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PloS one. 2015 Apr 1. doi: 10.1371/journal.pone.0120020. pii: PONE-D-14-28419. pmc: PMC4382299

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

Blanco I¹, Kuchenbaecker K², Cuadras D³, Wang X⁴, Barrowdale D⁵, de Garibay GR⁶, Librado P⁷, Sánchez-Gracia A⁸, Rozas J⁹, Bonifaci N¹⁰, McGuffog L¹¹, Pankratz VS¹², Islam A¹³, Mateo F¹⁴, Berenguer A¹⁵, Petit A¹⁶, Català I¹⁷, Brunet J¹⁸, Feliubadaló L¹⁹, Tornero E²⁰, Benítez J²¹, Osorio A²², Ramón y Cajal T²³, Nevanlinna H²⁴, Aittomäki K²⁵, Arun BK²⁶, Toland AE²⁷, Karlan BY²⁸, Walsh C²⁹, Lester J³⁰, Greene MH³¹, Mai PL³², Nussbaum RL³³, Andrulis IL³⁴, Domchek SM³⁵, Nathanson KL³⁶, Rebbeck TR³⁷, Barkardottir RB³⁸, Jakubowska A³⁹, Lubinski J⁴⁰, Durda K⁴¹, Jaworska-Bieniek K⁴², Claes K⁴³, Van Maerken T⁴⁴, Díez O⁴⁵, Hansen TV⁴⁶, Jønson L⁴⁷, Gerdes AM⁴⁸, Ejlertsen B⁴⁹, de la Hoya M⁵⁰, Caldés T⁵¹, Dunning AM⁵², Oliver C⁵³, Fineberg E⁵⁴, Cook M⁵⁵, Peock S⁵⁶, McCann E⁵⁷, Murray A⁵⁸, Jacobs C⁵⁹, Pichert G⁶⁰, Lalloo F⁶¹, Chu C⁶², Dorkins H⁶³, Paterson J⁶⁴, Ong KR⁶⁵, Teixeira MR⁶⁶, Hogervorst FB⁶⁷, van der Hout AH⁶⁸, Seynaeve C⁶⁹, van der Luijt RB⁷⁰, Ligtenberg MJ⁷¹, Devilee P⁷², Wijnen JT⁷³, Rookus MA⁷⁴, Meijers-Heijboer HE⁷⁵, Blok MJ⁷⁶, van den Ouweland AM⁷⁷, Aalfs CM⁷⁸, Rodriguez GC⁷⁹, Phillips KA⁸⁰, Piedmonte M⁸¹, Nerenstone SR⁸², Bae-Jump VL⁸³, O'Malley DM⁸⁴, Ratner ES⁸⁵, Schmutzler RK⁸⁶, Wappenschmidt B⁸⁷, Rhiem K⁸⁸, Engel C⁸⁹, Meindl A⁹⁰, Ditsch N⁹¹, Arnold N⁹², Plendl HJ⁹³, Niederacher D⁹⁴, Sutter C⁹⁵, Wang-Gohrke S⁹⁶, Steinemann D⁹⁷, Preisler-Adams S⁹⁸, Kast K⁹⁹, Varon-Mateeva R¹⁰⁰, Gehrig A¹⁰¹, Bojesen A¹⁰², Pedersen IS¹⁰³, Sunde L¹⁰⁴, Jensen UB¹⁰⁵, Thomassen M¹⁰⁶, Kruse TA¹⁰⁷, Foretova L¹⁰⁸, Peterlongo P¹⁰⁹, Bernard L¹¹⁰, Peissel B¹¹¹, Scuvera G¹¹², Manoukian S¹¹³, Radice P¹¹⁴, Ottini L¹¹⁵, Montagna M¹¹⁶, Agata S¹¹⁷, Maugard C¹¹⁸, Simard J¹¹⁹, Soucy P¹²⁰, Berger A¹²¹, Fink-Retter A¹²², Singer CF¹²³, Rappaport C¹²⁴, Geschwantler-Kaulich D¹²⁵, Tea MK¹²⁶, Pfeiler G¹²⁷, John EM¹²⁸, Miron A¹²⁹, Neuhausen SL¹³⁰, Terry MB¹³¹, Chung WK¹³², Daly MB¹³³, Goldgar DE¹³⁴, Janavicius R¹³⁵, Dorfling CM¹³⁶, van Rensburg EJ¹³⁷, Fostira F¹³⁸, Konstantopoulou I¹³⁹, Garber J¹⁴⁰, Godwin AK¹⁴¹, Olah E¹⁴², Narod SA¹⁴³, Rennert G¹⁴⁴, Paluch SS¹⁴⁵, Laitman Y¹⁴⁶, Friedman E¹⁴⁷, Liljegren A¹⁴⁸, Rantala J¹⁴⁹, Stenmark-Askmalm M¹⁵⁰, Loman N¹⁵¹, Imyanitov EN¹⁵², Hamann U¹⁵³, Spurdle AB¹⁵⁴, Healey S¹⁵⁵, Weitzel JN¹⁵⁶, Herzog J¹⁵⁷, Margileth D¹⁵⁸, Gorrini C¹⁵⁹, Esteller M¹⁶⁰, Gómez A¹⁶¹, Sayols S¹⁶², Vidal E¹⁶³, Heyn H¹⁶⁴, Stoppa-Lyonnet D¹⁶⁵, Léoné M¹⁶⁶, Barjhoux L¹⁶⁷, Fassy-Colcombet M¹⁶⁸, de Pauw A¹⁶⁹, Lasset C¹⁷⁰, Ferrer SF¹⁷¹, Castera L¹⁷², Berthet P¹⁷³, Cornelis F¹⁷⁴, Bignon YJ¹⁷⁵, Damiola F¹⁷⁶, Mazoyer S¹⁷⁷, Sinilnikova OM¹⁷⁸, Maxwell CA¹⁷⁹, Vijai J¹⁸⁰, Robson M¹⁸¹, Kauff N¹⁸², Corines MJ¹⁸³, Villano D¹⁸⁴, Cunningham J¹⁸⁵, Lee A¹⁸⁶, Lindor N¹⁸⁷, Lázaro C¹⁸⁸, Easton DF¹⁸⁹, Offit K¹⁹⁰, Chenevix-Trench G¹⁹¹, Couch FJ¹⁹², Antoniou AC¹⁹³, Pujana MA¹⁹⁴

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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.

Publikations ID: 25830658
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