Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

Ignacio Blanco; Karoline Kuchenbaecker; Daniel Cuadras; Xianshu Wang; Daniel Barrowdale; Gorka Ruiz de Garibay; Pablo Librado; Alejandro Sánchez-Gracia; Julio Rozas; Núria Bonifaci; Lesley McGuffog; Andrea Gehrig; Anders Bojesen; Inge Sokilde Pedersen; Lone Sunde; Uffe Birk Jensen; Mads Thomassen; Torben A Kruse; Lenka Foretova; Paolo Peterlongo; Loris Bernard; Vernon S Pankratz; Bernard Peissel; Giulietta Scuvera; Siranoush Manoukian; Paolo Radice; Laura Ottini; Marco Montagna; Simona Agata; Christine Maugard; Jacques Simard; Penny Soucy; Abul Islam; Andreas Berger; Anneliese Fink-Retter; Christian F Singer; Christine Rappaport; Daphne Geschwantler-Kaulich; Muy-Kheng Tea; Georg Pfeiler; Esther M John; Alex Miron; Susan L Neuhausen; Francesca Mateo; Mary Beth Terry; Wendy K Chung; Mary B Daly; David E Goldgar; Ramunas Janavicius; Cecilia M Dorfling; Elisabeth J van Rensburg; Florentia Fostira; Irene Konstantopoulou; Judy Garber; Antoni Berenguer; Andrew K Godwin; Edith Olah; Steven A Narod; Gad Rennert; Shani Shimon Paluch; Yael Laitman; Eitan Friedman; Annelie Liljegren; Johanna Rantala; Marie Stenmark-Askmalm; Anna Petit; Niklas Loman; Evgeny N Imyanitov; Ute Hamann; Amanda B Spurdle; Sue Healey; Jeffrey N Weitzel; Josef Herzog; David Margileth; Chiara Gorrini; Manel Esteller; Isabel Català; Antonio Gómez; Sergi Sayols; Enrique Vidal; Holger Heyn; Dominique Stoppa-Lyonnet; Melanie Léoné; Laure Barjhoux; Marion Fassy-Colcombet; Antoine de Pauw; Christine Lasset; Joan Brunet; Sandra Fert Ferrer; Laurent Castera; Pascaline Berthet; François Cornelis; Yves-Jean Bignon; Francesca Damiola; Sylvie Mazoyer; Olga M Sinilnikova; Christopher A Maxwell; Joseph Vijai; Lidia Feliubadaló; Mark Robson; Noah Kauff; Marina J Corines; Danylko Villano; Julie Cunningham; Adam Lee; Noralane Lindor; Conxi Lázaro; Douglas F Easton; Kenneth Offit; Eva Tornero; Georgia Chenevix-Trench; Fergus J Couch; Antonis C Antoniou; Miguel Angel Pujana; Javier Benítez; Ana Osorio; Teresa Ramón y Cajal; Heli Nevanlinna; Kristiina Aittomäki; Banu K Arun; Amanda E Toland; Beth Y Karlan; Christine Walsh; Jenny Lester; Mark H Greene; Phuong L Mai; Robert L Nussbaum; Irene L Andrulis; Susan M Domchek; Katherine L Nathanson; Timothy R Rebbeck; Rosa B Barkardottir; Anna Jakubowska; Jan Lubinski; Katarzyna Durda; Katarzyna Jaworska-Bieniek; Kathleen Claes; Tom Van Maerken; Orland Díez; Thomas V Hansen; Lars Jønson; Anne-Marie Gerdes; Bent Ejlertsen; Miguel de la Hoya; Trinidad Caldés; Alison M Dunning; Clare Oliver; Elena Fineberg; Margaret Cook; Susan Peock; Emma McCann; Alex Murray; Chris Jacobs; Gabriella Pichert; Fiona Lalloo; Carol Chu; Huw Dorkins; Joan Paterson; Kai-Ren Ong; Manuel R Teixeira; Frans B L Hogervorst; Annemarie H van der Hout; Caroline Seynaeve; Rob B van der Luijt; Marjolijn J L Ligtenberg; Peter Devilee; Juul T Wijnen; Matti A Rookus; Hanne E J Meijers-Heijboer; Marinus J Blok; Ans M W van den Ouweland; Cora M Aalfs; Gustavo C Rodriguez; Kelly-Anne A Phillips; Marion Piedmonte; Stacy R Nerenstone; Victoria L Bae-Jump; David M O'Malley; Elena S Ratner; Rita K Schmutzler; Barbara Wappenschmidt; Kerstin Rhiem; Christoph Engel; Alfons Meindl; Nina Ditsch; Norbert Arnold; Hansjoerg J Plendl; Dieter Niederacher; Christian Sutter; Shan Wang-Gohrke; Doris Steinemann; Sabine Preisler-Adams; Karin Kast; Raymonda Varon-Mateeva

doi:10.1371/journal.pone.0120020

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

Ignacio Blanco, Karoline Kuchenbaecker, Daniel Cuadras, Xianshu Wang, Daniel Barrowdale, Gorka Ruiz de Garibay, Pablo Librado, Alejandro Sánchez-Gracia, Julio Rozas, Núria Bonifaci, Lesley McGuffog, Andrea Gehrig, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Uffe Birk Jensen, Mads Thomassen, Torben A Kruse, Lenka Foretova, Paolo PeterlongoLoris Bernard, Vernon S Pankratz, Bernard Peissel, Giulietta Scuvera, Siranoush Manoukian, Paolo Radice, Laura Ottini, Marco Montagna, Simona Agata, Christine Maugard, Jacques Simard, Penny Soucy, Abul Islam, Andreas Berger, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler-Kaulich, Muy-Kheng Tea, Georg Pfeiler, Esther M John, Alex Miron, Susan L Neuhausen, Francesca Mateo, Mary Beth Terry, Wendy K Chung, Mary B Daly, David E Goldgar, Ramunas Janavicius, Cecilia M Dorfling, Elisabeth J van Rensburg, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Antoni Berenguer, Andrew K Godwin, Edith Olah, Steven A Narod, Gad Rennert, Shani Shimon Paluch, Yael Laitman, Eitan Friedman, Annelie Liljegren, Johanna Rantala, Marie Stenmark-Askmalm, Anna Petit, Niklas Loman, Evgeny N Imyanitov, Ute Hamann, Amanda B Spurdle, Sue Healey, Jeffrey N Weitzel, Josef Herzog, David Margileth, Chiara Gorrini, Manel Esteller, Isabel Català, Antonio Gómez, Sergi Sayols, Enrique Vidal, Holger Heyn, Dominique Stoppa-Lyonnet, Melanie Léoné, Laure Barjhoux, Marion Fassy-Colcombet, Antoine de Pauw, Christine Lasset, Joan Brunet, Sandra Fert Ferrer, Laurent Castera, Pascaline Berthet, François Cornelis, Yves-Jean Bignon, Francesca Damiola, Sylvie Mazoyer, Olga M Sinilnikova, Christopher A Maxwell, Joseph Vijai, Lidia Feliubadaló, Mark Robson, Noah Kauff, Marina J Corines, Danylko Villano, Julie Cunningham, Adam Lee, Noralane Lindor, Conxi Lázaro, Douglas F Easton, Kenneth Offit, Eva Tornero, Georgia Chenevix-Trench, Fergus J Couch, Antonis C Antoniou, Miguel Angel Pujana, Javier Benítez, Ana Osorio, Teresa Ramón y Cajal, Heli Nevanlinna, Kristiina Aittomäki, Banu K Arun, Amanda E Toland, Beth Y Karlan, Christine Walsh, Jenny Lester, Mark H Greene, Phuong L Mai, Robert L Nussbaum, Irene L Andrulis, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Rosa B Barkardottir, Anna Jakubowska, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Kathleen Claes, Tom Van Maerken, Orland Díez, Thomas V Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Miguel de la Hoya, Trinidad Caldés, Alison M Dunning, Clare Oliver, Elena Fineberg, Margaret Cook, Susan Peock, Emma McCann, Alex Murray, Chris Jacobs, Gabriella Pichert, Fiona Lalloo, Carol Chu, Huw Dorkins, Joan Paterson, Kai-Ren Ong, Manuel R Teixeira, Frans B L Hogervorst, Annemarie H van der Hout, Caroline Seynaeve, Rob B van der Luijt, Marjolijn J L Ligtenberg, Peter Devilee, Juul T Wijnen, Matti A Rookus, Hanne E J Meijers-Heijboer, Marinus J Blok, Ans M W van den Ouweland, Cora M Aalfs, Gustavo C Rodriguez, Kelly-Anne A Phillips, Marion Piedmonte, Stacy R Nerenstone, Victoria L Bae-Jump, David M O'Malley, Elena S Ratner, Rita K Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg J Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva

Landspitali - The National University Hospital of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Original language	English
Journal	PLoS ONE
DOIs	https://doi.org/10.1371/journal.pone.0120020
Publication status	Published - 2015

Other keywords

Brjóstakrabbamein
Arfgengi
Genome-Wide Association Study
Transcriptome
Genetic Loci
Cells
Polymorphism, Genetic
Survival
Elements
BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/genetics
Genes, BRCA1
Genes, BRCA2

Access to Document

10.1371/journal.pone.0120020

Cite this

Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, X., Barrowdale, D., de Garibay, G. R., Librado, P., Sánchez-Gracia, A., Rozas, J., Bonifaci, N., McGuffog, L., Gehrig, A., Bojesen, A., Pedersen, I. S., Sunde, L., Jensen, U. B., Thomassen, M., Kruse, T. A., Foretova, L., ... Varon-Mateeva, R. (2015). Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers. PLoS ONE. https://doi.org/10.1371/journal.pone.0120020

@article{3d96a47dd4394924a42aca0544ecdc63,

title = "Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.",

abstract = "While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.",

keywords = "Brj{\'o}stakrabbamein, Arfgengi, Genome-Wide Association Study, Transcriptome, Genetic Loci, Cells, Polymorphism, Genetic, Survival, Elements, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Genes, BRCA1, Genes, BRCA2, Brj{\'o}stakrabbamein, Arfgengi, Genome-Wide Association Study, Transcriptome, Genetic Loci, Cells, Polymorphism, Genetic, Survival, Elements, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Genes, BRCA1, Genes, BRCA2",

author = "Ignacio Blanco and Karoline Kuchenbaecker and Daniel Cuadras and Xianshu Wang and Daniel Barrowdale and {de Garibay}, {Gorka Ruiz} and Pablo Librado and Alejandro S{\'a}nchez-Gracia and Julio Rozas and N{\'u}ria Bonifaci and Lesley McGuffog and Andrea Gehrig and Anders Bojesen and Pedersen, {Inge Sokilde} and Lone Sunde and Jensen, {Uffe Birk} and Mads Thomassen and Kruse, {Torben A} and Lenka Foretova and Paolo Peterlongo and Loris Bernard and Pankratz, {Vernon S} and Bernard Peissel and Giulietta Scuvera and Siranoush Manoukian and Paolo Radice and Laura Ottini and Marco Montagna and Simona Agata and Christine Maugard and Jacques Simard and Penny Soucy and Abul Islam and Andreas Berger and Anneliese Fink-Retter and Singer, {Christian F} and Christine Rappaport and Daphne Geschwantler-Kaulich and Muy-Kheng Tea and Georg Pfeiler and John, {Esther M} and Alex Miron and Neuhausen, {Susan L} and Francesca Mateo and Terry, {Mary Beth} and Chung, {Wendy K} and Daly, {Mary B} and Goldgar, {David E} and Ramunas Janavicius and Dorfling, {Cecilia M} and {van Rensburg}, {Elisabeth J} and Florentia Fostira and Irene Konstantopoulou and Judy Garber and Antoni Berenguer and Godwin, {Andrew K} and Edith Olah and Narod, {Steven A} and Gad Rennert and Paluch, {Shani Shimon} and Yael Laitman and Eitan Friedman and Annelie Liljegren and Johanna Rantala and Marie Stenmark-Askmalm and Anna Petit and Niklas Loman and Imyanitov, {Evgeny N} and Ute Hamann and Spurdle, {Amanda B} and Sue Healey and Weitzel, {Jeffrey N} and Josef Herzog and David Margileth and Chiara Gorrini and Manel Esteller and Isabel Catal{\`a} and Antonio G{\'o}mez and Sergi Sayols and Enrique Vidal and Holger Heyn and Dominique Stoppa-Lyonnet and Melanie L{\'e}on{\'e} and Laure Barjhoux and Marion Fassy-Colcombet and {de Pauw}, Antoine and Christine Lasset and Joan Brunet and Ferrer, {Sandra Fert} and Laurent Castera and Pascaline Berthet and Fran{\c c}ois Cornelis and Yves-Jean Bignon and Francesca Damiola and Sylvie Mazoyer and Sinilnikova, {Olga M} and Maxwell, {Christopher A} and Joseph Vijai and Lidia Feliubadal{\'o} and Mark Robson and Noah Kauff and Corines, {Marina J} and Danylko Villano and Julie Cunningham and Adam Lee and Noralane Lindor and Conxi L{\'a}zaro and Easton, {Douglas F} and Kenneth Offit and Eva Tornero and Georgia Chenevix-Trench and Couch, {Fergus J} and Antoniou, {Antonis C} and Pujana, {Miguel Angel} and Javier Ben{\'i}tez and Ana Osorio and {Ram{\'o}n y Cajal}, Teresa and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Arun, {Banu K} and Toland, {Amanda E} and Karlan, {Beth Y} and Christine Walsh and Jenny Lester and Greene, {Mark H} and Mai, {Phuong L} and Nussbaum, {Robert L} and Andrulis, {Irene L} and Domchek, {Susan M} and Nathanson, {Katherine L} and Rebbeck, {Timothy R} and Barkardottir, {Rosa B} and Anna Jakubowska and Jan Lubinski and Katarzyna Durda and Katarzyna Jaworska-Bieniek and Kathleen Claes and {Van Maerken}, Tom and Orland D{\'i}ez and Hansen, {Thomas V} and Lars J{\o}nson and Anne-Marie Gerdes and Bent Ejlertsen and {de la Hoya}, Miguel and Trinidad Cald{\'e}s and Dunning, {Alison M} and Clare Oliver and Elena Fineberg and Margaret Cook and Susan Peock and Emma McCann and Alex Murray and Chris Jacobs and Gabriella Pichert and Fiona Lalloo and Carol Chu and Huw Dorkins and Joan Paterson and Kai-Ren Ong and Teixeira, {Manuel R} and Hogervorst, {Frans B L} and {van der Hout}, {Annemarie H} and Caroline Seynaeve and {van der Luijt}, {Rob B} and Ligtenberg, {Marjolijn J L} and Peter Devilee and Wijnen, {Juul T} and Rookus, {Matti A} and Meijers-Heijboer, {Hanne E J} and Blok, {Marinus J} and {van den Ouweland}, {Ans M W} and Aalfs, {Cora M} and Rodriguez, {Gustavo C} and Phillips, {Kelly-Anne A} and Marion Piedmonte and Nerenstone, {Stacy R} and Bae-Jump, {Victoria L} and O'Malley, {David M} and Ratner, {Elena S} and Schmutzler, {Rita K} and Barbara Wappenschmidt and Kerstin Rhiem and Christoph Engel and Alfons Meindl and Nina Ditsch and Norbert Arnold and Plendl, {Hansjoerg J} and Dieter Niederacher and Christian Sutter and Shan Wang-Gohrke and Doris Steinemann and Sabine Preisler-Adams and Karin Kast and Raymonda Varon-Mateeva",

year = "2015",

doi = "10.1371/journal.pone.0120020",

language = "English",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

}

Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, X, Barrowdale, D, de Garibay, GR, Librado, P, Sánchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Gehrig, A, Bojesen, A, Pedersen, IS, Sunde, L, Jensen, UB, Thomassen, M, Kruse, TA, Foretova, L, Peterlongo, P, Bernard, L, Pankratz, VS, Peissel, B, Scuvera, G, Manoukian, S, Radice, P, Ottini, L, Montagna, M, Agata, S, Maugard, C, Simard, J, Soucy, P, Islam, A, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Geschwantler-Kaulich, D, Tea, M-K, Pfeiler, G, John, EM, Miron, A, Neuhausen, SL, Mateo, F, Terry, MB, Chung, WK, Daly, MB, Goldgar, DE, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Fostira, F, Konstantopoulou, I, Garber, J, Berenguer, A, Godwin, AK, Olah, E, Narod, SA, Rennert, G, Paluch, SS, Laitman, Y, Friedman, E, Liljegren, A, Rantala, J, Stenmark-Askmalm, M, Petit, A, Loman, N, Imyanitov, EN, Hamann, U, Spurdle, AB, Healey, S, Weitzel, JN, Herzog, J, Margileth, D, Gorrini, C, Esteller, M, Català, I, Gómez, A, Sayols, S, Vidal, E, Heyn, H, Stoppa-Lyonnet, D, Léoné, M, Barjhoux, L, Fassy-Colcombet, M, de Pauw, A, Lasset, C, Brunet, J, Ferrer, SF, Castera, L, Berthet, P, Cornelis, F, Bignon, Y-J, Damiola, F, Mazoyer, S, Sinilnikova, OM, Maxwell, CA, Vijai, J, Feliubadaló, L, Robson, M, Kauff, N, Corines, MJ, Villano, D, Cunningham, J, Lee, A, Lindor, N, Lázaro, C, Easton, DF, Offit, K, Tornero, E, Chenevix-Trench, G, Couch, FJ, Antoniou, AC, Pujana, MA, Benítez, J, Osorio, A, Ramón y Cajal, T, Nevanlinna, H, Aittomäki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Díez, O, Hansen, TV, Jønson, L, Gerdes, A-M, Ejlertsen, B, de la Hoya, M, Caldés, T, Dunning, AM, Oliver, C, Fineberg, E, Cook, M, Peock, S, McCann, E, Murray, A, Jacobs, C, Pichert, G, Lalloo, F, Chu, C, Dorkins, H, Paterson, J, Ong, K-R, Teixeira, MR, Hogervorst, FBL, van der Hout, AH, Seynaeve, C, van der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, van den Ouweland, AMW, Aalfs, CM, Rodriguez, GC, Phillips, K-AA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K & Varon-Mateeva, R 2015, 'Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.', PLoS ONE. https://doi.org/10.1371/journal.pone.0120020

TY - JOUR

T1 - Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

AU - Blanco, Ignacio

AU - Kuchenbaecker, Karoline

AU - Cuadras, Daniel

AU - Wang, Xianshu

AU - Barrowdale, Daniel

AU - de Garibay, Gorka Ruiz

AU - Librado, Pablo

AU - Sánchez-Gracia, Alejandro

AU - Rozas, Julio

AU - Bonifaci, Núria

AU - McGuffog, Lesley

AU - Gehrig, Andrea

AU - Bojesen, Anders

AU - Pedersen, Inge Sokilde

AU - Sunde, Lone

AU - Jensen, Uffe Birk

AU - Thomassen, Mads

AU - Kruse, Torben A

AU - Foretova, Lenka

AU - Peterlongo, Paolo

AU - Bernard, Loris

AU - Pankratz, Vernon S

AU - Peissel, Bernard

AU - Scuvera, Giulietta

AU - Manoukian, Siranoush

AU - Radice, Paolo

AU - Ottini, Laura

AU - Montagna, Marco

AU - Agata, Simona

AU - Maugard, Christine

AU - Simard, Jacques

AU - Soucy, Penny

AU - Islam, Abul

AU - Berger, Andreas

AU - Fink-Retter, Anneliese

AU - Singer, Christian F

AU - Rappaport, Christine

AU - Geschwantler-Kaulich, Daphne

AU - Tea, Muy-Kheng

AU - Pfeiler, Georg

AU - John, Esther M

AU - Miron, Alex

AU - Neuhausen, Susan L

AU - Mateo, Francesca

AU - Terry, Mary Beth

AU - Chung, Wendy K

AU - Daly, Mary B

AU - Goldgar, David E

AU - Janavicius, Ramunas

AU - Dorfling, Cecilia M

AU - van Rensburg, Elisabeth J

AU - Fostira, Florentia

AU - Konstantopoulou, Irene

AU - Garber, Judy

AU - Berenguer, Antoni

AU - Godwin, Andrew K

AU - Olah, Edith

AU - Narod, Steven A

AU - Rennert, Gad

AU - Paluch, Shani Shimon

AU - Laitman, Yael

AU - Friedman, Eitan

AU - Liljegren, Annelie

AU - Rantala, Johanna

AU - Stenmark-Askmalm, Marie

AU - Petit, Anna

AU - Loman, Niklas

AU - Imyanitov, Evgeny N

AU - Hamann, Ute

AU - Spurdle, Amanda B

AU - Healey, Sue

AU - Weitzel, Jeffrey N

AU - Herzog, Josef

AU - Margileth, David

AU - Gorrini, Chiara

AU - Esteller, Manel

AU - Català, Isabel

AU - Gómez, Antonio

AU - Sayols, Sergi

AU - Vidal, Enrique

AU - Heyn, Holger

AU - Stoppa-Lyonnet, Dominique

AU - Léoné, Melanie

AU - Barjhoux, Laure

AU - Fassy-Colcombet, Marion

AU - de Pauw, Antoine

AU - Lasset, Christine

AU - Brunet, Joan

AU - Ferrer, Sandra Fert

AU - Castera, Laurent

AU - Berthet, Pascaline

AU - Cornelis, François

AU - Bignon, Yves-Jean

AU - Damiola, Francesca

AU - Mazoyer, Sylvie

AU - Sinilnikova, Olga M

AU - Maxwell, Christopher A

AU - Vijai, Joseph

AU - Feliubadaló, Lidia

AU - Robson, Mark

AU - Kauff, Noah

AU - Corines, Marina J

AU - Villano, Danylko

AU - Cunningham, Julie

AU - Lee, Adam

AU - Lindor, Noralane

AU - Lázaro, Conxi

AU - Easton, Douglas F

AU - Offit, Kenneth

AU - Tornero, Eva

AU - Chenevix-Trench, Georgia

AU - Couch, Fergus J

AU - Antoniou, Antonis C

AU - Pujana, Miguel Angel

AU - Benítez, Javier

AU - Osorio, Ana

AU - Ramón y Cajal, Teresa

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Arun, Banu K

AU - Toland, Amanda E

AU - Karlan, Beth Y

AU - Walsh, Christine

AU - Lester, Jenny

AU - Greene, Mark H

AU - Mai, Phuong L

AU - Nussbaum, Robert L

AU - Andrulis, Irene L

AU - Domchek, Susan M

AU - Nathanson, Katherine L

AU - Rebbeck, Timothy R

AU - Barkardottir, Rosa B

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Durda, Katarzyna

AU - Jaworska-Bieniek, Katarzyna

AU - Claes, Kathleen

AU - Van Maerken, Tom

AU - Díez, Orland

AU - Hansen, Thomas V

AU - Jønson, Lars

AU - Gerdes, Anne-Marie

AU - Ejlertsen, Bent

AU - de la Hoya, Miguel

AU - Caldés, Trinidad

AU - Dunning, Alison M

AU - Oliver, Clare

AU - Fineberg, Elena

AU - Cook, Margaret

AU - Peock, Susan

AU - McCann, Emma

AU - Murray, Alex

AU - Jacobs, Chris

AU - Pichert, Gabriella

AU - Lalloo, Fiona

AU - Chu, Carol

AU - Dorkins, Huw

AU - Paterson, Joan

AU - Ong, Kai-Ren

AU - Teixeira, Manuel R

AU - Hogervorst, Frans B L

AU - van der Hout, Annemarie H

AU - Seynaeve, Caroline

AU - van der Luijt, Rob B

AU - Ligtenberg, Marjolijn J L

AU - Devilee, Peter

AU - Wijnen, Juul T

AU - Rookus, Matti A

AU - Meijers-Heijboer, Hanne E J

AU - Blok, Marinus J

AU - van den Ouweland, Ans M W

AU - Aalfs, Cora M

AU - Rodriguez, Gustavo C

AU - Phillips, Kelly-Anne A

AU - Piedmonte, Marion

AU - Nerenstone, Stacy R

AU - Bae-Jump, Victoria L

AU - O'Malley, David M

AU - Ratner, Elena S

AU - Schmutzler, Rita K

AU - Wappenschmidt, Barbara

AU - Rhiem, Kerstin

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Ditsch, Nina

AU - Arnold, Norbert

AU - Plendl, Hansjoerg J

AU - Niederacher, Dieter

AU - Sutter, Christian

AU - Wang-Gohrke, Shan

AU - Steinemann, Doris

AU - Preisler-Adams, Sabine

AU - Kast, Karin

AU - Varon-Mateeva, Raymonda

PY - 2015

Y1 - 2015

N2 - While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

AB - While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

KW - Brjóstakrabbamein

KW - Arfgengi

KW - Genome-Wide Association Study

KW - Transcriptome

KW - Genetic Loci

KW - Cells

KW - Polymorphism, Genetic

KW - Survival

KW - Elements

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Brjóstakrabbamein

KW - Arfgengi

KW - Genome-Wide Association Study

KW - Transcriptome

KW - Genetic Loci

KW - Cells

KW - Polymorphism, Genetic

KW - Survival

KW - Elements

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Genes, BRCA1

KW - Genes, BRCA2

U2 - 10.1371/journal.pone.0120020

DO - 10.1371/journal.pone.0120020

M3 - Article

C2 - 25830658

SN - 1932-6203

JO - PLoS ONE

JF - PLoS ONE

ER -

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

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