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Title: Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers.
Authors: Blanco I,  Kuchenbaecker K,  Cuadras D,  Wang X,  Barrowdale D,  de Garibay GR,  Librado P,  Sánchez-Gracia A,  Rozas J,  Bonifaci N,  McGuffog L,  Pankratz VS,  Islam A,  Mateo F,  Berenguer A,  Petit A,  Català I,  Brunet J,  Feliubadaló L,  Tornero E,  Benítez J,  Osorio A,  Cajal TR,  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 AM,  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 KR,  Teixeira MR,  Teixeira,  Hogervorst FB,  van der Hout AH,  Seynaeve C,  van der Luijt RB,  Ligtenberg MJ,  Devilee P,  Wijnen JT,  Rookus MA,  Meijers-Heijboer HE,  Blok MJ,  van den Ouweland AM,  Aalfs CM,  Rodriguez GC,  Phillips KA,  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,  Gehrig A,  Bojesen A,  Pedersen IS,  Sunde L,  Jensen UB,  Thomassen M,  Kruse TA,  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 CF,  Rappaport C,  Geschwantler-Kaulich D,  Tea MK,  Pfeiler G,  BCFR,  John EM,  Miron A,  Neuhausen SL,  Terry MB,  Chung WK,  Daly MB,  Goldgar DE,  Janavicius R,  Dorfling CM,  van Rensburg EJ,  Fostira F,  Konstantopoulou I,  Garber J,  Godwin AK,  Olah E,  Narod SA,  Rennert G,  Paluch SS,  Laitman Y,  Friedman E,  SWE-BRCA,  Liljegren A,  Rantala J,  Stenmark-Askmalm M,  Loman N,  Imyanitov EN,  Hamann U,  kConFab Investigators,  Spurdle AB,  Healey S,  Weitzel JN,  Herzog J,  Margileth D,  Gorrini C,  Esteller M,  Gómez A,  Sayols S,  Vidal E,  Heyn H,  GEMO,  Stoppa-Lyonnet D,  Léoné M,  Barjhoux L,  Fassy-Colcombet M,  de Pauw A,  Lasset C,  Ferrer SF,  Castera L,  Berthet P,  Cornelis F,  Bignon YJ,  Damiola F,  Mazoyer S,  Sinilnikova OM,  Maxwell CA,  Vijai J,  Robson M,  Kauff N,  Corines MJ,  Villano D,  Cunningham J,  Lee A,  Lindor N,  Lázaro C,  Easton DF,  Offit K,  Chenevix-Trench G,  Couch FJ,  Antoniou AC,  Pujana MA
Journal: PLoS One
Date: 2015
Branches: CGB, GEB
PubMed ID: 25830658
PMC ID: PMC4382299
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.