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,
Vernon S Pankratz,
Abul Islam,
Francesca Mateo,
Antoni Berenguer,
Anna Petit,
Isabel Català,
Joan Brunet,
Lidia Feliubadaló,
Eva Tornero,
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,
Andrea Gehrig,
Anders Bojesen,
Inge Sokilde Pedersen,
Lone Sunde,
Uffe Birk Jensen,
Mads Thomassen,
Torben A Kruse,
Lenka Foretova,
Paolo Peterlongo,
Loris Bernard,
Bernard Peissel,
Giulietta Scuvera,
Siranoush Manoukian,
Paolo Radice,
Laura Ottini,
Marco Montagna,
Simona Agata,
Christine Maugard,
Jacques Simard,
Penny Soucy,
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,
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,
Andrew K Godwin,
Edith Olah,
Steven A Narod,
Gad Rennert,
Shani Shimon Paluch,
Yael Laitman,
Eitan Friedman,
,
Annelie Liljegren,
Johanna Rantala,
Marie Stenmark-Askmalm,
Niklas Loman,
Evgeny N Imyanitov,
Ute Hamann,
,
Amanda B Spurdle,
Sue Healey,
Jeffrey N Weitzel,
Josef Herzog,
David Margileth,
Chiara Gorrini,
Manel Esteller,
Antonio Gómez,
Sergi Sayols,
Enrique Vidal,
Holger Heyn,
,
Dominique Stoppa-Lyonnet,
Melanie Léoné,
Laure Barjhoux,
Marion Fassy-Colcombet,
Antoine de Pauw,
Christine Lasset,
Sandra Fert Ferrer,
Laurent Castera,
Pascaline Berthet,
François Cornelis,
Yves-Jean Bignon,
Francesca Damiola,
Sylvie Mazoyer,
Olga M Sinilnikova,
Christopher A Maxwell,
Joseph Vijai,
Mark Robson,
Noah Kauff,
Marina J Corines,
Danylko Villano,
Julie Cunningham,
Adam Lee,
Noralane Lindor,
Conxi Lázaro,
Douglas F Easton,
Kenneth Offit,
Georgia Chenevix-Trench,
Fergus J Couch,
Antonis C Antoniou,
Miguel Angel Pujana
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.