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; Teixeira

doi:10.1371/journal.pone.0120020

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 TorneroJavier 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, Teixeira

Institut for Klinisk Medicin

17 Citationer (Scopus)

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 × 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.

Originalsprog	Engelsk
Artikelnummer	e0120020
Tidsskrift	P L o S One
Vol/bind	10
Udgave nummer	4
Sider (fra-til)	1-18
Antal sider	18
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0120020
Status	Udgivet - 1 apr. 2015

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Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, X., Barrowdale, D., de Garibay, G. R., Librado, P., Sánchez-Gracia, A., Rozas, J., Bonifaci, N., McGuffog, L., Pankratz, V. S., Islam, A., Mateo, F., Berenguer, A., Petit, A., Català, I., Brunet, J., Feliubadaló, L., ... Teixeira (2015). Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers. P L o S One, 10(4), 1-18. [e0120020]. https://doi.org/10.1371/journal.pone.0120020

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, Ramón y Cajal, T, 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, A-M, Ejlertsen, B, de la Hoya, M & Teixeira 2015, 'Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers', P L o S One, bind 10, nr. 4, e0120020, s. 1-18. https://doi.org/10.1371/journal.pone.0120020

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

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 × 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.",

keywords = "Antigens, CD44, Aurora Kinase A, Breast Neoplasms, Carcinogenesis, Cell Cycle Proteins, Estrogen Receptor alpha, Evolution, Molecular, Extracellular Matrix Proteins, Female, Genes, BRCA1, Genes, BRCA2, Genetic Loci, Genetic Predisposition to Disease, Humans, Likelihood Functions, Mammary Glands, Human, Microtubule-Associated Proteins, Mutation, Nuclear Proteins, Polymorphism, Single Nucleotide, Retrospective Studies, Tubulin",

author = "Ignacio Blanco and Karoline Kuchenbaecker and Daniel Cuadras and Xianshu Wang and Daniel Barrowdale and {de Garibay}, {Gorka Ruiz} and Pablo Librado and Alejandro S{\'a}nchez-Gracia and Julio Rozas and N{\'u}ria Bonifaci and Lesley McGuffog and Pankratz, {Vernon S} and Abul Islam and Francesca Mateo and Antoni Berenguer and Anna Petit and Isabel Catal{\`a} and Joan Brunet and Lidia Feliubadal{\'o} and Eva Tornero and Javier Ben{\'i}tez and Ana Osorio and {Ram{\'o}n y Cajal}, Teresa and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Arun, {Banu K} and Toland, {Amanda E} and Karlan, {Beth Y} and Christine Walsh and Jenny Lester and Greene, {Mark H} and Mai, {Phuong L} and Nussbaum, {Robert L} and Andrulis, {Irene L} and Domchek, {Susan M} and Nathanson, {Katherine L} and Rebbeck, {Timothy R} and Barkardottir, {Rosa B} and Anna Jakubowska and Jan Lubinski and Katarzyna Durda and Katarzyna Jaworska-Bieniek and Kathleen Claes and {Van Maerken}, Tom and Orland D{\'i}ez and Hansen, {Thomas V} and Lars J{\o}nson and Anne-Marie Gerdes and Bent Ejlertsen and {de la Hoya}, Miguel and Teixeira",

year = "2015",

month = apr,

day = "1",

doi = "10.1371/journal.pone.0120020",

language = "English",

volume = "10",

pages = "1--18",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "4",

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TY - JOUR

T1 - Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

AU - Blanco, Ignacio

AU - Kuchenbaecker, Karoline

AU - Cuadras, Daniel

AU - Wang, Xianshu

AU - Barrowdale, Daniel

AU - de Garibay, Gorka Ruiz

AU - Librado, Pablo

AU - Sánchez-Gracia, Alejandro

AU - Rozas, Julio

AU - Bonifaci, Núria

AU - McGuffog, Lesley

AU - Pankratz, Vernon S

AU - Islam, Abul

AU - Mateo, Francesca

AU - Berenguer, Antoni

AU - Petit, Anna

AU - Català, Isabel

AU - Brunet, Joan

AU - Feliubadaló, Lidia

AU - Tornero, Eva

AU - Benítez, Javier

AU - Osorio, Ana

AU - Ramón y Cajal, Teresa

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Arun, Banu K

AU - Toland, Amanda E

AU - Karlan, Beth Y

AU - Walsh, Christine

AU - Lester, Jenny

AU - Greene, Mark H

AU - Mai, Phuong L

AU - Nussbaum, Robert L

AU - Andrulis, Irene L

AU - Domchek, Susan M

AU - Nathanson, Katherine L

AU - Rebbeck, Timothy R

AU - Barkardottir, Rosa B

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Durda, Katarzyna

AU - Jaworska-Bieniek, Katarzyna

AU - Claes, Kathleen

AU - Van Maerken, Tom

AU - Díez, Orland

AU - Hansen, Thomas V

AU - Jønson, Lars

AU - Gerdes, Anne-Marie

AU - Ejlertsen, Bent

AU - de la Hoya, Miguel

AU - Teixeira

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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 × 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.

AB - 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 × 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.

KW - Antigens, CD44

KW - Aurora Kinase A

KW - Breast Neoplasms

KW - Carcinogenesis

KW - Cell Cycle Proteins

KW - Estrogen Receptor alpha

KW - Evolution, Molecular

KW - Extracellular Matrix Proteins

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Humans

KW - Likelihood Functions

KW - Mammary Glands, Human

KW - Microtubule-Associated Proteins

KW - Mutation

KW - Nuclear Proteins

KW - Polymorphism, Single Nucleotide

KW - Retrospective Studies

KW - Tubulin

U2 - 10.1371/journal.pone.0120020

DO - 10.1371/journal.pone.0120020

M3 - Journal article

C2 - 25830658

SN - 1932-6203

VL - 10

SP - 1

EP - 18

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 4

M1 - e0120020

ER -

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

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