12794
2013
eng
e1003212
3
9
article
1
2016-02-25
--
--
Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
PLOS Genetics
10.1371/journal.pgen.1003212
1553-7404
urn:nbn:de:bvb:20-opus-127947
PLoS Genetics 9(3): e1003212. doi:10.1371/journal.pgen.1003212
223175
Fergus J. Couch
Xianshu Wang
Lesley McGuffog
Andrew Lee
Curtis Olswold
Karoline B. Kuchenbaecker
Penny Soucy
Zachary Fredericksen
Daniel Barrowdale
Joe Dennis
Mia M. Gaudet
Ed Dicks
Matthew Kosel
Sue Healey
Olga M. Sinilnikova
Adam Lee
Françios Bacot
Daniel Vincent
Frans B. L. Hogervorst
Susan Peock
Dominique Stoppa-Lyonnet
Anna Jakubowska
Paolo Radice
Rita Katharina Schmutzler
Susan M. Domchek
Marion Piedmonte
Christian F. Singer
Eitan Friedman
Mads Thomassen
Thomas V. O. Hansen
Susan L. Neuhausen
Csilla I. Szabo
Ingnacio Blanco
Mark H. Greene
Beth Y. Karlan
Judy Garber
Catherine M. Phelan
Jeffrey N. Weitzel
Marco Montagna
Edith Olah
Irene L. Andrulis
Andrew K. Godwin
Drakoulis Yannoukakos
David E. Goldgar
Trinidad Caldes
Heli Nevanlinna
Ana Osorio
Mary Beth Terry
Mary B. Daly
Elisabeth J. van Rensburg
Ute Hamann
Susan J. Ramus
Amanda Ewart Toland
Maria A. Caligo
Olufunmilayo I. Olopade
Nadine Tung
Kathleen Claes
Mary S. Beattie
Melissa C. Southey
Evgeny N. Imyanitov
Marc Tischkowitz
Ramunas Janavicius
Esther M. John
Ava Kwong
Orland Diez
Ava Kwong
Judith Balmaña
Rosa B. Barkardottir
Banu K. Arun
Gad Rennert
Soo-Hwang Teo
Patricia A. Ganz
Ian Campbell
Annemarie H. van der Hout
Carolien H. M. van Deurzen
Caroline Seynaeve
Encarna B. Gómez Garcia
Flora E. van Leeuwen
Hanne E. J. Meijers-Heijboer
Johannes J. P. Gille
Magreet G. E. M. Ausems
Marinus J. Blok
Marjolinjin J. L. Ligtenberg
Matti A. Rookus
Peter Devilee
Senno Verhoef
Theo A. M. van Os
Juul T. Wijnen
Debra Frost
Steve Ellis
Elena Fineberg
Radke Platte
D. Gareth Evans
Luise Izatt
Rosalind A. Eeles
Julian Adlard
Diana M. Eccles
Jackie Cook
Carole Brewer
Fiona Douglas
Shirley Hodgson
Patrick J. Morrison
Lucy E. Side
Alan Donaldson
Catherine Houghton
Mark T. Rogers
Huw Dorkins
Jacqueline Eason
Helen Gregory
Emma McCann
Alex Murray
Alain Calender
Agnès Hardouin
Pascaline Berthet
Capucine Delnatte
Catherine Nogues
Christine Lasset
Claude Houdayer
Dominique Leroux,
Etienne Rouleau
Fabienne Prieur
Francesca Damiola
Hagay Sobol
Isabelle Coupier
Laurence Venat-Bouvet
Laurent Castera
Marion Gauthier-Villars
Mélanie Léoné
Pascal Pujol
Sylvie Mazoyer
Yves-Jean Bignon
Elzbieta Zlowocka-Perlowska
Jacek Gronwald
Jan Lubinski,
Katarzyna Durda
Katarzyna Jaworska
Tomasz Huzarski
Amanda B. Spurdle
Alessandra Viel
Bernhard Peissel
Bernardo Bonanni
Guilia Melloni
Laura Ottini
Laura Papi
Liliana Varesco
Maria Grazia Tibiletti
Paolo Peterlongo
Sara Volorio
Siranoush Manoukian
Valeria Pensotti
Norbert Arnold
Christoph Engel
Helmut Deissler
Dorothea Gadzicki
Andrea Gehrig
Karin Kast
Kerstin Rhiem
Alfons Meindl
Dieter Niederacher
Nina Ditsch
Hansjoerg Plendl
Sabine Preisler-Adams
Stefanie Engert
Christian Sutter
Raymenda Varon-Mateeva
Barbara Wappenschmidt
Bernhard H. F. Weber
Brita Arver
Marie Stenmark-Askmalm
Niklas Loman
Richard Rosenquist
Zakaria Einbeigi
Katherine L. Nathanson
Timothy R. Rebbeck
Stephanie V. Blank
David E. Cohn
Gustavo C. Rodriguez
Laurie Small
Michael Friedlander
Victoria L. Bae-Jump
Anneliese Fink-Retter
Christine Rappaport
Daphne Gschwantler-Kaulich
Georg Pfeiler
Muy-Kheng Tea
Noralane M. Lindor
Bella Kaufman
Shani Shimon Paluch
Yael Laitman
Anne-Bine Skytte
Anne-Marie Gerdes
Inge Sokilde Pedersen
Sanne Traasdahl Moeller
Torben A. Kruse
Uffe Birk Jensen
Joseph Vijai
Kara Sarrel
Mark Robson
Noah Kauff
Anna Marie Mulligan
Gord Glendon
Hilmi Ozcelik
Bent Ejlertsen
Finn C. Nielsen
Lars Jønson
Mette K. Andersen
Yuan Chun Ding
Linda Steele
Lenka Foretova
Alex Teulé
Conxi Lazaro
Joan Brunet
Miquel Angel Pujana
Phuong L. Mai
Jennifer T. Loud
Christine Walsh
Jenny Lester
Sandra Orsulic
Steven A. Narod
Josef Herzog
Sharon R. Sand
Silvia Tognazzo
Simona Agata
Tibor Vaszko
Joellen Weaver
Alexandra V. Stravropoulou
Saundra S. Buys
Atocha Romero
Miguel de la Hoya
Kristiina Aittomäki
Taru A. Muranen
Mercedes Duran
Wendy K. Chung
Adriana Lasa
Cecilia M. Dorfling
Alexander Miron
Javier Benitez
Leigha Senter
Dezheng Huo
Salina B. Chan
Anna P. Sokolenko
Jocelyne Chiquette
Laima Tihomirova
Tara M. Friebel
Bjarne A. Agnarsson
Karen H. Lu
Flavio Lejbkowicz
Paul A. James
Per Hall
Alison M. Dunning
Daniel Tessier
Julie Cunningham
Susan L. Slager
Wang Chen
Steven Hart
Kristen Stevens
Jacques Simard
Tomi Pastinen
Vernon S. Pankratz
Kenneth Offit
Douglas F. Easton
Georgia Chenevix-Trench
Antonis C. Antoniou
eng
uncontrolled
common variants
eng
uncontrolled
susceptibility alleles
eng
uncontrolled
genetic variants
eng
uncontrolled
modifiers
eng
uncontrolled
ZNF365
eng
uncontrolled
investigators
eng
uncontrolled
population
eng
uncontrolled
consortium
eng
uncontrolled
selection
eng
uncontrolled
subtypes
Inzidenz und Prävention von Krankheiten
open_access
Institut für Humangenetik
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12794/063_Couch_Plos_Genetics.pdf
13044
2012
eng
R33
14
article
CIMBA; SWE-BRCA; HEBON; EMBRACE; GEMO Study Collaborators; kConFab Investigators
1
2016-03-22
--
--
Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
Breast Cancer Research
10.1186/bcr3121
urn:nbn:de:bvb:20-opus-130449
Breast Cancer Research 2012, 14:R33. DOI:10.1186/bcr3121
223175
Antonis C. Antoniou
Karoline B. Kuchenbaecker
Penny Soucy
Jonathan Beesley
Xiaoqing Chen
Lesley McGuffog
Andrew Lee
Daniel Barrowdale
Sue Healey
Olga M. Sinilnikova
Maria A. Caligo
Niklas Loman
Katja Harbst
Annika Lindblom
Brita Arver
Richard Rosenquist
Per Karlsson
Kate Nathanson
Susan Domchek
Tim Rebbeck
Anna Jakubowska
Jan Lubinski
Katarzyna Jaworska
Katarzyna Durda
Elżbieta Zlowowcka-Perłowska
Ana Osorio
Mercedes Durán
Raquel Andrés
Javier Benítez
Ute Hamann
Frans B. Hogervorst
Theo A. van Os
Senno Verhoef
Hanne E. J. Meijers-Heijboer
Juul Wijnen
Encarna B. Gómez Garcia
Marjolijn J. Ligtenberg
Mieke Kriege
Margriet Collée
Margreet G. E. M. Ausems
Jan C. Oosterwijk
Susan Peock
Debra Frost
Steve D. Ellis
Radka Platte
Elena Fineberg
D. Gareth Evans
Fiona Lalloo
Chris Jacobs
Ros Eeles
Julian Adlard
Rosemarie Davidson
Trevor Cole
Jackie Cook
Joan Paterson
Fiona Douglas
Carole Brewer
Shirley Hodgson
Patrick J. Morrison
Lisa Walker
Mark T. Rogers
Alan Donaldson
Huw Dorkins
Andrew K. Godwin
Betsy Bove
Dominique Stoppa-Lyonnet
Claude Houdayer
Bruno Buecher
Antoine de Pauw
Sylvie Mazoyer
Alain Calender
Mélanie Léoné
Brigitte Bressac-de Paillerets
Olivier Caron
Hagay Sobol
Marc Frenay
Fabienne Prieur
Sandra Fert Ferrer
Isabelle Mortemousque
Saundra Buys
Mary Daly
Alexander Miron
Mary Beth Terry
John L. Hopper
Esther M. John
Melissa Southey
David Goldgar
Christian F. Singer
Anneliese Fink-Retter
Tea Muy-Kheng
Daphne Geschwantler Kaulich
Thomas V. O. Hansen
Finn C. Nielsen
Rosa B. Barkardottir
Mia Gaudet
Tomas Kirchhoff
Vijai Joseph
Ana Dutra-Clarke
Kenneth Offit
Marion Piedmonte
Judy Kirk
David Cohn
Jean Hurteau
John Byron
James Fiorica
Amanda E. Toland
Marco Montagna
Cristina Oliani
Evgeny Imyanitov
Claudine Isaacs
Laima Tihomirova
Ignacio Blanco
Conxi Lazaro
Alex Teulé
J. Del Valle
Simon A. Gayther
Kunle Odunsi
Jenny Gross
Beth Y. Karlan
Edith Olah
Soo-Hwang Teo
Patricia A. Ganz
Mary S. Beattie
Cecelia M. Dorfling
Elizabeth Jansen van Rensburg
Orland Diez
Ava Kwong
Rita K. Schmutzler
Barbara Wappenschmidt
Christoph Engel
Alfons Meindl
Nina Ditsch
Norbert Arnold
Simone Heidemann
Dieter Niederacher
Sabine Preisler-Adams
Dorothea Gadzicki
Raymonda Varon-Mateeva
Helmut Deissler
Andrea Gehrig
Christian Sutter
Karin Kast
Britta Fiebig
Dieter Schäfer
Trinidad Caldes
Miguel de la Hoya
Heli Nevanlinna
Taru A. Muranen
Bernard Lespérance
Amanda B. Spurdle
Susan L. Neuhausen
Yuan C. Ding
Xianshu Wang
Zachary Fredericksen
Vernon S. Pankratz
Noralane M. Lindor
Paulo Peterlongo
Siranoush Manoukian
Bernard Peissel
Daniela Zaffaroni
Bernardo Bonanni
Loris Bernard
Riccardo Dolcetti
Laura Papi
Laura Ottini
Paolo Radice
Mark H. Greene
Jennifer T. Loud
Irene L. Andrulis
Hilmi Ozcelik
Anna Marie Mulligan
Gord Glendon
Mads Thomassen
Anne-Marie Gerdes
Uffe B. Jensen
Anne-Bine Skytte
Torben A. Kruse
Georgia Chenevix-Trench
Fergus J. Couch
Jacques Simard
Douglas F. Easton
eng
uncontrolled
investigators
eng
uncontrolled
genetic modifiers
eng
uncontrolled
mammographic density
eng
uncontrolled
susceptibility loci
eng
uncontrolled
ovarian cancer
eng
uncontrolled
hormone-related protein
eng
uncontrolled
genome-wide association
eng
uncontrolled
tumor subtypes
eng
uncontrolled
alleles
eng
uncontrolled
consortium
Menschliche Anatomie, Zytologie, Histologie
open_access
Institut für Humangenetik
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13044/Antoniou_A10.1186-Fbcr3121.pdf
14545
2015
eng
61
17
article
1
2017-03-07
--
--
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
Introduction:
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
Methods:
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
Results:
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
Conclusions:
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Breast Cancer Research
10.1186/s13058-015-0567-2
urn:nbn:de:bvb:20-opus-145458
Breast Cancer Research (2015) 17:61. DOI: 10.1186/s13058-015-0567-2
223175
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Sophie Blein
Claire Bardel
Vincent Danjean
Lesley McGuffog
Sue Healay
Daniel Barrowdale
Andrew Lee
Joe Dennis
Karoline B. Kuchenbaecker
Penny Soucy
Mary Beth Terry
Wendy K. Chung
David E. Goldgar
Saundra S. Buys
Ramunas Janavicius
Laima Tihomirova
Nadine Tung
Cecilia M. Dorfling
Elizabeth J. van Rensburg
Susan L. Neuhausen
Yuan Chun Ding
Anne-Marie Gerdes
Bent Ejlertsen
Finn C. Nielsen
Thomas V. O. Hansen
Ana Osorio
Javier Benitez
Raquel Andreas Conejero
Ena Segota
Jeffrey N. Weitzel
Margo Thelander
Paolo Peterlongo
Paolo Radice
Valeria Pensotti
Riccardo Dolcetti
Bernardo Bonanni
Bernard Peissel
Daniela Zaffaroni
Giulietta Scuvera
Siranoush Manoukian
Liliana Varesco
Gabriele L. Capone
Laura Papi
Laura Ottini
Drakoulis Yannoukakos
Irene Konstantopoulou
Judy Garber
Ute Hamann
Alan Donaldson
Angela Brady
Carole Brewer
Claire Foo
D. Gareth Evans
Debra Frost
Diana Eccles
Fiona Douglas
Jackie Cook
Julian Adlard
Julian Barwell
Lisa Walker
Louise Izatt
Lucy E. Side
M. John Kennedy
Marc Tischkowitz
Mark T. Rogers
Mary E. Porteous
Patrick J. Morrison
Radka Platte
Ros Eeles
Rosemarie Davidson
Shirley Hodgson
Trevor Cole
Andrew K Godwin
Claudine Isaacs
Kathleen Claes
Kim De Leeneer
Alfons Meindl
Andrea Gehrig
Barbara Wappenschmidt
Christian Sutter
Christoph Engel
Dieter Niederacher
Doris Steinemann
Hansjoerg Plendl
Karin Kast
Kerstin Rhiem
Nina Ditsch
Norbert Arnold
Raymonda Varon-Mateeva
Rita K. Schmutzler
Sabine Preisler-Adams
Nadja Bogdanova Markov
Shan Wang-Gohrke
Antoine de Pauw
Cedrick Lefol
Christine Lasset
Dominique Leroux
Etienne Rouleau
Francesca Damiola
Helene Dreyfus
Laure Barjhoux
Lisa Golmard
Nancy Uhrhammer
Valerie Bonadona
Valerie Sornin
Yves-Jean Bignon
Jonathan Carter
Linda Van Le
Marion Piedmonte
Paul A. DiSilvestro
Miguel de la Hoya
Trinidad Caldes
Heli Nevanlinna
Kristiina Aittomäki
Agnes Jager
Ans M. W. van den Ouweland
Carolien M. Kets
Cora M. Aalfs
Flora E. van Leeuwen
Frans B. L. Hogervorst
Hanne E. J. Meijers-Heijboer
Jan C. Oosterwijk
Kees E. P. van Roozendaal
Matti A. Rookus
Peter Devilee
Rob B. van der Luijt
Edith Olah
Orland Diez
Alex Teule
Conxi Lazaro
Ignacio Blanco
Jesus Del Valle
Anna Jakubowska
Grzegorz Sukiennicki
Jacek Gronwald
Amanda B. Spurdle
William Foulkes
Curtis Olswold
Noralene M. Lindor
Vernon S. Pankratz
Csilla I. Szabo
Anne Lincoln
Lauren Jacobs
Marina Corines
Mark Robson
Joseph Vijai
Andreas Berger
Anneliese Fink-Retter
Christian F. Singer
Christine Rappaport
Daphne Geschwantler Kaulich
Georg Pfeiler
Muy-Kheng Tea
Mark H. Greene
Phuong L. Mai
Gad Rennert
Evgeny N. Imyanitov
Anna Marie Mulligan
Gord Glendon
Irene L. Andrulis
Andrine Tchatchou
Amanda Ewart Toland
Inge Sokilde Pedersen
Mads Thomassen
Torben A. Kruse
Uffe Birk Jensen
Maria A. Caligo
Eitan Friedman
Jamal Zidan
Yael Laitman
Annika Lindblom
Beatrice Melin
Brita Arver
Niklas Loman
Richard Rosenquist
Olufunmilayo I. Olopade
Robert L. Nussbaum
Susan J. Ramus
Katherine L. Nathanson
Susan M. Domchek
Timothy R. Rebbeck
Banu K. Arun
Gillian Mitchell
Bethy Y. Karlan
Jenny Lester
Sandra Orsulic
Dominique Stoppa-Lyonnet
Gilles Thomas
Jacques Simard
Fergus J. Couch
Kenenth Offit
Douglas F. Easton
Georgia Chenevix-Trench
Antonis C. Antoniou
Sylvie Mazoyer
Catherine M. Phelan
Olga M. Sinilnikova
David G. Cox
eng
uncontrolled
single-nucleotide polymorphisms
eng
uncontrolled
genetic modifiers
eng
uncontrolled
oxidative stress
eng
uncontrolled
consortium
eng
uncontrolled
multiple diseases
eng
uncontrolled
DNA
eng
uncontrolled
haplogroups
eng
uncontrolled
susceptibility
eng
uncontrolled
Ovarian
eng
uncontrolled
variants
Krankheiten
open_access
Institut für Humangenetik
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14545/012_Blein_BREAST-CANCER-RESEARCH.pdf