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 Tornero; Javier 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; Rob B. van der Luijt

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 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, Rob B. van der Luijt, , , ,

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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 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 language	English
Article number	0120020
Number of pages	18
Journal	PLoS ONE [E]
Volume	10
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0120020
Publication status	Published - 1 Apr 2015

Keywords

GENETIC INTERACTION NETWORKS
GENOME-WIDE ASSOCIATION
EXPRESSION SIGNATURE
SUSCEPTIBILITY LOCI
CHIP-SEQ
CELL
POLYMORPHISM
MODIFIERS
SURVIVAL
ELEMENTS

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Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, X., Barrowdale, D., Ruiz de Garibay, G., Librado, P., Sanchez-Gracia, A., Rozas, J., Bonifaci, N., McGuffog, L., Pankratz, V. S., Islam, A., Mateo, F., Berenguer, A., Petit, A., Catala, I., Brunet, J., Feliubadalo, L. (2015). Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers. PLoS ONE [E], 10(4), Article 0120020. 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 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.",

keywords = "GENETIC INTERACTION NETWORKS, GENOME-WIDE ASSOCIATION, EXPRESSION SIGNATURE, SUSCEPTIBILITY LOCI, CHIP-SEQ, CELL, POLYMORPHISM, MODIFIERS, SURVIVAL, ELEMENTS",

author = "Ignacio Blanco and Karoline Kuchenbaecker and Daniel Cuadras and Xianshu Wang and Daniel Barrowdale and {Ruiz de Garibay}, Gorka and Pablo Librado and Alejandro Sanchez-Gracia and Julio Rozas and Nuria Bonifaci and Lesley McGuffog and Pankratz, {Vernon S.} and Abul Islam and Francesca Mateo and Antoni Berenguer and Anna Petit and Isabel Catala and Joan Brunet and Lidia Feliubadalo and Eva Tornero and Javier Benitez and Ana Osorio and Cajal, {Teresa Ramon Y.} and Heli Nevanlinna and Kristiina Aittomaki 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 Diez and Hansen, {Thomas V.} and Lars Jonson and Anne-Marie Gerdes and Bent Ejlertsen and {van der Luijt}, {Rob B.}",

year = "2015",

month = apr,

day = "1",

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

language = "English",

volume = "10",

journal = "PLoS ONE [E]",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "4",

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Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, X, Barrowdale, D, Ruiz de Garibay, G, Librado, P, Sanchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Catala, I, Brunet, J, Feliubadalo, L, Tornero, E, Benitez, J, Osorio, A, Cajal, TRY, Nevanlinna, H, Aittomaki, 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, Diez, O, Hansen, TV, Jonson, L, Gerdes, A-M, Ejlertsen, B, van der Luijt, RB 2015, 'Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers', PLoS ONE [E], vol. 10, no. 4, 0120020. https://doi.org/10.1371/journal.pone.0120020

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 - Ruiz de Garibay, Gorka

AU - Librado, Pablo

AU - Sanchez-Gracia, Alejandro

AU - Rozas, Julio

AU - Bonifaci, Nuria

AU - McGuffog, Lesley

AU - Pankratz, Vernon S.

AU - Islam, Abul

AU - Mateo, Francesca

AU - Berenguer, Antoni

AU - Petit, Anna

AU - Catala, Isabel

AU - Brunet, Joan

AU - Feliubadalo, Lidia

AU - Tornero, Eva

AU - Benitez, Javier

AU - Osorio, Ana

AU - Cajal, Teresa Ramon Y.

AU - Nevanlinna, Heli

AU - Aittomaki, 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 - Diez, Orland

AU - Hansen, Thomas V.

AU - Jonson, Lars

AU - Gerdes, Anne-Marie

AU - Ejlertsen, Bent

AU - van der Luijt, Rob B.

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 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.

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 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.

KW - GENETIC INTERACTION NETWORKS

KW - GENOME-WIDE ASSOCIATION

KW - EXPRESSION SIGNATURE

KW - SUSCEPTIBILITY LOCI

KW - CHIP-SEQ

KW - CELL

KW - POLYMORPHISM

KW - MODIFIERS

KW - SURVIVAL

KW - ELEMENTS

U2 - 10.1371/journal.pone.0120020

DO - 10.1371/journal.pone.0120020

M3 - Article

C2 - 25830658

SN - 1932-6203

VL - 10

JO - PLoS ONE [E]

JF - PLoS ONE [E]

IS - 4

M1 - 0120020

ER -

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

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Keywords

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