Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

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Blanco , I , Kuchenbaecker , K , Cuadras , D , Wang , X , Barrowdale , D , Ruiz de Garibay , G , Librado , P , Sanchez-Gracia , A , Rozas , J , Bonifaci , N , McGuffog , L , Pankratz , V S , Islam , A , Mateo , F , Berenguer , A , Petit , A , Catala , I , Brunet , J , Feliubadalo , L , Tornero , E , Benitez , J , Osorio , A , Cajal , T R Y , Nevanlinna , H , Aittomaki , K , Arun , B K , Toland , A E , Karlan , B Y , Walsh , C , Lester , J , Greene , M H , Mai , P L , Nussbaum , R L , Andrulis , I L , Domchek , S M , Nathanson , K L , Rebbeck , T R , Barkardottir , R B , Jakubowska , A , Lubinski , J , Durda , K , Jaworska-Bieniek , K , Claes , K , Van Maerken , T , Diez , O , Hansen , T V , Jonson , L , Gerdes , A-M , Ejlertsen , B , de la Hoya , M , Caldes , T , Dunning , A M , 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 , M R , Teixeira , Hogervorst , F B L , van der Hout , A H , Seynaeve , C , van der Luijt , R B , Ligtenberg , M J L , Devilee , P , Wijnen , J T , Rookus , M A , Meijers-Heijboer , H E J , Blok , M J , van den Ouweland , A M W , Aalfs , C M , Rodriguez , G C , Phillips , K-A A , Piedmonte , M , Nerenstone , S R , Bae-Jump , V L , O'Malley , D M , Ratner , E S , Schmutzler , R K , Wappenschmidt , B , Rhiem , K , Engel , C , Meindl , A , Ditsch , N , Arnold , N , Plendl , H J , Niederacher , D , Sutter , C , Wang-Gohrke , S , Steinemann , D , Preisler-Adams , S , Kast , K , Varon-Mateeva , R , Gehrig , A , Bojesen , A , Pedersen , I S , Sunde , L , Jensen , U B , Thomassen , M , Kruse , T A , Foretova , L , Peterlongo , P , Bernard , L , Peissel , B , Scuvera , G , Manoukian , S , Radice , P , Ottini , L , Montagna , M , Agata , S , Maugard , C , Simard , J , Soucy , P , Berger , A , Fink-Retter , A , Singer , C F , Rappaport , C , Geschwantler-Kaulich , D , Tea , M-K , Pfeiler , G , John , E M , Miron , A , Neuhausen , S L , Terry , M B , Chung , W K , Daly , M B , Goldgar , D E , Janavicius , R , Dorfling , C M , van Rensburg , E J , Fostira , F , Konstantopoulou , I , Garber , J , Godwin , A K , Olah , E , Narod , S A , Rennert , G , Paluch , S S , Laitman , Y , Friedman , E , Liljegren , A , Rantala , J , Stenmark-Askmalm , M , Loman , N , Imyanitov , E N , Hamann , U , Spurdle , A B , Healey , S , Weitzel , J N , Herzog , J , Margileth , D , Gorrini , C , Esteller , M , Gomez , A , Sayols , S , Vidal , E , Heyn , H , Stoppa-Lyonnet , D , Leone , M , Barjhoux , L , Fassy-Colcombet , M , de Pauw , A , Lasset , C , Ferrer , S F , Castera , L , Berthet , P , Cornelis , F , Bignon , Y-J , Damiola , F , Mazoyer , S , Sinilnikova , O M , Maxwell , C A , Vijai , J , Robson , M , Kauff , N , Corines , M J , Villano , D , Cunningham , J , Lee , A , Lindor , N , Lazaro , C , Easton , D F , Offit , K , Chenevix-Trench , G , Couch , F J , Antoniou , A C , Angel Pujana , M , BCFR , SWE-BRCA , KConFab Investigators & GEMO 2015 , ' Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers ' PLoS One , vol. 10 , no. 4 , 0120020 . DOI: 10.1371/journal.pone.0120020

Title: Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers
Author: Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; Ruiz de Garibay, Gorka; Librado, Pablo; Sanchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Nuria; McGuffog, Lesley; Pankratz, Vernon S.; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Catala, Isabel; Brunet, Joan; Feliubadalo, Lidia; Tornero, Eva; Benitez, Javier; Osorio, Ana; Cajal, Teresa Ramon Y.; Nevanlinna, Heli; Aittomaki, Kristiina; Arun, Banu K.; Toland, Amanda E.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Greene, Mark H.; Mai, Phuong L.; Nussbaum, Robert L.; Andrulis, Irene L.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Barkardottir, Rosa B.; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Diez, Orland; Hansen, Thomas V.; Jonson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldes, Trinidad; Dunning, Alison M.; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R.; Teixeira,; Hogervorst, Frans B. L.; van der Hout, Annemarie H.; Seynaeve, Caroline; van der Luijt, Rob B.; Ligtenberg, Marjolijn J. L.; Devilee, Peter; Wijnen, Juul T.; Rookus, Matti A.; Meijers-Heijboer, Hanne E. J.; Blok, Marinus J.; van den Ouweland, Ans M. W.; Aalfs, Cora M.; Rodriguez, Gustavo C.; Phillips, Kelly-Anne A.; Piedmonte, Marion; Nerenstone, Stacy R.; Bae-Jump, Victoria L.; O'Malley, David M.; Ratner, Elena S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J.; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A.; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M.; Miron, Alex; Neuhausen, Susan L.; Terry, Mary Beth; Chung, Wendy K.; Daly, Mary B.; Goldgar, David E.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elisabeth J.; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K.; Olah, Edith; Narod, Steven A.; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N.; Hamann, Ute; Spurdle, Amanda B.; Healey, Sue; Weitzel, Jeffrey N.; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gomez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Leone, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, Francois; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.; Maxwell, Christopher A.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J.; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lazaro, Conxi; Easton, Douglas F.; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J.; Antoniou, Antonis C.; Angel Pujana, Miguel; BCFR; SWE-BRCA; KConFab Investigators; GEMO
Contributor: University of Helsinki, Department of Obstetrics and Gynegology
University of Helsinki, Department of Medical and Clinical Genetics
Date: 2015-04-01
Language: eng
Number of pages: 18
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/157025
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 p(interaction) 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.
Subject: GENETIC INTERACTION NETWORKS
GENOME-WIDE ASSOCIATION
EXPRESSION SIGNATURE
SUSCEPTIBILITY LOCI
CHIP-SEQ
CELL
POLYMORPHISM
MODIFIERS
SURVIVAL
ELEMENTS
3111 Biomedicine
3122 Cancers
3123 Gynaecology and paediatrics
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