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99 results on '"Van Der Luijt, R. B."'

8. Classification of BRCA1 missense variants of unknown clinical significance

Author

Phelan, C M, Đapić, V, Tice, B, Favis, R, Kwan, E, Barany, F, Manoukian, S, Radice, P, van der Luijt, R B, van Nesselrooij, B P M, Chenevix-Trench, G, kConFab, Caldes, T, de La Hoya, M, Lindquist, S, Tavtigian, S V, Goldgar, D, Borg, Å, Narod, S A, and Monteiro, A N A

Published
2005

10. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Ferreira, M. A. (Manuel A.), Gamazon, E. R. (Eric R.), Al-Ejeh, F. (Fares), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Asseryanis, E. (Ella), Azzollini, J. (Jacopo), Balmana, J. (Judith), Barnes, D. R. (Daniel R.), Barrowdale, D. (Daniel), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campa, D. (Daniele), Campbell, I. (Ian), Canzian, F. (Federico), Carter, J. (Jonathan), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), de la Hoya, M. (Miguel), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Doerk, T. (Thilo), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P. A. (Peter A.), Fletcher, O. (Olivia), Flyger, H. (Henrik), Friedman, E. (Eitan), Frost, D. (Debra), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Ganz, P. A. (Patricia A.), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F. B. (Frans B. L.), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Hulick, P. J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. A. (Paul A.), Janavicius, R. (Ramunas), Jankowitz, R. C. (Rachel C.), John, E. M. (Esther M.), Johnson, N. (Nichola), Joseph, V. (Vijai), Karlan, B. Y. (Beth Y.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Ko, Y.-D. (Yon-Dschun), Jones, M. E. (Michael E.), Konstantopoulou, I. (Irene), Kristensen, V. N. (Vessela N.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lazaro, C. (Conxi), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, S. (Sara), Long, J. (Jirong), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Maurer, T. (Tabea), Mavroudis, D. (Dimitrios), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Pedersen, I. S. (Inge Sokilde), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Presneau, N. (Nadege), Radice, P. (Paolo), Rantala, J. (Johanna), Rennert, G. (Gad), Risch, H. A. (Harvey A.), Saloustros, E. (Emmanouil), Sanden, K. (Kristin), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C. F. (Christian F.), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Spurdle, A. B. (Amanda B.), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Teule, A. (Alex), Thomassen, M. (Mads), Thoene, K. (Kathrin), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Truong, T. (Therese), Tung, N. (Nadine), Vachon, C. M. (Celine M.), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Rensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Viel, A. (Alessandra), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weitzel, J. N. (Jeffrey N.), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Kraft, P. (Peter), Antoniou, A. C. (Antonis C.), Zheng, W. (Wei), Easton, D. F. (Douglas F.), Milne, R. L. (Roger L.), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), Arnold, N. (Norbert), Auber, B. (Bernd), Bogdanova-Markov, N. (Nadja), Borde, J. (Julika), Caliebe, A. (Almuth), Ditsch, N. (Nina), Dworniczak, B. (Bernd), Engert, S. (Stefanie), Faust, U. (Ulrike), Gehrig, A. (Andrea), Hahnen, E. (Eric), Hauke, J. (Jan), Hentschel, J. (Julia), Herold, N. (Natalie), Honisch, E. (Ellen), Just, W. (Walter), Kast, K. (Karin), Larsen, M. (Mirjam), Lemke, J. (Johannes), . (), Niederacher, D. (Dieter), Ott, C.-E. (Claus-Eric), Platzer, K. (Konrad), Pohl-Rescigno, E. (Esther), Ramser, J. (Juliane), Rhiem, K. (Kerstin), Steinemann, D. (Doris), Sutter, C. (Christian), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Weber, B. H. (Bernhard H. F.), Prieur, F. (Fabienne), Pujol, P. (Pascal), Sagne, C. (Charlotte), Sevenet, N. (Nicolas), Sobol, H. (Hagay), Sokolowska, J. (Johanna), Stoppa-Lyonnet, D. (Dominique), Venat-Bouvet, L. (Laurence), Adlard, J. (Julian), Ahmed, M. (Munaza), Barwell, J. (Julian), Brady, A. (Angela), Brewer, C. (Carole), Cook, J. (Jackie), Davidson, R. (Rosemarie), Donaldson, A. (Alan), Eason, J. (Jacqueline), Eeles, R. (Ros), Evans, D. G. (D. Gareth), Gregory, H. (Helen), Hanson, H. (Helen), Henderson, A. (Alex), Hodgson, S. (Shirley), Izatt, L. (Louise), Kennedy, M. J. (M. John), Lalloo, F. (Fiona), Miller, C. (Clare), Morrison, P. J. (Patrick J.), Ong, K.-r. (Kai-ren), Perkins, J. (Jo), Porteous, M. E. (Mary E.), Rogers, M. T. (Mark T.), Side, L. E. (Lucy E.), Snape, K. (Katie), Walker, L. (Lisa), Harrington, P. A. (Patricia A.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Rookus, M. A. (Matti A.), Seynaeve, C. M. (Caroline M.), van der Baan, F. H. (Frederieke H.), van der Hout, A. H. (Annemieke H.), van der Kolk, L. E. (Lizet E.), van der Luijt, R. B. (Rob B.), van Deurzen, C. H. (Carolien H. M.), van Doorn, H. C. (Helena C.), van Engelen, K. (Klaartje), van Hest, L. (Liselotte), van Os, T. A. (Theo A. M.), Verhoef, S. (Senno), Vogel, M. J. (Maartje J.), Wijnen, J. T. (Juul T.), Miron, A. (Alexander), Kapuscinski, M. (Miroslav), Bane, A. (Anita), Ross, E. (Eric), Buys, S. S. (Saundra S.), Conner, T. A. (Thomas A.), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, S. C. (Soon C.), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), Yip, D. (Desmond), Ferreira, M. A. (Manuel A.), Gamazon, E. R. (Eric R.), Al-Ejeh, F. (Fares), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Asseryanis, E. (Ella), Azzollini, J. (Jacopo), Balmana, J. (Judith), Barnes, D. R. (Daniel R.), Barrowdale, D. (Daniel), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campa, D. (Daniele), Campbell, I. (Ian), Canzian, F. (Federico), Carter, J. (Jonathan), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), de la Hoya, M. (Miguel), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Doerk, T. (Thilo), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P. A. (Peter A.), Fletcher, O. (Olivia), Flyger, H. (Henrik), Friedman, E. (Eitan), Frost, D. (Debra), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Ganz, P. A. (Patricia A.), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F. B. (Frans B. L.), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Hulick, P. J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. A. (Paul A.), Janavicius, R. (Ramunas), Jankowitz, R. C. (Rachel C.), John, E. M. (Esther M.), Johnson, N. (Nichola), Joseph, V. (Vijai), Karlan, B. Y. (Beth Y.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Ko, Y.-D. (Yon-Dschun), Jones, M. E. (Michael E.), Konstantopoulou, I. (Irene), Kristensen, V. N. (Vessela N.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lazaro, C. (Conxi), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, S. (Sara), Long, J. (Jirong), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Maurer, T. (Tabea), Mavroudis, D. (Dimitrios), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Pedersen, I. S. (Inge Sokilde), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Presneau, N. (Nadege), Radice, P. (Paolo), Rantala, J. (Johanna), Rennert, G. (Gad), Risch, H. A. (Harvey A.), Saloustros, E. (Emmanouil), Sanden, K. (Kristin), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C. F. (Christian F.), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Spurdle, A. B. (Amanda B.), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Teule, A. (Alex), Thomassen, M. (Mads), Thoene, K. (Kathrin), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Truong, T. (Therese), Tung, N. (Nadine), Vachon, C. M. (Celine M.), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Rensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Viel, A. (Alessandra), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weitzel, J. N. (Jeffrey N.), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Kraft, P. (Peter), Antoniou, A. C. (Antonis C.), Zheng, W. (Wei), Easton, D. F. (Douglas F.), Milne, R. L. (Roger L.), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), Arnold, N. (Norbert), Auber, B. (Bernd), Bogdanova-Markov, N. (Nadja), Borde, J. (Julika), Caliebe, A. (Almuth), Ditsch, N. (Nina), Dworniczak, B. (Bernd), Engert, S. (Stefanie), Faust, U. (Ulrike), Gehrig, A. (Andrea), Hahnen, E. (Eric), Hauke, J. (Jan), Hentschel, J. (Julia), Herold, N. (Natalie), Honisch, E. (Ellen), Just, W. (Walter), Kast, K. (Karin), Larsen, M. (Mirjam), Lemke, J. (Johannes), . (), Niederacher, D. (Dieter), Ott, C.-E. (Claus-Eric), Platzer, K. (Konrad), Pohl-Rescigno, E. (Esther), Ramser, J. (Juliane), Rhiem, K. (Kerstin), Steinemann, D. (Doris), Sutter, C. (Christian), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Weber, B. H. (Bernhard H. F.), Prieur, F. (Fabienne), Pujol, P. (Pascal), Sagne, C. (Charlotte), Sevenet, N. (Nicolas), Sobol, H. (Hagay), Sokolowska, J. (Johanna), Stoppa-Lyonnet, D. (Dominique), Venat-Bouvet, L. (Laurence), Adlard, J. (Julian), Ahmed, M. (Munaza), Barwell, J. (Julian), Brady, A. (Angela), Brewer, C. (Carole), Cook, J. (Jackie), Davidson, R. (Rosemarie), Donaldson, A. (Alan), Eason, J. (Jacqueline), Eeles, R. (Ros), Evans, D. G. (D. Gareth), Gregory, H. (Helen), Hanson, H. (Helen), Henderson, A. (Alex), Hodgson, S. (Shirley), Izatt, L. (Louise), Kennedy, M. J. (M. John), Lalloo, F. (Fiona), Miller, C. (Clare), Morrison, P. J. (Patrick J.), Ong, K.-r. (Kai-ren), Perkins, J. (Jo), Porteous, M. E. (Mary E.), Rogers, M. T. (Mark T.), Side, L. E. (Lucy E.), Snape, K. (Katie), Walker, L. (Lisa), Harrington, P. A. (Patricia A.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Rookus, M. A. (Matti A.), Seynaeve, C. M. (Caroline M.), van der Baan, F. H. (Frederieke H.), van der Hout, A. H. (Annemieke H.), van der Kolk, L. E. (Lizet E.), van der Luijt, R. B. (Rob B.), van Deurzen, C. H. (Carolien H. M.), van Doorn, H. C. (Helena C.), van Engelen, K. (Klaartje), van Hest, L. (Liselotte), van Os, T. A. (Theo A. M.), Verhoef, S. (Senno), Vogel, M. J. (Maartje J.), Wijnen, J. T. (Juul T.), Miron, A. (Alexander), Kapuscinski, M. (Miroslav), Bane, A. (Anita), Ross, E. (Eric), Buys, S. S. (Saundra S.), Conner, T. A. (Thomas A.), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, S. C. (Soon C.), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), and Yip, D. (Desmond)

Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Published
2019

15. Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study

Author

Schrijver, Lieske H., Olsson, Hakan, Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David E., Kast, Karin, Engel, Christoph, Mooij, Thea M., Adlard, Julian, Barrowdale, Daniel, Davidson, Rosemarie, Eeles, Ros, Ellis, Steve, Evans, D. Gareth, Frost, Debra, Izatt, Louise, Porteous, Mary E., Side, Lucy E., Walker, Lisa, Berthet, Pascaline, Bonadona, Val Erie, Leroux, Dominique, Mouret-Fourme, Emmanuelle, Venat-Bouvet, Laurence, Buys, Saundra S., Southey, Melissa C., John, Esther M., Chung, Wendy K., Daly, Mary B., Bane, Anita, van Asperen, Christi J., Garcia, Encarna B. Gomez, Mourits, Marian J. E., Roos-Blom, Marie-Jose, Friedlander, Michael L., McLachlan, Sue-Anne, Singer, Christian F., Foretova, Lenka, Gerdes, Anne-Marie, Caldes, Trinidad, Olah, Edith, Jakubowska, Anna, Nogues, Catherine, Andrieu, Nadine, Easton, Douglas F., van Leeuwen, Flora E., Hopper, John L., Milne, Roger L., Antoniou, Antonis C., Rookus, Matti A., Rookus, M. A., Hogervorst, F. B. L., van Leeuwen, F. E., Adank, M. A., Schmidt, M. K., Russell, N. S., de Lange, J. L., Wijnands, R., Jenner, D. J., Collee, J. M., van den Ouweland, A. M. W., Hooning, M. J., Seynaeve, C., van Deurzen, C. H. M., Obdeijn, I. M., van Asperen, C. J., Wijnen, J. T., Tollenaar, R. A. E. M., Devilee, P., van Cronenburg, T. C. T. E. F., Kets, C. M., Mensenkamp, A. R., Ausems, M. G. E. M., van der Luijt, R. B., van der Pol, C. C., Aalfs, C. M., Meijers-Heijboer, H. E. J., van Os, T. A. M., van Engelen, K., Gille, J. J. P., Waisfisz, Q., Gomez-Garcia, E. B., Blok, M. J., Oosterwijk, J. C., van der Hout, A. H., Mourits, M. J., de Bock, G. H., Siesling, S., Verloop, J., Overbeek, L. I. H., Schrijver, Lieske H., Olsson, Hakan, Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David E., Kast, Karin, Engel, Christoph, Mooij, Thea M., Adlard, Julian, Barrowdale, Daniel, Davidson, Rosemarie, Eeles, Ros, Ellis, Steve, Evans, D. Gareth, Frost, Debra, Izatt, Louise, Porteous, Mary E., Side, Lucy E., Walker, Lisa, Berthet, Pascaline, Bonadona, Val Erie, Leroux, Dominique, Mouret-Fourme, Emmanuelle, Venat-Bouvet, Laurence, Buys, Saundra S., Southey, Melissa C., John, Esther M., Chung, Wendy K., Daly, Mary B., Bane, Anita, van Asperen, Christi J., Garcia, Encarna B. Gomez, Mourits, Marian J. E., Roos-Blom, Marie-Jose, Friedlander, Michael L., McLachlan, Sue-Anne, Singer, Christian F., Foretova, Lenka, Gerdes, Anne-Marie, Caldes, Trinidad, Olah, Edith, Jakubowska, Anna, Nogues, Catherine, Andrieu, Nadine, Easton, Douglas F., van Leeuwen, Flora E., Hopper, John L., Milne, Roger L., Antoniou, Antonis C., Rookus, Matti A., Rookus, M. A., Hogervorst, F. B. L., van Leeuwen, F. E., Adank, M. A., Schmidt, M. K., Russell, N. S., de Lange, J. L., Wijnands, R., Jenner, D. J., Collee, J. M., van den Ouweland, A. M. W., Hooning, M. J., Seynaeve, C., van Deurzen, C. H. M., Obdeijn, I. M., van Asperen, C. J., Wijnen, J. T., Tollenaar, R. A. E. M., Devilee, P., van Cronenburg, T. C. T. E. F., Kets, C. M., Mensenkamp, A. R., Ausems, M. G. E. M., van der Luijt, R. B., van der Pol, C. C., Aalfs, C. M., Meijers-Heijboer, H. E. J., van Os, T. A. M., van Engelen, K., Gille, J. J. P., Waisfisz, Q., Gomez-Garcia, E. B., Blok, M. J., Oosterwijk, J. C., van der Hout, A. H., Mourits, M. J., de Bock, G. H., Siesling, S., Verloop, J., and Overbeek, L. I. H.

Abstract

Background: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. Methods: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. Results: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). Conclusions: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and non-hormonal contraceptive methods should be discussed.

Published
2018

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

Author

Gaudet, Mia M., Kuchenbaecker, Karoline B., Vijai, Joseph, Klein, Robert J., Kirchhoff, Tomas, McGuffog, Lesley, Barrowdale, Daniel, Dunning, Alison M., Lee, Andrew, Dennis, Joe, Healey, Sue, Dicks, Ed, Soucy, Penny, Sinilnikova, Olga M., Pankratz, Vernon S., Wang, Xianshu, Eldridge, Ronald C., Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Hogervorst, Frans B.L., Peock, Susan, Stoppa-Lyonnet, Dominique, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Peterlongo, Paolo, Schmutzler, Rita K., Nathanson, Katherine L., Piedmonte, Marion, Singer, Christian F., Thomassen, Mads, Sokolowska, Johanna, Bronner, Myriam, Hansen, Thomas V.O., Neuhausen, Susan L., Blanco, Ignacio, Greene, Mark H., Garber, Judith, Weitzel, Jeffrey N., Andrulis, Irene L., Goldgar, David E., D'Andrea, Emma, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, van Rensburg, Elizabeth J., Arason, Adalgeir, Rennert, Gad, van den Ouweland, Ans M.W., van der Hout, Annemarie H., Kets, Carolien M., Aalfs, Cora M., Wijnen, Juul T., Ausems, Margreet G.E.M., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Jacobs, Chris, Adlard, Julian, Tischkowitz, Marc, Porteous, Mary, Damiola, Francesca, Golmard, Lisa, Barjhoux, Laure, Longy, Michel, Belotti, Muriel, Ferrer, Sandra Fert, Mazoyer, Sylvie, Spurdle, Amanda B., Manoukian, Siranoush, Barile, Monica, Genuardi, Maurizio, Arnold, Norbert, Meindl, Alfons, Sutter, Christian, Wappenschmidt, Barbara, Domchek, Susan M., Pfeiler, Georg, Friedman, Eitan, Jensen, Uffe Birk, Robson, Mark, Shah, Sohela, Lazaro, Conxi, Mai, Phuong L., Benitez, Javier, Southey, Melissa C., Schmidt, M. K., Fasching, Peter A., Peto, Julian, Humphreys, Manjeet K., Wang, Qin, Michailidou, Kyriaki, Sawyer, Elinor J., Burwinkel, Barbara, Guénel, Pascal, Bojesen, Stig E., Milne, Roger L., Brenner, Hermann, Lochmann, Magdalena, Brauch, Hiltrud, Ko, Yon Dschun, Baisch, Christian, Fischer, Hand Peter, Bruening, Thomas, Pesch, Beate, Rabstein, Sylvia, Spickenheuer, Anne, Aittomäki, Kristiina, Dörk, Thilo, Margolin, Sara, Mannermaa, Arto, Lambrechts, Diether, Chang-Claude, Jenny, Radice, Paolo, Giles, Graham G., Haiman, Christopher A., Winqvist, Robert, Devillee, Peter, García-Closas, Montserrat, Schoof, Nils, Hooning, M. J., Cox, Angela, Pharoah, Paul D.P., Jakubowska, Anna, Orr, Nick, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Hall, Per, Couch, Fergus J., Simard, Jacques, Altshuler, David, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Offit, Kenneth, Rookus, M. A., van Leeuwen, F. E., Verhoef, S., de Lange, J. L., Collée, J. M., Seynaeve, C., van Deurzen, C. H.M., van Asperen, C. J., Tollenaar, R. A., Devilee, P., van Cronenburg, T. C.T.E.F., Mensenkamp, A. R., van der Luijt, R. B., van Os, T. A.M., Gille, J. J.P., Waisfisz, Q., Meijers-Heijboer, H. E.J., Gómez-Garcia, E. B., Blok, M. J., Oosterwijk, J. C., Mourits, M. J., de Bock, G. H., Vasen, H. F., Miedzybrodzka, Zosia, Gregory, Helen, Morrison, Patrick, Jeffers, Lisa, Cole, Trevor, Ong, Kai ren, Hoffman, Jonathan, Donaldson, Alan, James, Margaret, Paterson, Joan, Taylor, Amy, Murray, Alexandra, Rogers, Mark T., McCann, Emma, Kennedy, M. John, Barton, David, Drummond, Sarah, Brewer, Carole, Kivuva, Emma, Searle, Anne, Goodman, Selina, Hill, Kathryn, Davidson, Rosemarie, Murday, Victoria, Bradshaw, Nicola, Snadden, Lesley, Longmuir, Mark, Watt, Catherine, Gibson, Sarah, Haque, Eshika, Tobias, Ed, Duncan, Alexis, Izatt, Louise, Langman, Caroline, Brady, Angela, Dorkins, Huw, Melville, Athalie, Randhawa, Kashmir, Barwell, Julian, Serra-Feliu, Gemma, Ellis, Ian, Houghton, Catherine, Lalloo, Fiona, Taylor, Jane, Side, Lucy, Male, Alison, Berlin, Cheryl, Eason, Jacqueline, Douglas, Fiona, Claber, Oonagh, Collier, Rebecca, Jobson, Irene, Walker, Lisa, McLeod, Diane, Durell, Sarah, Stayner, Barbara, Eeles, Rosalind A., Shanley, Susan, Rahman, Nazneen, Houlston, Richard, Bancroft, Elizabeth, Page, Elizabeth, Ardern-Jones, Audrey, Kohut, Kelly, Wiggins, Jennifer, Castro, Elena, Killick, Emma, Martin, Sue, Rea, Gillian, Kulkarni, Anjana, Cook, Jackie, Quarrell, Oliver, Bardsley, Cathryn, Hodgson, Shirley, Goff, Sheila, Brice, Glen, Winchester, Lizzie, Eddy, Charlotte, Tripathi, Vishakha, Attard, Virginia, Lehmann, Anna, Eccles, Diana, Lucassen, Anneke, Crawford, Gillian, McBride, Donna, Smalley, Sarah, Sinilnikova, Olga, Verny-Pierre, Carole, Giraud, Sophie, Léone, Mélanie, Gauthier-Villars, Marion, Buecher, Bruno, Houdayer, Claude, Moncoutier, Virginie, Tirapo, Carole, de Pauw, Antoine, Bressac-de-Paillerets, Brigitte, Caron, Olivier, Bignon, Yves Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Handallou, Sandrine, Hardouin, Agnés, Berthet, Pascaline, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Coupier, Isabelle, Pujol, Pascal, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Vennin, Philippe, Adenis, Claude, Rouleau, Etienne, Lidereau, Rosette, Demange, Liliane, Nogues, Catherine, Muller, Danièle, Fricker, Jean Pierre, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Dreyfus, Hélène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Frénay, Marc, Vénat-Bouvet, Laurence, Delnatte, Capucine, Mortemousque, Isabelle, Lynch, Henry T., Snyder, Carrie L., Clinical Genetics, Medical Oncology, Human Genetics, Human genetics, EMGO - Quality of care, Anesthesiology, CCA - Oncogenesis, CCA - Cancer biology and immunology, Epidemiology and Data Science, Department of Obstetrics and Gynecology, Clinicum, and Department of Medical and Clinical Genetics

Subjects
Cancer Research, SUSCEPTIBILITY ALLELES, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], QH426-470, Settore MED/03 - GENETICA MEDICA, Genoma humà, SUBTYPES, Breast cancer, 0302 clinical medicine, Risk Factors, CDKN2A, Genotype, BRCA2 MUTATION CARRIERS, Malalties hereditàries, GWAS, skin and connective tissue diseases, Genetics (clinical), POPULATION, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, COMMON VARIANTS, genetic modifiers, BRCA2, cancer risk, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, Genetic diseases, Adult, Heterozygote, Medizinische Fakultät -ohne weitere Spezifikation, education, Population, Breast Neoplasms, Single-nucleotide polymorphism, Locus (genetics), Human chromosomes, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, BRCA2-specific modifier locus at 6p24, Càncer de mama, 03 medical and health sciences, TRANSCRIPTION FACTOR AP-2, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Allele, GENOME-WIDE ASSOCIATION, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, BRCA2 Protein, Cromosomes humans, Human genome, Hereditary cancer and cancer-related syndromes [ONCOL 1], CONSORTIUM, medicine.disease, Mutation, 3111 Biomedicine, ZNF365, Genome-Wide Association Study
Abstract

Contains fulltext : 118578.pdf (Publisher’s version ) (Open Access) Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9x10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013

17. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author

Couch, Fergus J., Xianshu, Wang, Lesley, Mcguffog, Andrew, Lee, Curtis, Olswold, Kuchenbaecker, Karoline B., Penny, Soucy, Zachary, Fredericksen, Daniel, Barrowdale, Joe, Dennis, Gaudet, Mia M., Dicks, Ed, Matthew, Kosel, Sue, Healey, Sinilnikova, Olga M., Adam, Lee, François, Bacot, Daniel, Vincent, Hogervorst, Frans B. L., Susan, Peock, Dominique Stoppa Lyonnet, Anna, Jakubowska, Paolo, Radice, Rita Katharina Schmutzler, Domchek, S. M., Piedmonte, M., Singer, C. F., Friedman, E., Thomassen, M., Hansen, T. V. O., Neuhausen, S. L., Szabo, C. I., Blanco, I., Greene, M. H., Karlan, B. Y., Garber, J., Phelan, C. M., Weitzel, J. N., Montagna, M., Olah, E., Andrulis, I. L., Godwin, A. K., Yannoukakos, D., Goldgar, D. E., Caldes, T., Nevanlinna, H., Osorio, A., Terry, M. B., Daly, M. B., Van Rensburg, E. J., Hamann, U., Ramus, S. J., Ewart Toland, A., Caligo, M. A., Olopade, O. I., Tung, N., Claes, K., Beattie, M. S., Southey, M. C., Imyanitov, E. N., Tischkowitz, M., Janavicius, R., John, E. M., Kwong, A., Diez, O., Balmana, J., Barkardottir, R. B., Arun, B. K., Rennert, G., Teo, S. H., Ganz, P. A., Campbell, I., Van Der Hout, A. H., Van Deurzen, C. H. M., Seynaeve, C., Gomez Garcia, E. B., Van Leeuwen, F. E., Meijers Heijboer, H. E. J., Gille, J. J. P., Ausems, M. G. E. M., Blok, M. J., Ligtenberg, M. J. L., Rookus, M. A., Devilee, P., Verhoef, S., Van Os, T. A. M., Wijnen, J. T., Frost, D., Ellis, S., Fineberg, E., Platte, R., Evans, D. G., Izatt, L., Eeles, R. A., Adlard, J., Eccles, D. M., Cook, J., Brewer, C., Douglas, F., Hodgson, S., Morrison, P. J., Side, L. E., Donaldson, A., Houghton, C., Rogers, M. T., Dorkins, H., Eason, J., Gregory, H., Mccann, E., Murray, A., Calender, A., Hardouin, A., Berthet, P., Delnatte, C., Nogues, C., Lasset, C., Houdayer, C., Leroux, D., Rouleau, E., Prieur, F., Damiola, F., Sobol, H., Coupier, I., Venat Bouvet, L., Castera, L., Gauthier Villars, M., Leone, M., Pujol, P., Mazoyer, S., Bignon, Y. J., Zlowocka Perlowska, E., Gronwald, J., Lubinski, J., Durda, K., Jaworska, K., Huzarski, T., Spurdle, A. B., Viel, A., Peissel, B., Bonanni, B., Melloni, G., Ottini, Laura, Papi, L., Varesco, L., Tibiletti, M. G., Peterlongo, P., Volorio, S., Manoukian, S., Pensotti, V., Arnold, N., Engel, C., Deissler, H., Gadzicki, D., Gehrig, A., Kast, K., Rhiem, K., Meindl, A., Niederacher, D., Ditsch, N., Plendl, H., Preisler Adams, S., Engert, S., Sutter, C., Varon Mateeva, R., Wappenschmidt, B., Weber, B. H. F., Arver, B., Stenmark Askmalm, M., Loman, N., Rosenquist, R., Einbeigi, Z., Nathanson, K. L., Rebbeck, T. R., Blank, S. V., Cohn, D. E., Rodriguez, G. C., Small, L., Friedlander, M., Bae Jump, V. L., Fink Retter, A., Rappaport, C., Gschwantler Kaulich, D., Pfeiler, G., Tea, M. K., Lindor, N. M., Kaufman, B., Shimon Paluch, S., Laitman, Y., Skytte, A. B., Gerdes, A. M., Pedersen, I. S., Moeller, S. T., Kruse, T. A., Jensen, U. B., Vijai, J., Sarrel, K., Robson, M., Kauff, N., Mulligan, A. M., Glendon, G., Ozcelik, H., Ejlertsen, B., Nielsen, F. C., Jonson, L., Andersen, M. K., Ding, Y. C., Steele, L., Foretova, L., Teule, A., Lazaro, C., Brunet, J., Pujana, M. A., Mai, P. L., Loud, J. T., Walsh, C., Lester, J., Orsulic, S., Narod, S. A., Herzog, J., Sand, S. R., Tognazzo, S., Agata, S., Vaszko, T., Weaver, J., Stavropoulou, A. V., Buys, S. S., Romero, A., De La Hoya, M., Aittomaki, K., Muranen, T. A., Duran, M., Chung, W. K., Lasa, A., Dorfling, C. M., Miron, A., Benitez, J., Senter, L., Huo, D., Chan, S. B., Sokolenko, A. P., Chiquette, J., Tihomirova, L., Friebel, T. M., Agnarsson, B. A., K. H., Lu, Lejbkowicz, F., James, P. A., Hall, P., Dunning, A. M., Tessier, D., Cunningham, J., Slager, S. L., Wang, C., Hart, S., Stevens, K., Simard, J., Pastinen, T., Pankratz, V. S., Offit, K., Easton, D. F., Chenevix Trench, G., Antoniou, A. C., Thorne, H., Niedermayr, E., Borg, A., Olsson, H., Jernstrom, H., Henriksson, K., Harbst, K., Soller, M., Kristoffersson, U., Ofverholm, A., Nordling, M., Karlsson, P., Von Wachenfeldt, A., Liljegren, A., Lindblom, A., Bustinza, G. B., Rantala, J., Melin, B., Ardnor, C. E., Emanuelsson, M., Ehrencrona, H., Pigg, M. H., Liedgren, S., Hogervorst, F. B. L., Schmidt, M. K., De Lange, J., Collee, J. M., Van Den Ouweland, A. M. W., Hooning, M. J., Van Asperen, C. J., Tollenaar, R. A., Van Cronenburg, T. C. T. E. F., Kets, C. M., Mensenkamp, A. R., Van Der Luijt, R. B., Aalfs, C. M., Waisfisz, Q., Oosterwijk, J. C., Van Der Hout, H., Mourits, M. J., De Bock, G. H., Peock, S., Miedzybrodzka, Z., Morrison, P., Jeffers, L., Cole, T., Ong, K. R., Hoffman, J., James, M., Paterson, J., Taylor, A., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Kivuva, E., Searle, A., Goodman, S., Hill, K., Davidson, R., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Brady, A., Melville, A., Randhawa, K., Barwell, J., Serra Feliu, G., Ellis, I., Lalloo, F., Taylor, J., Side, L., Male, A., Berlin, C., Collier, R., Claber, O., Jobson, I., Walker, L., Mcleod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Stormorken, A., Bancroft, E., Page, E., Ardern Jones, A., Kohut, K., Wiggins, J., Castro, E., Killick, E., Martin, S., Rea, G., Kulkarni, A., Quarrell, O., Bardsley, C., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Lehmann, A., Eccles, D., Lucassen, A., Crawford, G., Mcbride, D., Smalley, S., Sinilnikova, O., Barjhoux, L., Verny Pierre, C., Giraud, S., Stoppa Lyonnet, D., Buecher, B., Moncoutier, V., Belotti, M., Tirapo, C., De Pauw, A., Bressac De Paillerets, B., Caron, O., Uhrhammer, N., Bonadona, V., Handallou, S., Bourdon, V., Noguchi, T., Remenieras, A., Eisinger, F., Peyrat, J. P., Fournier, J., Revillion, F., Vennin, P., Adenis, C., Lidereau, R., Demange, L., Muller, D., Fricker, J. P., Barouk Simonet, E., Bonnet, F., Bubien, V., Sevenet, N., Longy, M., Toulas, C., Guimbaud, R., Gladieff, L., Feillel, V., Dreyfus, H., Rebischung, C., Peysselon, M., Coron, F., Faivre, L., Lebrun, M., Kientz, C., Ferrer, S. F., Frenay, M., Mortemousque, I., Coulet, F., Colas, C., Soubrier, F., Sokolowska, J., Bronner, M., Lynch, H. T., Snyder, C. L., Angelakos, M., Maskiell, J., Dite, G., MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - School for Oncology and Reproduction, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Kastler Brossel (LKB (Jussieu)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Generalitat de Catalunya, Asociación Española Contra el Cáncer, Fundación Ramón Areces, Instituto de Salud Carlos III, Clinical Genetics, Pathology, Medical Oncology, Pediatric Surgery, Department of Obstetrics and Gynecology, Clinicum, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Epidemiology and Data Science, Human genetics, CCA - Oncogenesis, Universitat de Barcelona, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, and Human Genetics

Subjects
SELECTION, Oncology, Cancer Research, Medicin och hälsovetenskap, endocrine system diseases, [SDV]Life Sciences [q-bio], 610 Medizin, Càncer d'ovari, SUSCEPTIBILITY ALLELES, MODIFIERS, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Genome-wide association study, QH426-470, Medical and Health Sciences, SUBTYPES, Breast cancer, 0302 clinical medicine, Human genetics, 3123 Gynaecology and paediatrics, Risk Factors, GENETIC-VARIANTS, Genotype, Naturvetenskap, Malalties hereditàries, INVESTIGATORS, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), POPULATION, Ovarian Neoplasms, Genetics, Subtypes, ddc:610, 0303 health sciences, education.field_of_study, Genètica humana, Susceptibility alleles, BRCA1 Protein, COMMON VARIANTS, Breast Cancer Epidemiology, Middle Aged, Prognosis, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, Female, Natural Sciences, Genetic diseases, Heterozygote, medicine.medical_specialty, Znf365, education, 3122 Cancers, Population, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Ovarian cancer, Translational research [ONCOL 3], Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], Molecular Biology, Selection, ddc:614, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Common variants, CONSORTIUM, Modifiers, Biology and Life Sciences, BRCA1, medicine.disease, R1, Genetic-variants, Cancer and Oncology, Mutation, Investigators, 3111 Biomedicine, ZNF365, Consortium, Genome-Wide Association Study
Abstract

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- CIMBA et al., BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., The study was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341), grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure; Cancer Research UK grants C12292/A11174 and C1287/A10118; the European Commission's Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175). Breast Cancer Family Registry Studies (BCFR): supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), and University of Melbourne (U01 CA69638). The Australian BCFR was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. Melissa C. Southey is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Carriers at FCCC were also identified with support from National Institutes of Health grants P01 CA16094 and R01 CA22435. The New York BCFR was also supported by National Institutes of Health grants P30 CA13696 and P30 ES009089. The Utah BCFR was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1 RR025764, and by Award Number P30 CA042014 from the National Cancer Institute. Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-19/2010, and Hereditary Cancer Association (Paveldimo vėžio asociacija)., Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/​016.BRCA-gene mutations and breast cancer in South African women (BMBSA): BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. Beckman Research Institute of the City of Hope (BRICOH): Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship. BRICOH was supported by NIH R01CA74415 and NIH P30 CA033752. Copenhagen Breast Cancer Study (CBCS): The CBCS study was supported by the NEYE Foundation. Spanish National Cancer Centre (CNIO): This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. City of Hope Cancer Center (COH): The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: Jeffrey N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): CONSIT TEAM was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”), Italian Association for Cancer Research (AIRC, IG 8713), Italian Minitry of Health (Extraordinary National Cancer Program 2006, “Alleanza contro il Cancro” and “Progetto Tumori Femminili), Italian Ministry of Education, University and Research (Prin 2008) Centro di Ascolto Donne Operate al Seno (CAOS) association and by funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’). German Cancer Research Center (DKFZ): The DKFZ study was supported by the DKFZ. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005, and the BBMRI grant CP46/NWO., Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Rosalind A. Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Canter (FCCC): The authors acknowledge support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): The GEMO study was supported by the Ligue National Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award and the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program. Gynecologic Oncology Group (GOG): This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), Statistical and Data Center (CA 37517), and GOG's Cancer Prevention and Control Committtee (CA 101165). Drs. Mark H. Greene and Phuong L. Mai were supported by funding from the Intramural Research Program, NCI, NIH. Hospital Clinico San Carlos (HCSC): HCSC was supported by RETICC 06/0020/0021, FIS research grant 09/00859, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitivity, and the European Regional Development Fund (ERDF)., Helsinki Breast Cancer Study (HEBCS): The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary (HUNBOCS): HUNBOCS was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/ÖP-9. Institut Català d'Oncologia (ICO): The ICO study was supported by the Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Ramón Areces Foundation, Carlos III Health Institute, Catalan Health Institute, and Autonomous Government of Catalonia and contract grant numbers: ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, and 2009SGR283. International Hereditary Cancer Centre (IHCC): Supported by the Polish Foundation of Science. Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. Iceland Landspitali–University Hospital (ILUH): The ILUH group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): INHERIT work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance grant 019511 and the Ministry of Economic Development, Innovation and Export Trade grant PSR-SIIRI-701. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics., Istituto Oncologico Veneto (IOVHBOCS): The IOVHBOCS study was supported by Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero della Salute (“Progetto Tumori Femminili” and RFPS 2006-5-341353,ACC2/R6.9”). Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Amanda B. Spurdle is an NHMRC Senior Research Fellow. The Clinical Follow Up Study was funded from 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333. Mayo Clinic (MAYO): MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. McGill University (MCGILL): The McGill Study was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation, and Export Trade. Memorial Sloan-Kettering Cancer Center (MSKCC): The MSKCC study was supported by Breast Cancer Research Foundation, Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Family Foundation, and Lymphoma Foundation. Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Women's College Research Institute, Toronto (NAROD): NAROD was supported by NIH grant: 1R01 CA149429-01. National Cancer Institute (NCI): Drs. Mark H. Greene and Phuong L. Mai were supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. National Israeli Cancer Control Center (NICCC): NICCC is supported by Clalit Health Services in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N. N. Petrov Institute of Oncology (NNPIO): The NNPIO study has been supported by the Russian Foundation for Basic Research (grants 11-04-00227, 12-04-00928, and 12-04-01490), the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780), and through a Royal Society International Joint grant (JP090615). The Ohio State University Comprehensive Cancer Center (OSU-CCG): OSUCCG is supported by the Ohio State University Comprehensive Cancer Center., South East Asian Breast Cancer Association Study (SEABASS): SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): The SMC study was partially funded through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium. Swedish Breast Cancer Study (SWE-BRCA): SWE-BRCA collaborators are supported by the Swedish Cancer Society. The University of Chicago Center for Clinical Cancer Genetics and Global Health (UCHICAGO): UCHICAGO is supported by grants from the US National Cancer Institute (NIH/NCI) and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. University of California Los Angeles (UCLA): The UCLA study was supported by the Jonsson Comprehensive Cancer Center Foundation and the Breast Cancer Research Foundation. University of California San Francisco (UCSF): The UCSF study was supported by the UCSF Cancer Risk Program and the Helen Diller Family Comprehensive Cancer Center. United Kingdom Familial Ovarian Cancer Registries (UKFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. University of Pennsylvania (UPENN): The UPENN study was supported by the National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855), Breast Cancer Research Foundation, Rooney Family Foundation, Susan G. Komen Foundation for the Cure, and the Macdonald Family Foundation. Victorian Familial Cancer Trials Group (VFCTG): The VFCTG study was supported by the Victorian Cancer Agency, Cancer Australia, and National Breast Cancer Foundation. Women's Cancer Research Initiative (WCRI): The WCRI at the Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN).

Published
2013

18. Homozygous <italic>TMEM127</italic> mutations in 2 patients with bilateral pheochromocytomas.

Author

Eijkelenkamp, K., Kerstens, M. N., Links, T. P., van der Horst‐Schrivers, A. N. A., Olderode‐Berends, M. J. W., van der Luijt, R. B., Robledo, M., van Dooren, M., Feelders, R. A., and de Vries, J.

Subjects
HOMOZYGOSITY, PARAGANGLIOMA, PHEOCHROMOCYTOMA, GENETIC mutation, NEUROENDOCRINE tumors
Abstract

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane‐protein‐127 (TMEM127) is one of the PCC/PGL‐susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127‐mutation. In a 31‐year‐old mentally retarded patient, the homozygous c.410‐2A > G mutation was discovered during an update of DNA analysis. A 26‐year‐old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC‐susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
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19. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Author

Ramus, Susan J., Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Sinilnikova, Olga M., Sue, Healey, Daniel, Barrowdale, Andrew, Lee, Mads, Thomassen, Anne Marie Gerdes, Kruse, Torben A., Uffe Birk Jensen, Anne Bine Skytte, Caligo, Maria A., Annelie, Liljegren, Annika, Lindblom, Hakan, Olsson, Ulf, Kristoffersson, Marie Stenmark Askmalm, Swe Brca Melin, B., Swe, Brca, Domchek, Susan M., Domchek, Sm, Nathanson, Katherine L., Rebbeck, Timothy R., Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Elzbieta, Złowocka, Jacek, Gronwald, Tomasz, Huzarski, Tomasz, Byrski, Cezary, Cybulski, Aleksandra Toloczko Grabarek, Ana, Osorio, Javier, Benitez, Mercedes, Duran, Maria Isabel Tejada, Ute, Hamann, Matti, Rookus, Van Leeuwen, Flora E., Aalfs, Cora M., Meijers Heijboer, Hanne E. J., Van Asperen, Christi J., Van Roozendaal, K. E. P., Nicoline, Hoogerbrugge, Collee, Margriet J., Margriet Collee, J., Mieke, Kriege, Hebon Van Der Luijt, R. B., Embrace, Embrace, Hebon, Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Diana, Eccles, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Porteous, Mary E., John Kennedy, M., Harsh, Pathak, Godwin, Andrew K., Dominique Stoppa Lyonnet, Virginie Caux Moncoutier, Antoine Pauw, D. E., De Pauw, A., Marion Gauthier Villars, Sylvie, Mazoyer, Melanie, Leone, Alain, Calender, Christine, Lasset, Valerie, Bonadona, Agnes, Hardouin, Pascaline, Berthet, Yves Jean Bignon, Nancy, Uhrhammer, Laurence, Faivre, Catherine, Loustalot, Gemo, Saundra, Buys, Mary, Daly, Buys, Daly, S., Alex, Miron, Beth, Terry M., Mary Beth Terry, Terry, M. B., Chung, Wendy K., Esther, John M., John, Em, Melissa, Southey, David, Goldgar, Singer, Christian F., Muy Kheng Tea, Georg, Pfeiler, Anneliese Fink Retter, Hansen, Thomas V. O., Hansen, Tv, Bent, Ejlertsen, Oskar Th Johannsson, Kenneth, Offit, Tomas, Kirchhoff, Gaudet, Mia M., Joseph, Vijai, Mark, Robson, Marion, Piedmonte, Kelly Anne Phillips, Linda Van Le, Hoffman, James S., Amanda Ewart Toland, Ewart Toland, A., Marco, Montagna, Silvia, Tognazzo, Evgeny, Imyanitov, Claudine, Isaacs, Issacs, C., Ramunas, Janavicius, Conxi, Lazaro, Ignacio, Blanco, Eva, Tornero, Matilde, Navarro, Moysich, Kirsten B., Karlan, Beth Y., Jenny, Gross, Edith, Olah, Tibor, Vaszko, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Van Rensburg, Elizabeth J., Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorotehea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Kristiina, Aittomaki, Marie, Plante, Kconfab Spurdle, A. B., Kconfab, Neuhausen, Susan L., Neuhausen, Sl, Yuan Chun Ding, Xianshu, Wang, Noralane, Lindor, Zachary, Fredericksen, Shane Pankratz, V., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Mai, Phuong L., Andrulis, Irene L., Gord, Glendon, Ocgn Ozcelik, H., Ocgn, Pharoah, Paul D. P., Pharoah, Pd, Gayther, Simon A., Jacques, Simard, Easton, Douglas F., Couch, Fergus J., Georgia Chenevix Trench, Behalf Of The Consortium Of Investigators Of Modifiers Of Brca1/2, O. N., Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Universitat de Barcelona, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM School for Cardiovascular Diseases, RS: GROW - School for Oncology and Reproduction, and Clinical Genetics

Subjects
Oncology, endocrine system diseases, [SDV]Life Sciences [q-bio], Càncer d'ovari, DCN PAC - Perception action and control, Cohort Studies, Breast cancer, 0302 clinical medicine, brca1, brca2, Odds Ratio, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, Hazard ratio, Middle Aged, 3. Good health, ovarian cancer, 030220 oncology & carcinogenesis, Female, Adult, Heterozygote, medicine.medical_specialty, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Population, Single-nucleotide polymorphism, Biology, Ovarian Neoplasms - genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], education, Retrospective Studies, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], association, Retrospective cohort study, snp, Odds ratio, BRCA1 Protein - genetics, medicine.disease, BRCA2 Protein - genetics, Mutation
Abstract

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., link_to_OA_fulltext

Published
2012

20. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

Author

Cox, D. G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M. H., Mai, P. L., Andrulis, I. L., Thomassen, M., Gerdes, A.-M., Caligo, M. A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S. S., Borg, A., Karlsson, P., Stenmark Askmalm, M., Barbany Bustinza, G., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Benitez, J., Hamann, U., Rookus, M. A., van den Ouweland, A. M. W., Ausems, M. G. E. M., Aalfs, C. M., van Asperen, C. J., Devilee, P., Gille, H. J. J. P., Peock, S., Frost, D., Evans, D. G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A. K., Remon, M.-A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M. C., Terry, M. B., Singer, C. F., Dressler, A.-C., Tea, M.-K., Hansen, T. V. O., Johannsson, O., Piedmonte, M., Rodriguez, G. C., Basil, J. B., Blank, S., Toland, A. E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S. A., Moysich, K. B., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O. M., Dumont, M., Greene, M., Glendon, G., Selander, T., Weerasooriya, N., Nordling, M., Bergman, A., Einbeigi, Z., Stenmark-Askmalm, M., Liedgren, S., Loman, N., Olsson, H., Kristoffersson, U., Soller, M., Jernstrom, H., Harbst, K., Henriksson, K., Lindblom, A., Arver, B., von Wachenfeldt, A., Liljegren, A., Barbany-Bustinza, G., Rantala, J., Melin, B., Gronberg, H., Stattin, E.-L., Emanuelsson, M., Ehrencrona, H., Torres, D., Rashid, M. U., Seidel-Renkert, A., Hogervorst, F. B. L., Verhoef, S., Verheus, M., van't Veer, L. J., van Leeuwen, F. E., Collee, M., Jager, A., Hooning, M. J., Tilanus-Linthorst, M. M. A., Seynaeve, C., Wijnen, J. T., Vreeswijk, M. P., Tollenaar, R. A., Ligtenberg, M. J., Hoogerbrugge, N., Ausems, M. G., van der Luijt, R. B., van Os, T. A., Gille, J. J. P., Waisfisz, Q., Meijers-Heijboer, H. E. J., Gomez-Garcia, E. B., van Roozendaal, C. E., Blok, M. J., Caanen, B., Oosterwijk, J. C., van der Hout, A. H., Mourits, M. J., Vasen, H. F., Cook, M., Platte, R., Miedzybrodzka, Z., Gregory, H., Morrison, P., Jeffers, L., Cole, T., Ong, K.-r., Hoffman, J., Donaldson, A., James, M., Downing, S., Taylor, A., Murray, A., Rogers, M. T., McCann, E., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Brewer, C., Kivuva, E., Searle, A., Goodman, S., Hill, K., Davidson, R., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Whaite, A., Dorkins, H., Barwell, J., Chu, C., Miller, J., Ellis, I., Houghton, C., Lalloo, F., Taylor, J., Side, L., Male, A., Berlin, C., Collier, R., Douglas, F., Claber, O., Jobson, I., Walker, L., McLeod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Bancroft, E., D'Mello, L., Page, E., Ardern-Jones, A., Kohut, K., Wiggins, J., Castro, E., Mitra, A., Robertson, L., Cook, J., Quarrell, O., Bardsley, C., Hodgson, S., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Eccles, D., Lucassen, A., Crawford, G., McBride, D., Smalley, S., Sinilnikova, O., Leone, M., Buecher, B., Houdayer, C., Belotti, M., Tirapo, C., de Pauw, A., Bressac-de-Paillerets, B., Remenieras, A., Byrde, V., Lenoir, G., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Bourdon, V., Noguchi, T., Coulet, F., Colas, C., Soubrier, F., Coupier, I., Pujol, P., Peyrat, J.-P., Fournier, J., Revillion, F., Vennin, P., Adenis, C., Rouleau, E., Lidereau, R., Demange, L., Nogues, C., Muller, D., Fricker, J.-P., Longy, M., Sevenet, N., Toulas, C., Guimbaud, R., Gladieff, L., Feillel, V., Leroux, D., Dreyfus, H., Rebischung, C., Coron, F., Faivre, L., Prieur, F., Lebrun, M., Ferrer, S. F., Frenay, M., Venat-Bouvet, L., Mortemousque, I., Lynch, H. T., Snyder, C. L., Ejlertsen, B., Andersen, M. K., Kjaergaard, S., Senter, L., Sweet, K., O'Connor, M., Craven, C., Pharoah, P., Ramus, S., Pye, C., Harrington, P., Wozniak, E., Varon-Mateeva, R., Kast, K., Preisler-Adams, S., Deissler, H., Schonbuchner, I., Heinritz, W., Schafer, D., Aittomaki, K., Blomqvist, C., Heikkinen, T., Erkkila, R. N. I., Thorne, H., Niedermayr, E., de la Hoya, M., Perez-Segura, P., Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Centre de recherche du CHU Sainte-Justine [Montreal], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Department of Pediatrics, CHU Sainte Justine [Montréal], Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Queensland Institute of Medical Research, University of Delaware [Newark], Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Clinical Genetics, Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Department of Oncology, Sahlgrenska University Hospital [Gothenburg], Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Addenbrookes Hospital, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, génétique, Institut Curie [Paris], Service de Génétique Oncologique, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Consultation d'Oncogénétique, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service d'Oncologie Génétique, de Prévention et Dépistage, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre René Gauducheau, CRLCC René Gauducheau, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Internal Medicine, Huntsman Cancer Institute, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Dept of OB/GYN and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Faculty of Medicine, University of Iceland [Reykjavik], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Lombardi Comprehensive Cancer Center, Georgetown University, Genetic Counselling Unit, IDIBELL-Catalan Institute of Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Ludwig-Maximilians-Universität München (LMU), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Heidelberg University Hospital [Heidelberg], Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), Universität Regensburg (UR), Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Laboratory Medicine and Pathology, Mayo Clinic, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 6, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Research Centre, CHU Ste Justine, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Génétique moléculaire, signalisation et cancer (GMSC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Human Genetics, Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Tel Aviv University (TAU), University of Pennsylvania-University of Pennsylvania, Universiteit Leiden-Universiteit Leiden, Nottingham University Hospitals NHS Trust (NUH), Roswell Park Cancer Institute [Buffalo] (RPCI), Georgetown University [Washington] (GU), Universität Leipzig, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Génétique moléculaire, signalisation et cancer ( GMSC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Cambridge [UK] ( CAM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Rigshospitalet [Copenhagen]-University of Copenhagen ( KU ), Sahlgrenska University Hospital, Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, Deutsches Krebsforschungszentrum ( DKFZ ), INSTITUT CURIE, Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre François Baclesse, Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM - U912 INSERM - AMU - IRD ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ), Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Mount Sinai Hospital ( MSH ), Medical University of Vienna-Department of OB/GYN, Medical University of Vienna, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, Technical University of Munich ( TUM ), Ludwig-Maximilians-Universität München, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel ( CAU ), University Hospital Düsseldorf-Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Hannover Medical School [Hannover] ( MHH ), University Regensburg, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Human genetics, and CCA - Oncogenesis

Subjects
endocrine system diseases, Electrophoretic Mobility Shift Assay, MESH : Breast Neoplasms, medicine.disease_cause, Linkage Disequilibrium, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Genes, Reporter, Risk Factors, MESH: Risk Factors, Genotype, MESH : Female, Luciferases, skin and connective tissue diseases, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, Genetics, 0303 health sciences, MESH : Linkage Disequilibrium, BRCA1 Protein, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH : Genes, Reporter, MESH : Risk Factors, 3. Good health, MESH: Linkage Disequilibrium, 030220 oncology & carcinogenesis, MESH : Electrophoretic Mobility Shift Assay, Female, Breast disease, MESH : Mutation, MESH : Heterozygote, Heterozygote, MESH: Mutation, Single-nucleotide polymorphism, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, medicine, Humans, MESH : BRCA1 Protein, MESH : HeLa Cells, Genetic Predisposition to Disease, ddc:610, Allele, Molecular Biology, MESH : Haplotypes, Alleles, Genetic Association Studies, 030304 developmental biology, MESH: BRCA1 Protein, MESH : Luciferases, MESH: Humans, Hereditary cancer and cancer-related syndromes [ONCOL 1], MESH: Alleles, Haplotype, MESH : Humans, MESH: Genes, Reporter, Cancer, MESH : Genetic Association Studies, MESH: Haplotypes, medicine.disease, Haplotypes, Mutation, MESH: Electrophoretic Mobility Shift Assay, MESH: HeLa Cells, Cancer research, MESH : Genetic Predisposition to Disease, MESH: Luciferases, Carcinogenesis, MESH : Alleles, MESH: Female, MESH: Breast Neoplasms, HeLa Cells
Abstract

Item does not contain fulltext Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Published
2011

21. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author

Antoniou, A. C., Kartsonaki, C., Sinilnikova, O. M., Soucy, P., Mcguffog, L., Healey, S., Lee, A., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Barile, M., Pensotti, V., Pasini, B., Dolcetti, R., Giannini, Giuseppe, Laura Putignano, A., Varesco, L., Radice, P., Mai, P. L., Greene, M. H., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Gerdes, A. M., Kruse, T. A., Jensen, U. B., Cruger, D. G., Caligo, M. A., Laitman, Y., Milgrom, R., Kaufman, B., Paluch Shimon, S., Friedman, E., Loman, N., Harbst, K., Lindblom, A., Arver, B., Ehrencrona, H., Melin, B., Nathanson, K. L., Domchek, S. M., Rebbeck, T., Jakubowska, A., Lubinski, J., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Gorski, B., Osorio, A., Cajal, T. R., Fostira, F., Andres, R., Benitez, J., Hamann, U., Hogervorst, F. B., Rookus, M. A., Hooning, M. J., Nelen, M. R., Van Der Luijt, R. B., Van Os, T. A. M., Van Asperen, C. J., Devilee, P., Meijers Heijboer, H. E. J., Garcia, E. B. G., Peock, S., Cook, M., Frost, D., Platte, R., Leyland, J., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Adlard, J., Davidson, R., Eccles, D., Ong, K. R., Cook, J., Douglas, F., Paterson, J., John Kennedy, M., Miedzybrodzka, Z., Godwin, A., Stoppa Lyonnet, D., Buecher, B., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Lasset, C., Leroux, D., Faivre, L., Bronner, M., Prieur, F., Nogues, C., Rouleau, E., Pujol, P., Coupier, I., Frenay, M., Hopper, J. L., Daly, M. B., Terry, M. B., John, E. M., Buys, S. S., Yassin, Y., Miron, A., Goldgar, D., Singer, C. F., Tea, M. K., Pfeiler, G., Catharina Dressler, A., Hansen, T. V. O., Jonson, L., Ejlertsen, B., Barkardottir, R. B., Kirchhoff, T., Offit, K., Piedmonte, M., Rodriguez, G., Small, L., Boggess, J., Blank, S., Basil, J., Azodi, M., Toland, A. E., Montagna, M., Tognazzo, S., Agata, S., Imyanitov, E., Janavicius, R., Lazaro, C., Blanco, I., Pharoah, P. D. P., Sucheston, L., Karlan, B. Y., Walsh, C. S., Olah, E., Bozsik, A., Teo, S. H., Seldon, J. L., Beattie, M. S., Van Rensburg, E. J., Sluiter, M. D., Diez, O., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ruehl, I., Varon Mateeva, R., Kast, K., Deissler, H., Niederacher, D., Arnold, N., Gadzicki, D., Schonbuchner, I., Caldes, T., De La Hoya, M., Nevanlinna, H., Aittomaki, K., Dumont, M., Chiquette, J., Tischkowitz, M., Chen, X. Q., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Fredericksen, Z., Wang, X., Pankratz, V. S., Couch, F., Simard, J., Easton, D. F., Chenevix Trench, G., Karlsson, P., Nordling, M., Bergman, A., Einbeigi, Z., Stenmark Askmalm, M., Liedgren, S., Borg, A., Olsson, H., Kristoffersson, U., Jernstrom, H., Henriksson, K., Von Wachenfeldt, A., Liljegren, A., Barbany Bustinza, G., Rantala, J., Gronberg, H., Stattin, E. L., Emanuelsson, M., Brandell, R. R., Dahl, N., Hogervorst, F. B. L., Verhoef, S., Verheus, M., Veer, L. V., Van Leeuwen, F. E., Collee, M., Van Den Ouweland, A. M. W., Jager, A., Tilanus Linthorst, M. M. A., Seynaeve, C., Wijnen, J. T., Vreeswijk, M. P., Tollenaar, R. A., Ligtenberg, M. J., Hoogerbrugge, N., Ausems, M. G., Aalfs, C. M., Van Os, T. A., Gille, J. J. P., Waisfisz, Q., Gomez Garcia, E. B., Van Roozendaal, C. E., Blok, M. J., Caanen, B., Oosterwijk, J. C., Van Der Hout, A. H., Mourits, M. J., Vasen, H. F., Gregory, H., Morrison, P., Jeffers, L., Cole, T., Mckeown, C., Hoffman, J., Donaldson, A., Downing, S., Taylor, A., Murray, A., Rogers, M. T., Mccann, E., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Brewer, C., Kivuva, E., Searle, A., Goodman, S., Hill, K., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Whaite, A., Dorkins, H., Barwell, J., Chu, C., Miller, J., Ellis, I., Houghton, C., Taylor, J., Side, L., Male, A., Berlin, C., Eason, J., Collier, R., Claber, O., Jobson, I., Walker, L., Mcleod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Bancroft, E., D'Mello, L., Page, E., Ardern Jones, A., Kohut, K., Wiggins, J., Castro, E., Mitra, A., Robertson, L., Quarrell, O., Bardsley, C., Hodgson, S., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Lucassen, A., Crawford, G., Mcbride, D., Smalley, S., University of Groningen, Clinical Genetics, Medical Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Queensland Institute of Medical Research, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Consortium for Genomics Technology (Cogentech), Department of Genetics, Biology and Biochemistry, University of Turin, Cancer Bioimmunotherapy Unit, IRCCS-Centro di Riferimento Oncologico, Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' [Rome], Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Ontario Cancer Genetics Network, Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital ( MSH ), Department of Clinical Genetics, Odense University Hospital, Rigshospitalet [Copenhagen]-University of Copenhagen ( KU ), The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Department of Oncology, Lund University Hospital, Karolinska University Hospital [Stockholm], Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Radiation Sciences and Oncology, Umeå University, Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine-Abramson Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University-International Hereditary Cancer Centre, Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, International Hereditary Cancer Center, Pomeranian Medical University, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Department of Medical Oncology, Hospital Sant Pau, Medical Oncology Division, Hospital Clínico de Zaragoza, Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum ( DKFZ ), Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Wessex Clinical Genetics Service, Princess Anne Hospital, West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Addenbrookes Hospital, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Service de Génétique Oncologique, INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), génétique, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Service d'onco-hématologie et génétique, CHU Grenoble, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Santé Publique, Hôpital René HUGUENIN (Saint-Cloud)-INSTITUT CURIE, Laboratoire d'Oncogénétique, CRLCC René Huguenin, Institut de recherche en cancérologie de Montpellier ( IRCM - U896 Inserm - UM1 ), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, Consultation d'oncogénétique, CRLCC Antoine Lacassagne, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] ( HMS ), Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Division of Special Gynecology, Medical University of Vienna-Department of OB/GYN, Department of Clinical Biochemistry, Rigshospitalet [Copenhagen], Copenhagen University Hospital-Rigshospitalet [Copenhagen], Department of Pathology, Landspitali-University Hospital, Department of Environmental Medicine, New York University School of Medicine-NYU Cancer Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, State Research Institute Innovative Medicine Center, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Genetic Counselling Unit, Department of Molecular Genetics, National Institute of Oncology, Cancer Research Initiatives Foundation, Sime Darby Medical Centre-Malaysia and University Malaya Cancer Research Institute-University Malaya Medical Centre, Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, Technical University of Munich ( TUM ), Ludwig-Maximillians University, Charite berlin, University Hospital Carl Gustav Carus, University Hospital Ulm, University Hospital Düsseldorf-Heinrich-Heine-Universität Düsseldorf [Düsseldorf], University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel ( CAU ), Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] ( MHH ), University of Würzburg, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Genetics, Portuguese Oncology Institute, Department of Medical Genetics, Mayo Clinic, Department of Laboratory Medicine and Pathology, Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Clinical Genetics [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Tel Aviv University (TAU), Uppsala University, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Abramson Cancer Center-Perelman School of Medicine, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Pomeranian Medical University [Szczecin] (PUM), Hospital de la Santa Creu i Sant Pau, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universiteit Leiden-Universiteit Leiden, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Newcastle Upon Tyne Hospitals NHS Foundation Trust, University of Kansas Medical Center [Kansas City, KS, USA], Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut Curie [Paris]-Hôpital René HUGUENIN (Saint-Cloud), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Harvard Medical School [Boston] (HMS), Medizinische Universität Wien = Medical University of Vienna, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Department of Clinical Biochemistry [Rigshospitalet], Copenhagen University Hospital, New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-NYU Cancer Institute, Roswell Park Cancer Institute [Buffalo] (RPCI), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Hannover Medical School [Hannover] (MHH), Julius-Maximilians-Universität Würzburg (JMU), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital René HUGUENIN (Saint-Cloud)-Institut Curie [Paris], CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Universität Leipzig [Leipzig], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), University of Florence (UNIFI), Mount Sinai Hospital (MSH), Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Hôpital René HUGUENIN (Saint-Cloud), Technical University of Munich (TUM), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Human genetics, CCA - Oncogenesis, Human Genetics, Klinische Genetica, and RS: GROW - School for Oncology and Reproduction

Subjects
MESH : BRCA2 Protein, MESH : Aged, Estrogen receptor, Genome-wide association study, MESH : Breast Neoplasms, VARIANTS, MESH : Chromosomes, Human, Pair 1, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Chromosomes, Human, Pair 6, MESH: BRCA2 Protein, 0302 clinical medicine, MESH: Risk Factors, Risk Factors, Genotype, CONFER SUSCEPTIBILITY, Chromosomes, Human, MESH : Female, skin and connective tissue diseases, Genetics (clinical), POPULATION, MESH: Heterozygote, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Middle Aged, BRCA1 Protein, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH : Adult, Middle Aged, MESH : Risk Factors, 3. Good health, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, MESH : Mutation, Adult, MESH : Heterozygote, Heterozygote, MESH: Mutation, MESH: Chromosomes, Human, Pair 6, MESH: Chromosomes, Human, Pair 1, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Breast Neoplasms, Biology, MESH: Chromosomes, Human, Polymorphism, Single Nucleotide, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, LOCUS, SNP, Humans, MESH : Middle Aged, MESH : BRCA1 Protein, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Alleles, MESH: BRCA1 Protein, 030304 developmental biology, Aged, BRCA2 Protein, MESH: Humans, 2Q35, MESH: Alleles, MESH : Humans, MESH: Adult, medicine.disease, MESH : Chromosomes, Human, ESTROGEN-RECEPTOR, Mutation, Cancer research, MESH : Genetic Predisposition to Disease, GENETIC MODIFIERS, MESH : Alleles, MESH: Female, MESH: Breast Neoplasms
Abstract

Item does not contain fulltext Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Published
2011

22. Erratum

Author

Hes, F. J., Van der Luijt, R. B., Janssen, A. L.W., Zewald, R. A., De Jong, G. J., Lenders, J. W., Links, T. P., Luyten, G. P.M., Sijmons, R. H., Eussen, H. J., Halley, D. J.J., Lips, C. J.M., Pearson, P. L., van den Ouweland, A. M.W., Majoor-Krakauer, D. F., Clinical sciences, Medical Genetics, and Geology

Subjects
genetics, Genetics(clinical)
Published
2008

23. Impact of rapid genetic counselling and testing on the decision to undergo immediate or delayed prophylactic mastectomy in newly diagnosed breast cancer patients: findings from a randomised controlled trial

Author

Wevers, M R, primary, Aaronson, N K, additional, Verhoef, S, additional, Bleiker, E M A, additional, Hahn, D E E, additional, Kuenen, M A, additional, van der Sanden-Melis, J, additional, Brouwer, T, additional, Hogervorst, F B L, additional, van der Luijt, R B, additional, Valdimarsdottir, H B, additional, van Dalen, T, additional, Theunissen, E B M, additional, van Ooijen, B, additional, de Roos, M A, additional, Borgstein, P J, additional, Vrouenraets, B C, additional, Vriens, E, additional, Bouma, W H, additional, Rijna, H, additional, Vente, J P, additional, Witkamp, A J, additional, Rutgers, E J T, additional, and Ausems, M G E M, additional

Published
2014
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24. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers : results from a multicenter study

Author

Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R. J., McGuffog, L., Healy, S., Sinilnikova, O. M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., Von Wachenfeldt, A., Liljegren, A., Loman, N., Herbst, K., Kristoffersson, U., Rosenquist, Richard, Karlsson, P., Stenmark-Askmalm, M., Melin, B., Nathanson, K. L., Domchek, S. M., Byrski, T., Huzarski, T., Gronwald, J., Menkiszak, J., Cybulski, C., Serrano, P., Osorio, A., Cajal, T. R., Tsitlaidou, M., Benitez, J., Gilbert, M., Rookus, M., Aalfs, C. M., Kluijt, I., Boessenkool-Pape, J. L., Meijers-Heijboer, H. E. J., Oosterwijk, J. C., van Asperen, C. J., Blok, M. J., Nelen, M. R., van den Ouweland, A. M. W., Seynaeve, C., van der Luijt, R. B., Devilee, P., Easton, D. F., Peock, S., Frost, D., Platte, R., Ellis, S. D., Fineberg, E., Evans, D. G., Lalloo, F., Eeles, R., Jacobs, C., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Godwin, A., Bove, B., Stoppa-Lyonnet, D., Caux-Moncoutier, V., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Boutry-Kryza, N., Pujol, P., Coupier, I., Peyrat, J-P, Vennin, P., Muller, D., Fricker, J-P, Venat-Bouvet, L., Johannsson, OTh, Isaacs, C., Schmutzler, R., Wappenschmidt, B., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Preisler-Adams, S., Simard, J., Soucy, P., Durocher, F., Chenevix-Trench, G., Beesley, J., Chen, X., Rebbeck, T., Couch, F., Wang, X., Lindor, N., Fredericksen, Z., Pankratz, V. S., Peterlongo, P., Bonanni, B., Fortuzzi, S., Peissel, B., Szabo, C., Mai, P. L., Loud, J. T., Lubinski, J., Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R. J., McGuffog, L., Healy, S., Sinilnikova, O. M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., Von Wachenfeldt, A., Liljegren, A., Loman, N., Herbst, K., Kristoffersson, U., Rosenquist, Richard, Karlsson, P., Stenmark-Askmalm, M., Melin, B., Nathanson, K. L., Domchek, S. M., Byrski, T., Huzarski, T., Gronwald, J., Menkiszak, J., Cybulski, C., Serrano, P., Osorio, A., Cajal, T. R., Tsitlaidou, M., Benitez, J., Gilbert, M., Rookus, M., Aalfs, C. M., Kluijt, I., Boessenkool-Pape, J. L., Meijers-Heijboer, H. E. J., Oosterwijk, J. C., van Asperen, C. J., Blok, M. J., Nelen, M. R., van den Ouweland, A. M. W., Seynaeve, C., van der Luijt, R. B., Devilee, P., Easton, D. F., Peock, S., Frost, D., Platte, R., Ellis, S. D., Fineberg, E., Evans, D. G., Lalloo, F., Eeles, R., Jacobs, C., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Godwin, A., Bove, B., Stoppa-Lyonnet, D., Caux-Moncoutier, V., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Boutry-Kryza, N., Pujol, P., Coupier, I., Peyrat, J-P, Vennin, P., Muller, D., Fricker, J-P, Venat-Bouvet, L., Johannsson, OTh, Isaacs, C., Schmutzler, R., Wappenschmidt, B., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Preisler-Adams, S., Simard, J., Soucy, P., Durocher, F., Chenevix-Trench, G., Beesley, J., Chen, X., Rebbeck, T., Couch, F., Wang, X., Lindor, N., Fredericksen, Z., Pankratz, V. S., Peterlongo, P., Bonanni, B., Fortuzzi, S., Peissel, B., Szabo, C., Mai, P. L., Loud, J. T., and Lubinski, J.

Abstract

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Published
2012
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25. Multiple endocrine neoplasia type I (MEN-I):Recent developments and guidelines for DNA-diagnosis and periodic clinical monitoring

Author

Dreijerink, K. M A, Roijers, J. F M, Van Der Luijt, R. B., Höppener, J. W M, and Lips, C. J M

Abstract

Multiple endocrine neoplasia type I (MEN-I) is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as neuroendocrine carcinoid tumours. Since the identification of the responsible gene in 1997, the diagnosis MEN-I can be assessed easily, and even presymptomatically, by DNA analysis. An early diagnosis is of importance because through periodic clinical monitoring of (putative) MENI gene germline mutation carriers, tumour development can be detected and treated at an early stage. Eligible for DNA analysis are MEN-I patients and their family members, as well as patients with seemingly sporadic MEN-I related tumours in whom on clinical grounds carriership of a MENI gene germline mutation is suspected. Eligible for periodic clinical monitoring are putative and confirmed carriers of a MENI germline mutation from the age of 5.

Published
2000

26. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers : Implications for risk prediction

Author

Antoniou, A. C., Beesley, J., McGuffog, L., Sinilnikova, O. M., Healey, S., Neuhausen, S. L., Ding, Y. C., Rebbeck, T. R., Weitzel, J. N., Lynch, H. T., Isaacs, C., Ganz, P. A., Tomlinson, G., Olopade, O. I., Couch, F. J., Wang, X., Lindor, N. M., Pankratz, V. S., Radice, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Viel, A., Allavena, A., Dall'Olio, V., Peterlongo, P., Szabo, C. I., Zikan, M., Claes, K., Poppe, B., Foretova, L., Mai, P. L., Greene, M. H., Rennert, G., Lejbkowicz, F., Glendon, G., Ozcelik, H., Andrulis, I. L., Thomassen, M., Gerdes, A. -M, Sunde, L., Cruger, D., Jensen, U. B., Caligo, M., Friedman, E., Kaufman, B., Laitman, Y., Milgrom, R., Dubrovsky, M., Cohen, S., Borg, A., Jernström, H., Lindblom, A., Rantala, J., Stenmark-Askmalm, M., Melin, B., Nathanson, K., Domchek, S., Jakubowska, A., Lubinski, J., Huzarski, T., Osorio, A., Lasa, A., Durán, M., Tejada, M. -I, Godino, J., Benitez, J., Hamann, U., Kriege, M., Hoogerbrugge, N., Van Der Luijt, R. B., Van Asperen, C. J., Devilee, P., Meijers-Heijboer, E. J., Blok, M. J., Aalfs, C. M., Hogervorst, F., Rookus, M., Cook, M., Oliver, C., Frost, D., Conroy, D., Evans, D. G., Lalloo, F., Pichert, G., Davidson, R., Cole, T., Cook, J., Paterson, J., Hodgson, S., Morrison, P. J., Porteous, M. E., Walker, L., Kennedy, M. J., Dorkins, H., Peock, S., Godwin, A. K., Stoppa-Lyonnet, D., De Pauw, A., Mazoyer, S., Bonadona, V., Lasset, C., Dreyfus, H., Leroux, D., Hardouin, A., Berthet, P., Faivre, L., Loustalot, C., Noguchi, T., Sobol, H., Rouleau, E., Nogues, C., Frénay, M., Vénat-Bouvet, L., Hopper, J. L., Daly, M. B., Terry, M. B., John, E. M., Buys, S. S., Yassin, Y., Miron, A., Goldgar, D., Singer, C. F., Dressler, A. C., Gschwantler-Kaulich, D., Pfeiler, G., Hansen, T. V. O., Jnson, L., Agnarsson, B. A., Kirchhoff, T., Offit, K., Devlin, V., Dutra-Clarke, A., Piedmonte, M., Rodriguez, G. C., Wakeley, K., Boggess, J. F., Basil, J., Schwartz, P. E., Blank, S. V., Toland, A. E., Montagna, M., Casella, C., Imyanitov, E., Tihomirova, L., Blanco, I., Lazaro, C., Ramus, S. J., Sucheston, L., Karlan, B. Y., Gross, J., Schmutzler, R., Wappenschmidt, B., Engel, C., Meindl, A., Lochmann, M., Arnold, N., Heidemann, S., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Preisler-Adams, S., Kast, K., Schönbuchner, I., Caldes, T., De La Hoya, M., Aittomäki, K., Nevanlinna, H., Simard, J., Spurdle, A. B., Holland, H., Chen, X., Platte, R., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C., Beesley, J., McGuffog, L., Sinilnikova, O. M., Healey, S., Neuhausen, S. L., Ding, Y. C., Rebbeck, T. R., Weitzel, J. N., Lynch, H. T., Isaacs, C., Ganz, P. A., Tomlinson, G., Olopade, O. I., Couch, F. J., Wang, X., Lindor, N. M., Pankratz, V. S., Radice, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Viel, A., Allavena, A., Dall'Olio, V., Peterlongo, P., Szabo, C. I., Zikan, M., Claes, K., Poppe, B., Foretova, L., Mai, P. L., Greene, M. H., Rennert, G., Lejbkowicz, F., Glendon, G., Ozcelik, H., Andrulis, I. L., Thomassen, M., Gerdes, A. -M, Sunde, L., Cruger, D., Jensen, U. B., Caligo, M., Friedman, E., Kaufman, B., Laitman, Y., Milgrom, R., Dubrovsky, M., Cohen, S., Borg, A., Jernström, H., Lindblom, A., Rantala, J., Stenmark-Askmalm, M., Melin, B., Nathanson, K., Domchek, S., Jakubowska, A., Lubinski, J., Huzarski, T., Osorio, A., Lasa, A., Durán, M., Tejada, M. -I, Godino, J., Benitez, J., Hamann, U., Kriege, M., Hoogerbrugge, N., Van Der Luijt, R. B., Van Asperen, C. J., Devilee, P., Meijers-Heijboer, E. J., Blok, M. J., Aalfs, C. M., Hogervorst, F., Rookus, M., Cook, M., Oliver, C., Frost, D., Conroy, D., Evans, D. G., Lalloo, F., Pichert, G., Davidson, R., Cole, T., Cook, J., Paterson, J., Hodgson, S., Morrison, P. J., Porteous, M. E., Walker, L., Kennedy, M. J., Dorkins, H., Peock, S., Godwin, A. K., Stoppa-Lyonnet, D., De Pauw, A., Mazoyer, S., Bonadona, V., Lasset, C., Dreyfus, H., Leroux, D., Hardouin, A., Berthet, P., Faivre, L., Loustalot, C., Noguchi, T., Sobol, H., Rouleau, E., Nogues, C., Frénay, M., Vénat-Bouvet, L., Hopper, J. L., Daly, M. B., Terry, M. B., John, E. M., Buys, S. S., Yassin, Y., Miron, A., Goldgar, D., Singer, C. F., Dressler, A. C., Gschwantler-Kaulich, D., Pfeiler, G., Hansen, T. V. O., Jnson, L., Agnarsson, B. A., Kirchhoff, T., Offit, K., Devlin, V., Dutra-Clarke, A., Piedmonte, M., Rodriguez, G. C., Wakeley, K., Boggess, J. F., Basil, J., Schwartz, P. E., Blank, S. V., Toland, A. E., Montagna, M., Casella, C., Imyanitov, E., Tihomirova, L., Blanco, I., Lazaro, C., Ramus, S. J., Sucheston, L., Karlan, B. Y., Gross, J., Schmutzler, R., Wappenschmidt, B., Engel, C., Meindl, A., Lochmann, M., Arnold, N., Heidemann, S., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Preisler-Adams, S., Kast, K., Schönbuchner, I., Caldes, T., De La Hoya, M., Aittomäki, K., Nevanlinna, H., Simard, J., Spurdle, A. B., Holland, H., Chen, X., Platte, R., Chenevix-Trench, G., and Easton, D. F.

Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers., SWE-BRCA SWE-BRCA collaborators: Per Karlsson, Margareta Nordling, Annika Bergman, and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Sigrun Liedgren, Linkoping University Hospital; Niklas Loman, Ha kan Olsson, Ulf Kristoffersson, Helena Jernstr€om, Katja Harbst, and Karin Henriksson, Lund University Hospital; Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, and Gisela Barbany-Bustinza, Stockholm, Karolinska University Hospital; Henrik Gronberg, Eva-Lena Stattin, and Monica Emanuelsson, Umea University Hos- € pital; Hans Ehrencrona, Richard Rosenquist Brandell, and Niklas Dahl, Uppsala University Hospital

Published
2010
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27. Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Author

Engel, C., Versmold, B., Wappenschmidt, B., Simard, J., Easton, D. F., Peock, S., Cook, M., Oliver, C., Frost, D., Mayes, R., Evans, D. G., Eeles, R., Paterson, J., Brewer, C., McGuffog, L., Antoniou, A. C., Stoppa-Lyonnet, D., Sinilnikova, O. M., Barjhoux, L., Frenay, M., Michel, C., Leroux, D., Dreyfus, H., Toulas, C., Gladieff, L., Uhrhammer, N., Bignon, Y. -J, Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Preisler-Adams, S., Kast, K., Deissler, H., Sutter, C., Gadzicki, D., Chenevix-Trench, G., Spurdle, A. B., Chen, X., Beesley, J., Olsson, H., Kristoffersson, U., Ehrencrona, H., Liljegren, A., Van Der Luijt, R. B., Van Os, T. A., Van Leeuwen, F. E., Domchek, S. M., Rebbeck, T. R., Nathanson, K. L., Osorio, A., Ramón Y Cajal, T., Konstantopoulou, I., Benítez, J., Friedman, E., Kaufman, B., Laitman, Y., Mai, P. L., Greene, M. H., Nevanlinna, H., Aittomäki, K., Szabo, C. I., Caldes, T., Couch, F. J., Andrulis, I. L., Godwin, A. K., Hamann, U., Schmutzler, R. K., Engel, C., Versmold, B., Wappenschmidt, B., Simard, J., Easton, D. F., Peock, S., Cook, M., Oliver, C., Frost, D., Mayes, R., Evans, D. G., Eeles, R., Paterson, J., Brewer, C., McGuffog, L., Antoniou, A. C., Stoppa-Lyonnet, D., Sinilnikova, O. M., Barjhoux, L., Frenay, M., Michel, C., Leroux, D., Dreyfus, H., Toulas, C., Gladieff, L., Uhrhammer, N., Bignon, Y. -J, Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Preisler-Adams, S., Kast, K., Deissler, H., Sutter, C., Gadzicki, D., Chenevix-Trench, G., Spurdle, A. B., Chen, X., Beesley, J., Olsson, H., Kristoffersson, U., Ehrencrona, H., Liljegren, A., Van Der Luijt, R. B., Van Os, T. A., Van Leeuwen, F. E., Domchek, S. M., Rebbeck, T. R., Nathanson, K. L., Osorio, A., Ramón Y Cajal, T., Konstantopoulou, I., Benítez, J., Friedman, E., Kaufman, B., Laitman, Y., Mai, P. L., Greene, M. H., Nevanlinna, H., Aittomäki, K., Szabo, C. I., Caldes, T., Couch, F. J., Andrulis, I. L., Godwin, A. K., Hamann, U., and Schmutzler, R. K.

Abstract

Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; Ptrend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; Ptrend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact: The combined application of these and other recently identified genetic riskmodifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers., The Swedish BRCA1 and BRCA2 study (SWE-BRCA) SWE-BRCA collaborators: Per Karlsson, Margareta Nordling, Annika Bergman, and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linkoping University Hospital; Ake Borg, Niklas Loman, Hakan Olsson, Ulf Kristoffersson, Helena Jernstrom, Katja Harbst, and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza, and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Malmer, Henrik Gronberg, Eva-Lena Stattin, and Monica Emanuelsson, Umea University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell, and Niklas Dahl, Uppsala University Hospital. We thank the Swedish Cancer Society.

Published
2010
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28. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author

Antoniou, A. C., Sinilnikova, O. M., McGuffog, L., Healey, S., Nevanlinna, H., Heikkinen, T., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Fredericksen, Z., Peterlongo, P., Peissel, B., Bonanni, B., Viel, A., Bernard, L., Radice, P., Szabo, C. I., Foretova, L., Zikan, M., Claes, K., Greene, M. H., Mai, P. L., Rennert, G., Lejbkowicz, F., Andrulis, I. L., Ozcelik, H., Glendon, G., Gerdes, A. -M, Thomassen, M., Sunde, L., Caligo, M. A., Laitman, Y., Kontorovich, T., Cohen, S., Kaufman, B., Dagan, E., Baruch, R. G., Friedman, E., Harbst, K., Barbany-Bustinza, G., Rantala, J., Ehrencrona, H., Karlsson, P., Domchek, S. M., Nathanson, K. L., Osorio, A., Blanco, I., Lasa, A., Benítez, J., Hamann, U., Hogervorst, F. B. L., Rookus, M. A., Collee, J. M., Devilee, P., Ligtenberg, M. J., van der Luijt, R. B., Aalfs, C. M., Waisfisz, Q., Wijnen, J., van Roozendaal, C. E. P., Peock, S., Cook, M., Frost, D., Oliver, C., Platte, R., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Chu, C., Eccles, D., Cole, T., Hodgson, S., Godwin, A. K., Stoppa-Lyonnet, D., Buecher, B., Léoné, M., Bressac-de Paillerets, B., Remenieras, A., Caron, O., Lenoir, G. M., Sevenet, N., Longy, M., Ferrer, S. F., Prieur, F., Goldgar, D., Miron, A., John, E. M., Buys, S. S., Daly, M. B., Hopper, J. L., Terry, M. B., Yassin, Y., Singer, C., Gschwantler-Kaulich, D., Staudigl, C., Hansen, T. V. O., Barkardottir, R. B., Kirchhoff, T., Pal, P., Kosarin, K., Offit, K., Piedmonte, M., Rodriguez, G. C., Wakeley, K., Boggess, J. F., Basil, J., Schwartz, P. E., Blank, S. V., Toland, A. E., Montagna, M., Casella, C., Imyanitov, E. N., Allavena, A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Deißler, H., Fiebig, B., Suttner, C., Schönbuchner, I., Gadzicki, D., Caldes, T., de la Hoya, M., Pooley, K. A., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Sinilnikova, O. M., McGuffog, L., Healey, S., Nevanlinna, H., Heikkinen, T., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Fredericksen, Z., Peterlongo, P., Peissel, B., Bonanni, B., Viel, A., Bernard, L., Radice, P., Szabo, C. I., Foretova, L., Zikan, M., Claes, K., Greene, M. H., Mai, P. L., Rennert, G., Lejbkowicz, F., Andrulis, I. L., Ozcelik, H., Glendon, G., Gerdes, A. -M, Thomassen, M., Sunde, L., Caligo, M. A., Laitman, Y., Kontorovich, T., Cohen, S., Kaufman, B., Dagan, E., Baruch, R. G., Friedman, E., Harbst, K., Barbany-Bustinza, G., Rantala, J., Ehrencrona, H., Karlsson, P., Domchek, S. M., Nathanson, K. L., Osorio, A., Blanco, I., Lasa, A., Benítez, J., Hamann, U., Hogervorst, F. B. L., Rookus, M. A., Collee, J. M., Devilee, P., Ligtenberg, M. J., van der Luijt, R. B., Aalfs, C. M., Waisfisz, Q., Wijnen, J., van Roozendaal, C. E. P., Peock, S., Cook, M., Frost, D., Oliver, C., Platte, R., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Chu, C., Eccles, D., Cole, T., Hodgson, S., Godwin, A. K., Stoppa-Lyonnet, D., Buecher, B., Léoné, M., Bressac-de Paillerets, B., Remenieras, A., Caron, O., Lenoir, G. M., Sevenet, N., Longy, M., Ferrer, S. F., Prieur, F., Goldgar, D., Miron, A., John, E. M., Buys, S. S., Daly, M. B., Hopper, J. L., Terry, M. B., Yassin, Y., Singer, C., Gschwantler-Kaulich, D., Staudigl, C., Hansen, T. V. O., Barkardottir, R. B., Kirchhoff, T., Pal, P., Kosarin, K., Offit, K., Piedmonte, M., Rodriguez, G. C., Wakeley, K., Boggess, J. F., Basil, J., Schwartz, P. E., Blank, S. V., Toland, A. E., Montagna, M., Casella, C., Imyanitov, E. N., Allavena, A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Deißler, H., Fiebig, B., Suttner, C., Schönbuchner, I., Gadzicki, D., Caldes, T., de la Hoya, M., Pooley, K. A., Easton, D. F., and Chenevix-Trench, G.

Abstract

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 × 10-4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not., The Swedish BRCA1 and BRCA2 Study (SWE-BRCA) SWE-BRCA collaborators: P.K., Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linkoping University Hospital; Ake Borg, Niklas Loman, Hakan Olsson, Ulf Kristoffersson, Helena Jernstrom, K.H. and Karin Henrisson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, G.B.-B. and J.R., Stockholm, Karolinska. University Hospital; Beatrice Malmer, Eva-Lena Stattin and Monica Emanuelsson, Umea University Hospital; H.E., Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital.

Published
2009
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29. No evidence that GATA3 rs570613 SNP modifies breast cancer risk

Author

Johnatty, S. E., Couch, F. J., Fredericksen, Z., Tarrell, R., Spurdle, A. B., Beesley, J., Chen, X., Gschwantler-Kaulich, D., Singer, C. F., Fuerhauser, C., Fink-Retter, A., Domchek, S. M., Nathanson, K. L., Pankratz, V. S., Lindor, N. M., Godwin, A. K., Caligo, M. A., Hopper, J., Southey, M. C., Giles, G. G., Justenhoven, C., Brauch, H., Hamann, U., Ko, Y. -D, Heikkinen, T., Aaltonen, K., Aittomäki, K., Blomqvist, C., Nevanlinna, H., Hall, P., Czene, K., Liu, J., Peock, S., Cook, M., Platte, R., Gareth Evans, D., Lalloo, F., Eeles, R., Pichert, G., Eccles, D., Davidson, R., Cole, T., Cook, J., Douglas, F., Chu, C., Hodgson, S., Paterson, J., Hogervorst, F. B. L., Rookus, M. A., Seynaeve, C., Wijnen, J., Vreeswijk, M., Ligtenberg, M., Van Der Luijt, R. B., Van Os, T. A. M., Gille, H. J. P., Blok, M. J., Issacs, C., Humphreys, M. K., McGuffog, L., Healey, S., Sinilnikova, O., Antoniou, A. C., Easton, D. F., Chenevix-Trench, G., Johnatty, S. E., Couch, F. J., Fredericksen, Z., Tarrell, R., Spurdle, A. B., Beesley, J., Chen, X., Gschwantler-Kaulich, D., Singer, C. F., Fuerhauser, C., Fink-Retter, A., Domchek, S. M., Nathanson, K. L., Pankratz, V. S., Lindor, N. M., Godwin, A. K., Caligo, M. A., Hopper, J., Southey, M. C., Giles, G. G., Justenhoven, C., Brauch, H., Hamann, U., Ko, Y. -D, Heikkinen, T., Aaltonen, K., Aittomäki, K., Blomqvist, C., Nevanlinna, H., Hall, P., Czene, K., Liu, J., Peock, S., Cook, M., Platte, R., Gareth Evans, D., Lalloo, F., Eeles, R., Pichert, G., Eccles, D., Davidson, R., Cole, T., Cook, J., Douglas, F., Chu, C., Hodgson, S., Paterson, J., Hogervorst, F. B. L., Rookus, M. A., Seynaeve, C., Wijnen, J., Vreeswijk, M., Ligtenberg, M., Van Der Luijt, R. B., Van Os, T. A. M., Gille, H. J. P., Blok, M. J., Issacs, C., Humphreys, M. K., McGuffog, L., Healey, S., Sinilnikova, O., Antoniou, A. C., Easton, D. F., and Chenevix-Trench, G.

Abstract

GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P trend = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269-2275]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (ORper-allele = 1.00, 95% CI 0.94-1.05), in ER negative BCAC cases (ORper-allele = 1.02, 95% CI 0.91-1.13), in BRCA1 mutation carriers RRper-allele = 0.99, 95% CI 0.90-1.09) or BRCA2 mutation carriers (RRper-allele = 0.93, 95% CI 0.80-1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women., The Swedish BRCA1 and BRCA2 study (SWE-BRCA) collaborators are Per Karlsson, Margareta Nordling, Annika Bergman, and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linkoping University Hospital; Ake Borg, Niklas Loman, Hakan Olsson, Ulf Kristoffersson, Helena Jernstrom, and Katja Backenhorn, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza, and Johanna Rantala, Stockholm, Karolinska University Hospital; Henrik Gronberg, Eva-Lena Stattin, and Monica Emanuelsson, Umea University Hospital; Hans Bostrom, Richard Rosenquist Brandell, and Niklas Dahl, Uppsala University Hospital.

Published
2009
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31. Distress in partners of individuals diagnosed with or at high risk of developing tumors due to rare hereditary cancer syndromes

Author

Lammens, C. R. M., primary, Bleiker, E. M. A., additional, Verhoef, S., additional, Ausems, M. G. E. M., additional, Majoor‐Krakauer, D., additional, Sijmons, R. H., additional, Hes, F. J., additional, Gómez‐García, E. B., additional, Van Os, T. A. M., additional, Spruijt, L., additional, van der Luijt, R. B., additional, van den Ouweland, A. M. W., additional, Ruijs, M. W. G., additional, Gundy, C., additional, Nagtegaal, T., additional, and Aaronson, N. K., additional

Published
2011
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36. Classification of BRCA 1 missense variants of unknown clinical significance.

Author

Phelan, C. M., Ðapić, V., Tice, B., Favis, R., Kwan, E., Barany, F., Manoukian, S., Radice, P., van der Luijt, R. B., van Nesselrooij, B. P. M., Chenevix-Trench, G., Caldes, T., de La Hoya, M., Lindquist, S., Tavilgian, S. V., Goldgar, D., Borg, Å., Narod, S. A., and Monteiro, A. N. A.

Subjects
TUMOR suppressor genes, CANCER genetics, GENETIC mutation, CANCER, CANCER in women, GENETIC transcription
Abstract

Background: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCAI are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. Objective: To investigate a panel of missense variants. Methods and results: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396–1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S15121, M1628T, M1628V, T16851, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R were specifically investigated. Contusions: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability. [ABSTRACT FROM AUTHOR]

Published
2005
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37. Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer

Author

Gao, C., Patel, C. J., Michailidou, K., Peters, U., Gong, J., Schildkraut, J., Schumacher, F. R., Zheng, W., Boffetta, P., Stucker, I., Willett, W., Gruber, S., Easton, D. F., Hunter, D. J., Sellers, T. A., Haiman, C., Henderson, B. E., Hung, R. J., Amos, C., Pierce, B. L., Lindström, S., Kraft, P., Hunter, D., Henderson, B., Sellers, T., Hopper, J. L., Southey, M. C., Makalic, E., Schmidt, D. F., Fletcher, O., Peto, J., Gibson, L., Silva, I. S., Waisfisz, Q., Meijers-Heijboer, H., Adank, M., van der Luijt, R. B., Uitterlinden, A. G., Hofman, A., Meindl, A., Schmutzler, R. K., Müller-Myhsok, B., Lichtner, P., Nevanlinna, H., Muranen, T. A., Aittomäki, K., Blomqvist, C., Chang-Claude, J., Hein, R., Dahmen, N., Beckman, L., Hall, P., Czene, K., Irwanto, A., Liu, J., Turnbull, C., Rahman, N., Cramer, D., Terry, K., Sutphen, R., Narod, S., Phelan, C., Risch, H., Pharoah, P., Gayther, S., Menon, U., Wentzensen, N., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Oncogenesis, CCA - Quality of life, and Gao, C. and Patel, C.J. and Michailidou, K. and Peters, U. and Gong, J. and Schildkraut, J. and Schumacher, F.R. and Zheng, W. and Boffetta, P. and Stucker, I. and Willett, W. and Gruber, S. and Easton, D.F. and Hunter, D.J. and Sellers, T.A. and Haiman, C. and Henderson, B.E. and Hung, R.J. and Amos, C. and Pierce, B.L. and Lindström, S. and Kraft, P. and Hunter, D. and Henderson, B. and Sellers, T. and Amos, C. and Hopper, J.L. and Southey, M.C. and Makalic, E. and Schmidt, D.F. and Fletcher, O. and Peto, J. and Gibson, L. and Silva, I.S. and Waisfisz, Q. and Meijers-Heijboer, H. and Adank, M. and van der Luijt, R.B. and Uitterlinden, A.G. and Hofman, A. and Meindl, A. and Schmutzler, R.K. and Müller-Myhsok, B. and Lichtner, P. and Nevanlinna, H. and Muranen, T.A. and Aittomäki, K. and Blomqvist, C. and Chang-Claude, J. and Hein, R. and Dahmen, N. and Beckman, L. and Hall, P. and Czene, K. and Irwanto, A. and Liu, J. and Turnbull, C. and Rahman, N. and Cramer, D. and Terry, K. and Sutphen, R. and Narod, S. and Phelan, C. and Risch, H. and Pharoah, P. and Gayther, S. and Menon, U. and Wentzensen, N.

Subjects
Male, Oncology, obesity, Epidemiology, smoking, adcy3 gene, health statu, Colorectal Neoplasm, cancer risk, genetic risk, lung tumor, Body Mass Index, genetic heterogeneity, 0302 clinical medicine, single nucleotide polymorphism, Epidemiology of cancer, Odds Ratio, tnn13k gene, 030212 general & internal medicine, sec16b gene, 2. Zero hunger, prostate tumor, breast tumor, adult, public health, allele, ovary cancer, General Medicine, prostate cancer, 3. Good health, gnpda2 gene, waist hip ratio, female, Phenotype, risk factor, priority journal, ovary tumor, 030220 oncology & carcinogenesis, child health, gnat2 gene, childhood obesity, Breast Neoplasm, cancer epidemiology, Human, single nucleotide polymorphism, Adiposity, medicine.medical_specialty, gpr61 gene, colorectal cancer, Polymorphism, Single Nucleotide, Article, olfm4 gene, Regression Analysi, 03 medical and health sciences, mc4r gene, Breast cancer, SDG 3 - Good Health and Well-being, tmem18 gene, Internal medicine, pleiotropy, Mendelian randomization, medicine, cancer, controlled study, Mendelian Randomization Analysi, Risk factor, gene, Lung cancer, Post-GWAS study, health risk, genome-wide association study, fto gene, Waist-Hip Ratio, business.industry, Ovarian Neoplasm, Waist-to-hip ratio, birth weight, Cancer, Odds ratio, medicine.disease, major clinical study, Lung Neoplasm, lung cancer, confidence interval, genetic variation, Prostatic Neoplasm, Neoplasm, genetic, business, Body mass index, body ma, colorectal tumor
Abstract

Background: Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers. Methods: We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium. Results: We found an inverse association between the genetic score for childhood BMI and risk of breast cancer [odds ratio (OR)=0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P=6.5×10-5). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR=0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P=2.5×10-7), and positively associated with ovarian cancer (OR=1.35; 95% CI: 1.05, 1.72; P=0.017), lung cancer (OR=1.27; 95% CI: 1.09, 1.49; P=2.9×10-3) and colorectal cancer (OR=1.39; 95% CI: 1.06, 1.82, P=0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression. Conclusions: Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status. © The Author 2016; Published by Oxford University Press on behalf of the International Epidemiological Association All rights reserved.

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40. Rapid genetic counseling and testing in newly diagnosed breast cancer patients, findings from an RCT.

Author

Wevers, M. R., Ausems, M. G., Bleiker, E. M., Rutgers, E. J., Witkamp, A. J., Hahn, D. E., Brouwer, T., Kuenen, M. A., van der Sanden-Melis, J., van der Luijt, R. B., Hogervorst, F. B., van Dalen, T., Theunissen, E. B., van Ooijen, B., de Roos, M. A., Borgstein, P. J., Vrouenraets, B. C., Huisman, J. J., Bouma, W. H., and Rijna, H.

Subjects
*BREAST cancer patients, *BRCA genes, *BREAST cancer research, *GENETIC mutation, *OVARIAN tumors, *BREAST cancer treatment
Abstract

Introduction: Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast and ovarian tumors. Rapid genetic counseling and testing (RGCT) may aid in making informed decisions about therapeutic and preventive surgery and adjuvant treatment. Little is known about the effects of RGCT on treatment decisions and psychosocial well-being. We have performed a randomized controlled trial to investigate these issues. Methods: Newly diagnosed breast cancer patients from 12 Dutch hospitals with at least a 10% risk of carrying a BRCA1/2 mutation were randomized to an intervention group (RGCT) or a usual care control group (ratio 2:1). Study outcomes included uptake of RGCT, choice of type of surgery, cancer risk perception, cancer-specific distress, quality of life and decisional satisfaction. Assessments took place at study entry, and at 6 and 12 months follow-up. Results: Between 2008 and 2010, 271 patients were recruited, of whom 3 subsequently withdrew. The remaining 268 patients were randomized to the intervention (n = 181) or control (n = 87) group. Complete questionnaire data were available for 250 (93%) and 243 (91%) patients at 6 and 12 months follow-up, respectively. Of the 181 women in the intervention group, 180 (98%) underwent genetic counseling after a median of 4 days. One-hundred thirteen (63%) of them opted for accelerated DNA test procedures, of whom 72 underwent rapid testing (results available in <4 weeks) and 41 semi-rapid testing (results available in 4 weeks to 4 months). DNA test results were available before primary surgery for 65 patients (36%) in the intervention group. Of these 65 patients, 8 (12%) were BRCA1/2 carriers and 11 (20%) had a bilateral mastectomy. Of the remaining 68 patients in the intervention group, 67 opted for standard DNA test procedures at some time during the study period. In the control group, 8 patients (9%) underwent rapid genetic counseling, of whom 7 underwent rapid DNA testing. In total, 22/220 (10%) of patients who had their DNA tested were BRCA1/2 mutation carriers. There was no statistically significant difference between the intervention and control group in percentage of patients with unilateral breast cancer opting for a bilateral mastectomy (12% versus 9%, p = 0.33). Of the BRCA1/2 carriers in the intervention group with unilateral breast cancer, 27% opted for a bilateral mastectomy. There was also no significant difference observed between the intervention and control groups in the percentage of patients opting for breast-conserving surgery rather than unilateral mastectomy (45% and 46% in the intervention and control group, respectively). Data on additional surgery performed during follow-up and psychosocial outcomes will be available at the time of the conference. Conclusion: The uptake of rapid genetic counseling among high-risk breast cancer patients was high, and the majority of patients underwent accelerated DNA-testing procedures. However, RGCT did not have a significant effect on choice of type of primary surgery. In part, this may be explained by the fact that surgeons and patients often did not wait for DNA test results before primary surgery. Conclusions regarding the psychosocial impact of RGCT will be presented at the time of the conference. [ABSTRACT FROM AUTHOR]

Published
2012
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41. Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas.

Author

Eijkelenkamp K, Olderode-Berends MJW, van der Luijt RB, Robledo M, van Dooren M, Feelders RA, de Vries J, Kerstens MN, Links TP, and van der Horst-Schrivers ANA

Subjects
Adrenal Gland Neoplasms pathology, Adult, Female, Genetic Testing, Germ-Line Mutation, Homozygote, Humans, Male, Middle Aged, Pheochromocytoma pathology, Adrenal Gland Neoplasms genetics, Genetic Predisposition to Disease, Membrane Proteins genetics, Pheochromocytoma genetics
Abstract

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL-susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year-old mentally retarded patient, the homozygous c.410-2A > G mutation was discovered during an update of DNA analysis. A 26-year-old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC-susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2018
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42. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

Author

Jakubowska A, Rozkrut D, Antoniou A, Hamann U, Scott RJ, McGuffog L, Healy S, Sinilnikova OM, Rennert G, Lejbkowicz F, Flugelman A, Andrulis IL, Glendon G, Ozcelik H, Thomassen M, Paligo M, Aretini P, Kantala J, Aroer B, von Wachenfeldt A, Liljegren A, Loman N, Herbst K, Kristoffersson U, Rosenquist R, Karlsson P, Stenmark-Askmalm M, Melin B, Nathanson KL, Domchek SM, Byrski T, Huzarski T, Gronwald J, Menkiszak J, Cybulski C, Serrano P, Osorio A, Cajal TR, Tsitlaidou M, Benítez J, Gilbert M, Rookus M, Aalfs CM, Kluijt I, Boessenkool-Pape JL, Meijers-Heijboer HE, Oosterwijk JC, van Asperen CJ, Blok MJ, Nelen MR, van den Ouweland AM, Seynaeve C, van der Luijt RB, Devilee P, Easton DF, Peock S, Frost D, Platte R, Ellis SD, Fineberg E, Evans DG, Lalloo F, Eeles R, Jacobs C, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Godwin A, Bove B, Stoppa-Lyonnet D, Caux-Moncoutier V, Belotti M, Tirapo C, Mazoyer S, Barjhoux L, Boutry-Kryza N, Pujol P, Coupier I, Peyrat JP, Vennin P, Muller D, Fricker JP, Venat-Bouvet L, Johannsson OT, Isaacs C, Schmutzler R, Wappenschmidt B, Meindl A, Arnold N, Varon-Mateeva R, Niederacher D, Sutter C, Deissler H, Preisler-Adams S, Simard J, Soucy P, Durocher F, Chenevix-Trench G, Beesley J, Chen X, Rebbeck T, Couch F, Wang X, Lindor N, Fredericksen Z, Pankratz VS, Peterlongo P, Bonanni B, Fortuzzi S, Peissel B, Szabo C, Mai PL, Loud JT, and Lubinski J

Subjects
Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Prohibitins, Risk, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Methylenetetrahydrofolate Reductase (NADPH2) genetics, Ovarian Neoplasms genetics, Polymorphism, Genetic, Repressor Proteins genetics
Abstract

Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity., Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively., Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele., Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Published
2012
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43. [From gene to disease; Von Hippel-Lindau disease].

Author

Hes FJ, Los M, and van der Luijt RB

Subjects
Genetic Predisposition to Disease, Humans, Genes, Tumor Suppressor, Germ-Line Mutation, Neoplasms genetics, von Hippel-Lindau Disease genetics
Abstract

Von Hippel-Lindau (VHL) disease is an autosomal, dominantly inherited, tumour syndrome. Carriers of a germline mutation in the VHL tumour suppressor genes are predisposed to develop tumours in various organs including the eye, cerebellum and kidney. These tumours are often multicentric or bilateral, and manifest at a younger age than in situations without a VHL germline mutation. VHL germline mutations are identified in virtually all families and sporadic patients with classic VHL disease. VHL associated tumours are richly vascularised. This is consistent with the involvement of the VHL protein in multiprotein complexes that degrade hypoxia-inducible factors dependent on cellular oxygen levels.

Published
2002

44. [From gene to disease; from the RET gene to multiple endocrine neoplasia types 2A and 2B, sporadic and familial medullary thyroid carcinoma, Hirschsprung disease and papillary thyroid carcinoma].

Author

Hofstra RM, van der Luijt RB, and Lips CJ

Subjects
DNA Mutational Analysis, Disease Management, Humans, Multiple Endocrine Neoplasia Type 2a epidemiology, Multiple Endocrine Neoplasia Type 2b epidemiology, Netherlands epidemiology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases metabolism, Carcinoma, Medullary genetics, Carcinoma, Papillary genetics, Drosophila Proteins, Hirschsprung Disease genetics, Multiple Endocrine Neoplasia Type 2a genetics, Multiple Endocrine Neoplasia Type 2b genetics, Mutation, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, Thyroid Neoplasms genetics
Abstract

The RET gene encodes a receptor tyrosine kinase involved in normal and neoplastic development of neural crest cell lineages. Activating RET mutations are present in patients with multiple endocrine neoplasia types 2A and 2B (MEN2A, 2B) and in familial medullary thyroid carcinoma (FMTC) patients, whereas inactivating RET mutations are found in patients with Hirschsprung (HSCR) disease. In particular for MEN2A and FMTC, the clinical management largely depends on the specific mutation found.

Published
2001

45. Clinical management of Von Hippel-Lindau (VHL) disease.

Author

Hes FJ, van der Luijt RB, and Lips CJ

Subjects
Humans, von Hippel-Lindau Disease diagnosis, von Hippel-Lindau Disease therapy
Abstract

Von Hippel-Lindau (VHL) disease is an autosomal, dominant inherited tumour syndrome with an estimated prevalence of 2-3 per 100,000 persons. A germline mutation in the VHL gene predisposes carriers to tumours in multiple organs. These tumours may include haemangioblastoma in the retina and central nervous system (CNS), renal cell carcinoma, phaeochromocytoma, islet cell tumours of the pancreas, and endolymphatic sac tumours, as well as cysts and cystadenoma in the kidney, pancreas, epididymis and broad ligament. Penetrance of VHL disease is high, most carriers of a VHL germline mutation develop one or more tumours by the age of 60 years. The most common symptoms include: loss of vision, raised intracranial pressure, neurological deficits, paroxysmal raised blood pressure and local pain. At present, metastases from renal cell carcinoma and neurological complications from cerebellar haemangioblastoma are the most common causes of death. However, it is anticipated that intensive radiological and clinical monitoring, and advanced operation techniques will reduce both morbidity and mortality in patients with VHL disease.

Published
2001
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46. Molecular genetic aspects of Von Hippel-Lindau (VHL) disease and criteria for DNA analysis in subjects at risk.

Author

Hes FJ, Lips CJ, and van der Luijt RB

Subjects
Ethics, Medical, Germ-Line Mutation, Humans, von Hippel-Lindau Disease diagnosis, von Hippel-Lindau Disease psychology, von Hippel-Lindau Disease genetics
Abstract

Von Hippel-Lindau (VHL) disease is an autosomal, dominantly inherited tumour syndrome. Carriers of a germline mutation in the VHL tumour suppressor gene tumours are predisposed to develop tumours that are multicentric or bilateral, and manifest at a younger age than in situations without a VHL germline mutation. The mutation spectrum is heterogeneous, with mutations scattered throughout most of the VHL gene. Although some recurrent mutations have been reported, most families have their own unique germline mutation. Tested individuals are no longer uncertain regarding their risk for developing the disease and family members who are non-carriers are relieved of the burden of repeated clinical monitoring.VHL germline mutations are identified in virtually all families and sporadic patients with classic VHL disease, but also in patients who do not meet clinical diagnostic criteria. The chance of finding a VHL germline mutation in (apparently) sporadic patients not fulfilling the criteria increases with: young age at diagnosis, the presence of multi-centric or bilateral tumours, involvement of multiple organs and a positive family history of VHL associated tumours.

Published
2001
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47. [Multiple endocrine neoplasia type 1: recent developments and guidelines for DNA diagnosis and periodic clinical monitoring].

Author

Dreijerink KM, Roijers JF, van der Luijt RB, Höppener JW, and Lips CJ

Subjects
Adult, Child, Diagnosis, Differential, Genetic Carrier Screening methods, Genetic Testing methods, Humans, Neoplasms, Multiple Primary genetics, Netherlands, Patient Selection, Practice Guidelines as Topic, DNA Mutational Analysis methods, Germ-Line Mutation genetics, Multiple Endocrine Neoplasia Type 1 diagnosis, Multiple Endocrine Neoplasia Type 1 genetics, Neoplasms, Multiple Primary diagnosis
Abstract

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as neuroendocrine carcinoid tumours. Since the identification of the responsible gene in 1997, the diagnosis MEN-1 can be assessed easily, and even presymptomatically, by DNA analysis. An early diagnosis is of importance because through periodic clinical monitoring of (putative) MEN1 gene germline mutation carriers, tumour development can be detected and treated at an early stage. Eligible for DNA analysis are MEN-1 patients and their family members, as well as patients with seemingly sporadic MEN-1 related tumours in whom on clinical grounds carriership of a MEN1 gene germline mutation is suspected. Eligible for periodic clinical monitoring are putative and confirmed carriers of a MEN1 germline mutation from the age of 5.

Published
2000

48. [From gene to disease; the APC gene and familial adenomatous polyposis coli].

Author

van der Luijt RB, Tops CM, and Vasen HF

Subjects
Adenomatous Polyposis Coli physiopathology, Adenomatous Polyposis Coli prevention & control, Adenomatous Polyposis Coli Protein, Cadherins genetics, Chromosomes, Human, Pair 5 genetics, Colorectal Neoplasms genetics, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genetic Testing, Humans, beta Catenin, Adenomatous Polyposis Coli genetics, Cytoskeletal Proteins genetics, Genes, APC genetics, Mutation, Missense, Trans-Activators
Abstract

Familial adenomatous polyposis coli is an autosomal dominant hereditary form of colorectal cancer associated with mutations in the adenomatous polyposis coli (APC) gene on chromosome 5. The APC protein is thought to mediate the stability of beta-catenin in the WNT signaling transduction pathway ('wingless-type mouse mammary tumor virus integration site family member') in normal colonic epithelial cells, thereby indirectly regulating the expression of WNT target genes such as the c-myc-oncogene. APC gene mutations cause the development of multiple adenomatous polyps in the colorectum, which strongly predisposes gene carriers to colorectal cancer. Extracolonic manifestations, including gastric and duodenal polyps, osteomas, desmoids, epidermoid cysts, and retinal lesions, are commonly observed in patients with familial adenomatous polyposis. Detection of mutations in the APC gene allows genetic counselling and reliable identification of at-risk individuals.

Published
2000

49. Criteria for mutation analysis in MEN 1-suspected patients: MEN 1 case-finding.

Author

Roijers JF, de Wit MJ, van der Luijt RB, Ploos van Amstel HK, Höppener JW, and Lips CJ

Subjects
Adult, Aged, DNA, Neoplasm isolation & purification, Exons, Family Health, Female, Humans, Introns, Male, Middle Aged, RNA, Neoplasm isolation & purification, DNA Mutational Analysis methods, Genetic Testing methods, Germ-Line Mutation, Multiple Endocrine Neoplasia Type 1 diagnosis, Multiple Endocrine Neoplasia Type 1 genetics
Abstract

Background: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal, dominantly inherited cancer syndrome, with tumours in various endocrine glands. In 1997 the responsible tumour suppressor gene was identified. MEN1 gene germ-line mutations are detected in the vast majority of MEN 1 patients, however, with regard to case-finding, unfortunately only at a very low frequency in patients with apparently sporadic MEN 1-related tumours. In order to increase the detection rate of disease gene carriers among patients with apparently sporadic MEN 1-related tumours, clinical criteria were needed., Design and Results: In this study MEN1 gene germ-line mutations were revealed in 16/16 MEN 1 patients/families (100%). Based on our clinical experience with MEN 1 patients/families we formulated clinical criteria to identify disease gene carriers among patients with apparently sporadic MEN 1-related tumours. The criteria for MEN 1-suspected patients are: young age at onset (< 35 years) and/or multiple MEN 1-related lesions in a single organ or two distinct organs affected. Application of these criteria yielded MEN1 gene germ-line mutations in nine of 15 MEN 1-suspected patients (60%), thus identifying novel MEN 1 families. Follow up was also guaranteed for patients not fulfilling these criteria., Conclusions: The clinical criteria for MEN 1-suspected patients increase the detection rate of germ-line MEN1 gene mutations among patients with apparently sporadic MEN 1-related tumours. These criteria may be used for (presymptomatic) identification of MEN 1 disease gene-carriers, thus enabling early detection of tumour development and timely treatment, as well as genetic counselling.

Published
2000
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50. [Von Hippel-Lindau disease: protocols for diagnosis and periodical clinical monitoring. National Von Hippel-Lindau Disease Working Group].

Author

Hes FJ and van der Luijt RB

Subjects
Clinical Protocols, Disease Management, Genetic Testing, Humans, Neoplasms genetics, Netherlands, Neoplasms diagnosis, von Hippel-Lindau Disease complications, von Hippel-Lindau Disease diagnosis, von Hippel-Lindau Disease genetics, von Hippel-Lindau Disease prevention & control
Abstract

Von Hippel-Lindau disease (VHL) is an autosomal dominantly inherited syndrome with high penetrance, characterised by tumours in various organs. The Dutch VHL working group presents guidelines for DNA testing and clinical monitoring, to enhance early detection and treatment of VHL patients in the Netherlands. Diagnosis of VHL is justified in patients presenting with a typical VHL tumour with a positive family history, but patients with a VHL tumour and a negative family history may also have VHL. Diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene which is informative in virtually all VHL families. In a patient with (suspicion for) VHL there is an indication for genetic counselling. A protocol for clinical monitoring of VHL is presented and is recommended for: carriers of a VHL germline mutation; members of VHL families with an unknown familial mutation; members of VHL families who decline testing of the familial mutation; patients suspected for VHL, but without a detectable VHL gene mutation.

Published
2000

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