14346
2015
eng
e0120020
4
10
article
1
2017-01-27
--
--
Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers
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.
PLoS ONE
10.1371/journal.pone.0120020
urn:nbn:de:bvb:20-opus-143469
PLoS ONE 10(4): e0120020 (2015). DOI: 10.1371/journal.pone.0120020
CC 0: Public Domain Dedication
Ignacio Blanco
Karoline Kuchenbaecker
Daniel Cuadras
Xianshu Wang
Daniel Barrowdale
Gorka Ruiz de Garibay
Pablo Librado
Alejandro Sanchez-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
Kristina 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
Chris Jacobs
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
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
eng
uncontrolled
genetic interaction networks
eng
uncontrolled
genome-wide association
eng
uncontrolled
expression signature
eng
uncontrolled
susceptibility loci
eng
uncontrolled
survival
eng
uncontrolled
modifiers
eng
uncontrolled
polymorphism
eng
uncontrolled
cell
eng
uncontrolled
chip-seq
eng
uncontrolled
elements
Menschliche Anatomie, Zytologie, Histologie
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14346/028_Blanco_PLOS ONE.pdf
16686
2016
eng
e0158801
7
11
article
1
2018-08-08
--
--
Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
PLoS ONE
10.1371/journal.pone.0158801
urn:nbn:de:bvb:20-opus-166869
PLoS ONE 11(7):e0158801 (2016). DOI: 10.1371/journal.pone.0158801
false
true
CC 0: Public Domain Dedication
Elena Vigorito
Karoline B. Kuchenbaecker
Jonathan Beesley
Julian Adlard
Bjarni A. Agnarsson
Irene L. Andrulis
Banu K. Arun
Laure Barjhoux
Muriel Belotti
Javier Benitez
Andreas Berger
Anders Bojesen
Bernardo Bonanni
Carole Brewer
Trinidad Caldes
Maria A. Caligo
Ian Campbell
Salina B. Chan
Kathleen B. M. Claes
David E. Cohn
Jackie Cook
Mary B. Daly
Francesca Damiola
Rosemarie Davidson
Antoine de Pauw
Capucine Delnatte
Orland Diez
Susan M. Domchek
Martine Dumont
Katarzyna Durda
Bernd Dworniczak
Douglas F. Easton
Diana Eccles
Christina Edwinsdotter Ardnor
Ros Eeles
Bent Ejlertsen
Steve Ellis
D. Gareth Evans
Lidia Feliubadalo
Florentia Fostira
William D. Foulkes
Eitan Friedman
Debra Frost
Pragna Gaddam
Patricia A. Ganz
Judy Garber
Vanesa Garcia-Barberan
Marion Gauthier-Villars
Andrea Gehrig
Anne-Marie Gerdes
Sophie Giraud
Andrew K. Godwin
David E. Goldgar
Christopher R. Hake
Thomas V. O. Hansen
Sue Healey
Shirley Hodgson
Frans B. L. Hogervorst
Claude Houdayer
Peter J. Hulick
Evgeny N. Imyanitov
Claudine Isaacs
Louise Izatt
Angel Izquierdo
Lauren Jacobs
Anna Jakubowska
Ramunas Janavicius
Katarzyna Jaworska-Bieniek
Uffe Birk Jensen
Esther M. John
Joseph Vijai
Beth Y. Karlan
Karin Kast
Sofia Khan
Ava Kwong
Yael Laitman
Jenny Lester
Fabienne Lesueur
Annelie Liljegren
Jan Lubinski
Phuong L. Mai
Siranoush Manoukian
Sylvie Mazoyer
Alfons Meindl
Arjen R. Mensenkamp
Marco Montagna
Katherine L. Nathanson
Susan L. Neuhausen
Heli Nevanlinna
Dieter Niederacher
Edith Olah
Olufunmilayo I. Olopade
Kai-ren Ong
Ana Osorio
Sue Kyung Park
Ylva Paulsson-Karlsson
Inge Sokilde Pedersen
Bernard Peissel
Paolo Peterlongo
Georg Pfeiler
Catherine M. Phelan
Marion Piedmonte
Bruce Poppe
Miquel Angel Pujana
Paolo Radice
Gad Rennert
Gustavo C. Rodriguez
Matti A. Rookus
Eric A. Ross
Rita Katharina Schmutzler
Jacques Simard
Christian F. Singer
Thomas P. Slavin
Penny Soucy
Melissa Southey
Doris Steinemann
Dominique Stoppa-Lyonnet
Grzegorz Sukiennicki
Christian Sutter
Csilla I. Szabo
Muy-Kheng Tea
Manuel R. Teixeira
Soo-Hwang Teo
Mary Beth Terry
Mads Thomassen
Maria Grazia Tibiletti
Laima Tihomirova
Silvia Tognazzo
Elizabeth J. van Rensburg
Liliana Varesco
Raymonda Varon-Mateeva
Athanassios Vratimos
Jeffrey N. Weitzel
Lesley McGuffog
Judy Kirk
Amanda Ewart Toland
Ute Hamann
Noralane Lindor
Susan J. Ramus
Mark H. Greene
Fergus J. Couch
Kenneth Offit
Paul D. P. Pharoah
Georgia Chenevix-Trench
Antonis C. Antoniou
eng
uncontrolled
fine-scale mapping
eng
uncontrolled
ovarian cancer
eng
uncontrolled
genetics
eng
uncontrolled
BRCA1
eng
uncontrolled
BRCA2
Medizin und Gesundheit
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16686/Vigorito_PLoS_ONE.PDF