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
11682
2014
eng
e1004256
4
article
SWE-BRCA ; HEBON ; kConFab Investigators
1
2015-07-27
--
--
DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7x10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95% CI: 1.03-1.21, p = 4.8x10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
PLOS Genetics
10.1371/journal.pgen.1004256
1553-7404
24698998
urn:nbn:de:bvb:20-opus-116820
PLoS Genetics 10(4): e1004256. doi:10.1371/journal.pgen.1004256
CC 0: Public Domain Dedication
Ana Osorio
Roger L. Milne
Karoline Kuchenbaecker
Tereza Vaclová
Guillermo Pita
Rosario Alonso
Paolo Peterlongo
Ignacio Blanco
Miguel de la Hoya
Mercedes Duran
Orland Diez
Teresa Ramón y Cajal
Irene Konstantopoulou
Christina Martínez-Bouzas
Raquel Andrés Conejero
Penny Soucy
Lesley McGuffog
Daniel Barrowdale
Andrew Lee
Brita Arver
Johanna Rantala
Niklas Loman
Hans Ehrencrona
Olufunmilayo I. Olopade
Mary S. Beattie
Susan M. Domchek
Katherine Nathanson
Timothy R. Rebbeck
Banu K. Arun
Beth Y. Karlan
Christine Walsh
Jenny Lester
Esther M. John
Alice S. Whittemore
Mary B. Daly
Melissa Southey
John Hopper
Mary B. Terry
Saundra S. Buys
Ramunas Janavicius
Cecilia M. Dorfling
Elizabeth J. van Rensburg
Linda Steele
Susan L. Neuhausen
Yuan Chun Ding
Thomas V. O. Hansen
Lars Jønson
Bent Ejlertsen
Anne-Marie Gerdes
Mar Infante
Belén Herráez
Leticia Thais Moreno
Jeffrey N. Weitzel
Josef Herzog
Kisa Weeman
Siranoush Manoukian
Bernard Peissel
Daniela Zaffaroni
Guilietta Scuvera
Bernardo Bonanni
Frederique Mariette
Sara Volorio
Alessandra Viel
Liliana Varesco
Laura Papi
Laura Ottini
Maria Grazia Tibiletti
Paolo Radice
Drakoulis Yannoukakos
Judy Garber
Steve Ellis
Debra Frost
Radka Platte
Elena Fineberg
Gareth Evans
Fiona Lalloo
Louise Izatt
Ros Eeles
Julian Adlard
Rosemarie Davidson
Trevor Cole
Diana Eccles
Jackie Cook
Shirley Hodgson
Carole Brewer
Marc Tischkowitz
Fiona Douglas
Mary Porteous
Lucy Side
Lisa Walker
Patrick Morrison
Alan Donaldson
John Kennedy
Claire Foo
Andrew K. Godwin
Rita Katharina Schmutzler
Barbara Wappenschmidt
Kerstin Rhiem
Christoph Engel
Alftons Meindl
Nina Ditsch
Norbert Arnold
Hans Jörg Plendl
Dieter Niederacher
Christian Sutter
Shan Wang-Gohrke
Doris Steinemann
Sabine Preisler-Adams
Karin Kast
Raymonda Varon-Mateeva
Andrea Gehrig
Dominique Stoppa-Lyonnet
Olga M. Sinilnikova
Sylvie Mazoyer
Francesca Damiola
Bruce Poppe
Kathleen Claes
Marion Piedmonte
Kathy Tucker
Floor Backes
Gustavo Rodríguez
Wendy Brewster
Katie Wakeley
Thomas Rutherford
Trinidad Caldés
Heli Nevanlinna
Kristiina Aittomäki
Matti A. Rookus
Theo A. M. van Os
Lizet van der Kolk
J. L. de Lange
Hanne E. J. Meijers-Heijboer
A. H. van der Hout
Christi J. van Asperen
Encarna B. Goméz Garcia
B. Encarna
Nicoline Hoogerbrugge
J. Margriet Collée
Carolien H. M. van Deurzen
Rob B. van der Luijt
Peter Devilee
Edith Olah
Conxi Lázaro
Alex Teulé
Mireia Menéndez
Anna Jakubowska
Cezary Cybulski
Jecek Gronwald
Jan Lubinski
Katarzyna Durda
Katarzyna Jaworska-Bieniek
Oskar Th. Johannsson
Christine Maugard
Marco Montagna
Silvia Tognazzo
Manuel R. Teixeira
Sue Healey
Curtis Olswold
Lucia Guidugli
Noralane Lindor
Susan Slager
Csilla I. Szabo
Joseph Vijai
Mark Robson
Noah Kauff
Liying Zhang
Rohini Rau-Murthy
Anneliese Fink-Retter
Christine F. Singer
Christine Rappaport
Daphne Geschwantler Kaulich
Georg Pfeiler
Muy-Kheng Tea
Andreas Berger
Catherine M. Phelan
Mark H. Greene
Phuong L. Mai
Flavio Lejbkowicz
Irene Andrulis
Anna Marie Mulligan
Gord Glendon
Amanda Ewart Toland
Anders Bojesen
Inge Sokilde Pedersen
Lone Sunde
Mads Thomassen
Torben A. Kruse
Uffe Birk Jensen
Eitan Friedman
Yeal Laitman
Shanie Paluch Shimon
Jaques Simard
Douglas F. Easton
Kenneth Offit
Fergus J. Couch
Georgia Chenevix-Trench
Antonis C. Antoniou
Javier Benitez
eng
uncontrolled
single-nucleotide polymorphisms
eng
uncontrolled
breast cancer
eng
uncontrolled
ovarian cancer
eng
uncontrolled
genetic modifiers
eng
uncontrolled
common variants
eng
uncontrolled
NEIL2
eng
uncontrolled
OGG1
eng
uncontrolled
investigators
eng
uncontrolled
consortium
eng
uncontrolled
damage
Medizin und Gesundheit
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11682/097_Osario_Plos_Genetics.pdf
28175
2022
eng
13
14
article
1
--
2022-07-05
--
Prevalence of cancer predisposition germline variants in male breast cancer patients: results of the German Consortium for Hereditary Breast and Ovarian Cancer
Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54–26.82, p < 10\(^{−5}\); BRCA2: OR = 77.71, 95% CI = 58.71–102.33, p < 10\(^{−5}\)). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59–7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02–36.02, p < 10\(^{−5}\); ATM: OR = 3.36, 95% CI = 0.89–8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.
Cancers
2072-6694
10.3390/cancers14133292
urn:nbn:de:bvb:20-opus-281758
2022-08-03T11:51:45+00:00
sword
swordwue
attachment; filename=deposit.zip
3ac09c613e39876ac974e962adbe6504
Cancers (2022) 14:13, 3292. https://doi.org/10.3390/cancers14133292
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Muriel Rolfes
Julika Borde
Kathrin Möllenhoff
Mohamad Kayali
Corinna Ernst
Andrea Gehrig
Christian Sutter
Juliane Ramser
Dieter Niederacher
Judit Horváth
Norbert Arnold
Alfons Meindl
Bernd Auber
Andreas Rump
Shan Wang-Gohrke
Julia Ritter
Julia Hentschel
Holger Thiele
Janine Altmüller
Peter Nürnberg
Kerstin Rhiem
Christoph Engel
Barbara Wappenschmidt
Rita K. Schmutzler
Eric Hahnen
Jan Hauke
eng
uncontrolled
breast neoplasms
eng
uncontrolled
male breast cancer
eng
uncontrolled
breast cancer predisposition genes
eng
uncontrolled
genetic testing
eng
uncontrolled
familial breast cancer
Medizin und Gesundheit
open_access
Institut für Humangenetik
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/28175/cancers-14-03292-v2.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
28176
2022
eng
14
14
article
1
--
2022-07-11
--
Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
Cancers
2072-6694
10.3390/cancers14143363
urn:nbn:de:bvb:20-opus-281768
2022-08-03T11:57:22+00:00
sword
swordwue
attachment; filename=deposit.zip
4e4675a09a24bc2701fd9f04c78ac863
Cancers (2022) 14:14, 3363. https://doi.org/10.3390/cancers14143363
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Martine Dumont
Nana Weber-Lassalle
Charles Joly-Beauparlant
Corinna Ernst
Arnaud Droit
Bing-Jian Feng
Stéphane Dubois
Annie-Claude Collin-Deschesnes
Penny Soucy
Maxime Vallée
Frédéric Fournier
Audrey Lemaçon
Muriel A. Adank
Jamie Allen
Janine Altmüller
Norbert Arnold
Margreet G. E. M. Ausems
Riccardo Berutti
Manjeet K. Bolla
Shelley Bull
Sara Carvalho
Sten Cornelissen
Michael R. Dufault
Alison M. Dunning
Christoph Engel
Andrea Gehrig
Willemina R. R. Geurts-Giele
Christian Gieger
Jessica Green
Karl Hackmann
Mohamed Helmy
Julia Hentschel
Frans B. L. Hogervorst
Antoinette Hollestelle
Maartje J. Hooning
Judit Horváth
M. Arfan Ikram
Silke Kaulfuß
Renske Keeman
Da Kuang
Craig Luccarini
Wolfgang Maier
John W. M. Martens
Dieter Niederacher
Peter Nürnberg
Claus-Eric Ott
Annette Peters
Paul D. P. Pharoah
Alfredo Ramirez
Juliane Ramser
Steffi Riedel-Heller
Gunnar Schmidt
Mitul Shah
Martin Scherer
Antje Stäbler
Tim M. Strom
Christian Sutter
Holger Thiele
Christi J. van Asperen
Lizet van der Kolk
Rob B. van der Luijt
Alexander E. Volk
Michael Wagner
Quinten Waisfisz
Qin Wang
Shan Wang-Gohrke
Bernhard H. F. Weber
Peter Devilee
Sean Tavtigian
Gary D. Bader
Alfons Meindl
David E. Goldgar
Irene L. Andrulis
Rita K. Schmutzler
Douglas F. Easton
Marjanka K. Schmidt
Eric Hahnen
Jacques Simard
eng
uncontrolled
breast cancer
eng
uncontrolled
genetic susceptibility
eng
uncontrolled
whole-exome sequencing
eng
uncontrolled
moderate-penetrance genes
Medizin und Gesundheit
open_access
Institut für Humangenetik
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/28176/cancers-14-03363-v2.pdf
23343
2018
eng
20
article
1
2021-04-06
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BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer
Background
Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial.
Methods
To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants.
Results
BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients.
Conclusions
To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded.
Breast Cancer Research
10.1186/s13058-018-0935-9
urn:nbn:de:bvb:20-opus-233433
publish
Breast Cancer Research (2018) 20:7. https://doi.org/10.1186/s13058-018-0935-9
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Nana Weber-Lassalle
Jan Hauke
Juliane Ramser
Lisa Richters
Eva Groß
Britta Blümcke
Andrea Gehrig
Anne-Karin Kahlert
Clemens R. Müller
Karl Hackmann
Ellen Honisch
Konstantin Weber-Lassalle
Dieter Niederacher
Julika Borde
Holger Thiele
Corinna Ernst
Janine Altmüller
Guido Neidhardt
Peter Nürnberg
Kristina Klaschik
Christopher Schroeder
Konrad Platzer
Alexander E. Volk
Shan Wang-Gohrke
Walter Just
Bernd Auber
Christian Kubisch
Gunnar Schmidt
Judit Horvath
Barbara Wappenschmidt
Christoph Engel
Norbert Arnold
Bernd Dworniczak
Kerstin Rhiem
Alfons Meindl
Rita K. Schmutzler
Eric Hahnen
eng
uncontrolled
breast cancer
eng
uncontrolled
ovarian cancer
eng
uncontrolled
BRIP1 gene
eng
uncontrolled
germline mutations
Medizin und Gesundheit
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23343/s13058-018-0935-9.pdf