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 Sanchez-Gracia, Julio Rozas, Nuria Bonifaci, Lesley McGuffog, Vernon S. Pankratz, Abul Islam, Francesca Mateo, Antoni Berenguer, Anna Petit, Isabel Catala, Joan Brunet, Lidia Feliubadalo, Eva TorneroJavier Benitez, Ana Osorio, Teresa Ramon Y. Cajal, Heli Nevanlinna, Kristiina Aittomaki, 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 Diez, Thomas V. Hansen, Lars Jonson, Anne-Marie Gerdes, Bent Ejlertsen, Annemarie H. van der Hout, BCFR, SWE-BRCA, kConFab Investigators, GEMO

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    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.

    Original languageEnglish
    Article numbere0120020
    Number of pages18
    JournalPLoS ONE
    Issue number4
    Publication statusPublished - 1-Apr-2015


    • CHIP-SEQ
    • CELL

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