Marieke, Jager, Agnes, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Vreeswijk, M (Marlies), Waisfisz, Q, Van Roozendaal, CE, Ligtenberg, MJ, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Curzon, B, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Davidson, R, Adlard, J, Eccles, D, Ong, KR, Douglas, F, Downing, S, Brewer, C, Walker, L, Nevanlinna, H, Aittomaki, K, Couch, FJ, Fredericksen, Z, Lindor, NM, Godwin, A, Isaacs, C, Caligo, MA, Loman, N, Jernstrom, H, Barbany-Bustinza, G, Liljegren, A, Ehrencrona, H, Stenmark-Askmalm, M, Feliubadalo, L, Manoukian, S, Peissel, B, Zaffaroni, D, Bonanni, B, Fortuzzi, S, Johannsson, OT, Chenevix-Trench, G, Chen, XC, Beesley, J, Spurdle, AB, Sinilnikova, OM, Healey, S, McGuffog, L, Antoniou, AC, Brunet, J, Radice, P, and Benitez, J
- Abstract
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers. British Journal of Cancer (2011) 104, 1356-1361. doi:10.1038/bjc.2011.91 www.bjcancer.com Published online 22 March 2011 (C) 2011 Cancer Research UK
- Published
- 2011
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