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

Ignacio Blanco; Chris Jacobs; 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; Trinidad Caldés; Alison M Dunning; Clare Oliver; Elena Fineberg; Margaret Cook; Susan Peock; Emma McCann; Alex Murray; Gabriella Pichert; Fiona Lalloo; Carol Chu; Huw Dorkins; Joan Paterson; Kai-Ren Ong; Manuel R Teixeira; Frans B L Hogervorst; Annemarie H van der Hout; Caroline Seynaeve; Rob B van der Luijt; Marjolijn J L Ligtenberg; Peter Devilee; Juul T Wijnen; Matti A Rookus; Hanne E J Meijers-Heijboer; Marinus J Blok; Ans M W van den Ouweland; Cora M Aalfs; Gustavo C Rodriguez; Kelly-Anne A Phillips; Marion Piedmonte; Stacy R Nerenstone; Victoria L Bae-Jump; David M O'Malley; Elena S Ratner; Rita K Schmutzler; Barbara Wappenschmidt; Kerstin Rhiem; Christoph Engel; Alfons Meindl; Nina Ditsch; Norbert Arnold; Hansjoerg J Plendl; Dieter Niederacher; Christian Sutter; Shan Wang-Gohrke; Doris Steinemann; Sabine Preisler-Adams; Karin Kast; Raymonda Varon-Mateeva; Andrea Gehrig; Anders Bojesen; Inge Sokilde Pedersen; Lone Sunde; Uffe Birk Jensen; Mads Thomassen; Torben A Kruse; Lenka Foretova; Paolo Peterlongo; Loris Bernard; Bernard Peissel; Giulietta Scuvera; Siranoush Manoukian; Paolo Radice; Laura Ottini; Marco Montagna; Simona Agata; Christine Maugard; Jacques Simard; Penny Soucy; Andreas Berger; Anneliese Fink-Retter; Christian F Singer; Christine Rappaport; Daphne Geschwantler-Kaulich; Muy-Kheng Tea; Georg Pfeiler; Esther M John; Alex Miron; Susan L Neuhausen; Mary Beth Terry; Wendy K Chung; Mary B Daly; David E Goldgar; Ramunas Janavicius; Cecilia M Dorfling; Elisabeth J van Rensburg; Florentia Fostira; Irene Konstantopoulou; Judy Garber; Andrew K Godwin; Edith Olah; Steven A Narod; Gad Rennert; Shani Shimon Paluch; Yael Laitman; Eitan Friedman; Annelie Liljegren; Johanna Rantala; Marie Stenmark-Askmalm; Niklas Loman; Evgeny N Imyanitov; Ute Hamann; Amanda B Spurdle; Sue Healey; Jeffrey N Weitzel; Josef Herzog; David Margileth; Chiara Gorrini; Manel Esteller; Antonio Gómez; Sergi Sayols; Enrique Vidal; Holger Heyn; Dominique Stoppa-Lyonnet; Melanie Léoné; Laure Barjhoux; Marion Fassy-Colcombet; Antoine de Pauw; Christine Lasset; Sandra Fert Ferrer; Laurent Castera; Pascaline Berthet; François Cornelis; Yves-Jean Bignon; Francesca Damiola; Sylvie Mazoyer; Olga M Sinilnikova; Christopher A Maxwell; Joseph Vijai; Mark Robson; Noah Kauff; Marina J Corines; Danylko Villano; Julie Cunningham; Adam Lee; Noralane Lindor; Conxi Lázaro; Douglas F Easton; Kenneth Offit; Georgia Chenevix-Trench; Fergus J Couch; Antonis C Antoniou; Miguel Angel Pujana; GEMO

doi:10.1371/journal.pone.0120020

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

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

Ignacio Blanco, Chris Jacobs, Karoline Kuchenbaecker, Daniel Cuadras, Xianshu Wang, Daniel Barrowdale, Gorka Ruiz de Garibay, Pablo Librado, Alejandro Sánchez-Gracia, Julio Rozas, …

PloS one, Vol.10(4), pp.e0120020-e0120020

01/04/2015

DOI: https://doi.org/10.1371/journal.pone.0120020

PMID: 25830658

Abstract

Aurora Kinase A - genetics

Breast Neoplasms - enzymology

Breast Neoplasms - genetics

Breast Neoplasms - pathology

Carcinogenesis - genetics

Cell Cycle Proteins - genetics

Estrogen Receptor alpha - metabolism

Evolution, Molecular

Extracellular Matrix Proteins - genetics

Female

Genes, BRCA1

Genes, BRCA2

Genetic Loci - genetics

Genetic Predisposition to Disease - genetics

Humans

Hyaluronan Receptors - genetics

Likelihood Functions

Mammary Glands, Human - metabolism

Microtubule-Associated Proteins - genetics

Nuclear Proteins - genetics

Polymorphism, Single Nucleotide

Retrospective Studies

Tubulin - genetics

Mutation

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.

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Title: Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers
Creators: Ignacio Blanco - Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Chris Jacobs - Clinical Genetics, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, United Kingdom
Karoline Kuchenbaecker - University of Cambridge
Daniel Cuadras - Statistics Unit, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Xianshu Wang - Mayo Clinic in Arizona
Daniel Barrowdale - University of Cambridge
Gorka Ruiz de Garibay - Breast Cancer and Systems Biology Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Pablo Librado - Universitat de Barcelona
Alejandro Sánchez-Gracia - Universitat de Barcelona
Julio Rozas - Universitat de Barcelona
Núria Bonifaci - Breast Cancer and Systems Biology Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Lesley McGuffog - University of Cambridge
Vernon S Pankratz - Winneshiek Medical Center
Abul Islam - University of Dhaka
Francesca Mateo - Breast Cancer and Systems Biology Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Antoni Berenguer - Statistics Unit, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Anna Petit - Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Isabel Català - Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Joan Brunet - Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IDIBGI), Hospital Josep Trueta, Girona, Catalonia, Spain
Lidia Feliubadaló - Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Eva Tornero - Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Javier Benítez - Human Genetics Group, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases, Madrid, Spain
Ana Osorio - Human Genetics Group, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases, Madrid, Spain
Teresa Ramón y Cajal - Hospital de Sant Pau
Heli Nevanlinna - Helsinki University Central Hospital
Kristiina Aittomäki - Helsinki University Central Hospital
Banu K Arun - The University of Texas MD Anderson Cancer Center
Amanda E Toland - The Ohio State University
Beth Y Karlan - Cedars-Sinai Medical Center
Christine Walsh - Cedars-Sinai Medical Center
Jenny Lester - Cedars-Sinai Medical Center
Mark H Greene - Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Maryland, Rockville, United States of America
Phuong L Mai - Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Maryland, Rockville, United States of America
Robert L Nussbaum - University of California, San Francisco
Irene L Andrulis - University of Toronto
Susan M Domchek - University of Pennsylvania
Katherine L Nathanson - University of Pennsylvania
Timothy R Rebbeck - University of Pennsylvania
Rosa B Barkardottir - University of Iceland
Anna Jakubowska - Pomeranian Medical University
Jan Lubinski - Pomeranian Medical University
Katarzyna Durda - Pomeranian Medical University
Katarzyna Jaworska-Bieniek - Pomeranian Medical University
Kathleen Claes - Ghent University
Tom Van Maerken - Ghent University
Orland Díez - Vall d'Hebron Institut de Recerca
Thomas V Hansen - Copenhagen University Hospital
Lars Jønson - Copenhagen University Hospital
Anne-Marie Gerdes - Copenhagen University Hospital
Bent Ejlertsen - Copenhagen University Hospital
Miguel de la Hoya - Hospital Clínico San Carlos
Trinidad Caldés - Hospital Clínico San Carlos
Alison M Dunning - University of Cambridge
Clare Oliver - University of Cambridge
Elena Fineberg - University of Cambridge
Margaret Cook - University of Cambridge
Susan Peock - University of Cambridge
Emma McCann - Glan Clwyd Hospital
Alex Murray - Singleton Hospital
Gabriella Pichert - Clinical Genetics, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, United Kingdom
Fiona Lalloo - University of Manchester
Carol Chu - Yorkshire Regional Genetics Service, Leeds, United Kingdom
Huw Dorkins - North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, United Kingdom
Joan Paterson - Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom
Kai-Ren Ong - Birmingham Women's Hospital
Manuel R Teixeira - Universidade do Porto
Frans B L Hogervorst - The Netherlands Cancer Institute
Annemarie H van der Hout - University of Groningen
Caroline Seynaeve - Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
Rob B van der Luijt - University Medical Center Utrecht
Marjolijn J L Ligtenberg - Department of Human Genetics and Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands
Peter Devilee
Juul T Wijnen
Matti A Rookus - The Netherlands Cancer Institute
Hanne E J Meijers-Heijboer - Department of Clinical Genetics, Vrije Universiteit (VU) University Medical Centre, Amsterdam, The Netherlands
Marinus J Blok - Maastricht University
Ans M W van den Ouweland - Erasmus MC
Cora M Aalfs - Academic Medical Center
Gustavo C Rodriguez - NorthShore University HealthSystem
Kelly-Anne A Phillips - Peter MacCallum Cancer Centre
Marion Piedmonte - Roswell Park Cancer Institute
Stacy R Nerenstone - Central Connecticut Cancer Consortium, Hartford Hospital/Helen and Harry Gray Cancer Center, Hartford, Connecticut, United States of America
Victoria L Bae-Jump - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina, United States of America
David M O'Malley - The Ohio State University
Elena S Ratner - Yale University
Rita K Schmutzler - University Hospital Cologne
Barbara Wappenschmidt - University Hospital Cologne
Kerstin Rhiem - University Hospital Cologne
Christoph Engel - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Alfons Meindl - Technical University of Munich
Nina Ditsch - Ludwig Maximilian University of Munich
Norbert Arnold - Kiel University
Hansjoerg J Plendl - Kiel University
Dieter Niederacher - Heinrich Heine University Düsseldorf
Christian Sutter - University Hospital Heidelberg
Shan Wang-Gohrke - University Hospital Ulm
Doris Steinemann - Medizinische Hochschule Hannover
Sabine Preisler-Adams - University of Münster
Karin Kast - University Hospital Carl Gustav Carus
Raymonda Varon-Mateeva - Institute of Human Genetics
Andrea Gehrig - University of Würzburg
Anders Bojesen - Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark
Inge Sokilde Pedersen - Aalborg University Hospital
Lone Sunde - Aarhus University Hospital
Uffe Birk Jensen - Aarhus University Hospital
Mads Thomassen - Odense University Hospital
Torben A Kruse - Odense University Hospital
Lenka Foretova - Masaryk Memorial Cancer Institute
Paolo Peterlongo - Mylan
Loris Bernard - Mylan
Bernard Peissel - Mylan
Giulietta Scuvera - Mylan
Siranoush Manoukian - Mylan
Paolo Radice - Mylan
Laura Ottini - Sapienza University of Rome
Marco Montagna - Istituto Oncologico Veneto
Simona Agata - Istituto Oncologico Veneto
Christine Maugard - Hôpital Civil, Strasbourg
Jacques Simard - Université du Québec
Penny Soucy - Université du Québec
Andreas Berger - Medical University of Vienna
Anneliese Fink-Retter - Medical University of Vienna
Christian F Singer - Medical University of Vienna
Christine Rappaport - Medical University of Vienna
Daphne Geschwantler-Kaulich - Medical University of Vienna
Muy-Kheng Tea - Medical University of Vienna
Georg Pfeiler - Medical University of Vienna
Esther M John - Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America
Alex Miron - Dana-Farber Cancer Institute
Susan L Neuhausen - City of Hope
Mary Beth Terry - Columbia University
Wendy K Chung - Columbia University Irving Medical Center
Mary B Daly - Fox Chase Cancer Center
David E Goldgar - University of Utah
Ramunas Janavicius - Vilnius University
Cecilia M Dorfling - University of Pretoria
Elisabeth J van Rensburg - University of Pretoria
Florentia Fostira - National Centre of Scientific Research "Demokritos"
Irene Konstantopoulou - National Centre of Scientific Research "Demokritos"
Judy Garber - Dana-Farber Cancer Institute
Andrew K Godwin - University of Kansas Medical Center
Edith Olah - Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
Steven A Narod - University of Toronto
Gad Rennert - Carmel Medical Center
Shani Shimon Paluch - Sheba Medical Center
Yael Laitman - Sheba Medical Center
Eitan Friedman
Annelie Liljegren - Karolinska University Hospital
Johanna Rantala - Karolinska University Hospital
Marie Stenmark-Askmalm - Linköping University
Niklas Loman - Lund University
Evgeny N Imyanitov - N&N Pharmaceuticals
Ute Hamann - German Cancer Research Center
Amanda B Spurdle - QIMR Berghofer Medical Research Institute
Sue Healey - QIMR Berghofer Medical Research Institute
Jeffrey N Weitzel - City of Hope
Josef Herzog - Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America
David Margileth - St. Joseph Hospital of Orange, Care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California, United States of America
Chiara Gorrini - The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Canada
Manel Esteller
Antonio Gómez - Cancer Epigenetics and Biology Program (PEBC), IDIBELL, L'Hospitalet del Llobregat, Catalonia, Spain
Sergi Sayols - Cancer Epigenetics and Biology Program (PEBC), IDIBELL, L'Hospitalet del Llobregat, Catalonia, Spain
Enrique Vidal - Cancer Epigenetics and Biology Program (PEBC), IDIBELL, L'Hospitalet del Llobregat, Catalonia, Spain
Holger Heyn - Cancer Epigenetics and Biology Program (PEBC), IDIBELL, L'Hospitalet del Llobregat, Catalonia, Spain
Dominique Stoppa-Lyonnet
Melanie Léoné - Hospices Civils de Lyon
Laure Barjhoux - Centre National pour la Recherche Scientifique et Technique (CNRST)
Marion Fassy-Colcombet - Institute Curie
Antoine de Pauw - Institute Curie
Christine Lasset - Centre National pour la Recherche Scientifique et Technique (CNRST)
Sandra Fert Ferrer - Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, Chambéry, France
Laurent Castera - Institute Curie
Pascaline Berthet - Centre François Baclesse
François Cornelis - Genetic Unit, Avicenne Hospital, Assitance Publique-Hôpitaux de Paris, Paris, Sud-Francilien Hospital, Evry-Corbeil, and University Hospital, Clermont-Ferrand, France
Yves-Jean Bignon - Centre Jean Perrin
Francesca Damiola - Centre National pour la Recherche Scientifique et Technique (CNRST)
Sylvie Mazoyer - Centre National pour la Recherche Scientifique et Technique (CNRST)
Olga M Sinilnikova
Christopher A Maxwell - University of British Columbia
Joseph Vijai - Memorial Sloan Kettering Cancer Center
Mark Robson - Memorial Sloan Kettering Cancer Center
Noah Kauff - Memorial Sloan Kettering Cancer Center
Marina J Corines - Memorial Sloan Kettering Cancer Center
Danylko Villano - Memorial Sloan Kettering Cancer Center
Julie Cunningham
Adam Lee - Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America
Noralane Lindor - Winneshiek Medical Center
Conxi Lázaro - Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
Douglas F Easton - University of Cambridge
Kenneth Offit - Memorial Sloan Kettering Cancer Center
Georgia Chenevix-Trench - QIMR Berghofer Medical Research Institute
Fergus J Couch
Antonis C Antoniou - University of Cambridge
Miguel Angel Pujana - Breast Cancer and Systems Biology Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain
GEMO
Publication Details: PloS one, Vol.10(4), pp.e0120020-e0120020
Date published: 01/04/2015
Grant note: U10 CA180868 / NCI NIH HHS N02CP65504 / NCI NIH HHS U24 CA196067 / NCI NIH HHS UG1 CA189867 / NCI NIH HHS CA125183 / NCI NIH HHS P30 CA168524 / NCI NIH HHS RC4 CA153828 / NCI NIH HHS R01CA140323 / NCI NIH HHS U10 CA180850 / NCI NIH HHS UM1 CA164920 / NCI NIH HHS U10 CA037517 / NCI NIH HHS C1287/A11990 / Cancer Research UK R01 CA149429 / NCI NIH HHS R01 CA142996 / NCI NIH HHS Intramural NIH HHS P30 CA016672 / NCI NIH HHS R01 CA128978 / NCI NIH HHS R01 CA102776 / NCI NIH HHS CA116201 / NCI NIH HHS U10 CA180838 / NCI NIH HHS RC4CA153828 / NCI NIH HHS N02CP11019 / NCI NIH HHS CA 37517 / NCI NIH HHS C1287/A10118 / Cancer Research UK R01-CA102776 / NCI NIH HHS P50 CA116201 / NCI NIH HHS 1U01CA161032 / NCI NIH HHS CIHR U10 CA027469 / NCI NIH HHS 1R01 CA149429-01 / NCI NIH HHS C12292/A11174 / Cancer Research UK R01 CA083855 / NCI NIH HHS 11174 / Cancer Research UK CA 101165 / NCI NIH HHS P50 CA125183 / NCI NIH HHS U01 CA113916 / NCI NIH HHS 5U01CA113916 / NCI NIH HHS R01 CA140323 / NCI NIH HHS U10 CA101165 / NCI NIH HHS R01-CA083855 / NCI NIH HHS U01 CA161032 / NCI NIH HHS CA 27469 / NCI NIH HHS CA128978 / NCI NIH HHS C5047/A8385 / Cancer Research UK
Identifiers: 99822259802346
Academic Unit: School of Health Sciences
Language: English
Resource Type: Journal article

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

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