16911
2011
eng
1-14
R40
13
article
1
2018-10-12
--
--
Exploring the link between MORF4L1 and risk of breast cancer
Introduction:
Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens.
Methods:
Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk.
Results:
A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells.
However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively.
Conclusions:
While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2
mutation carriers.
Breast Cancer Research
10.1186/bcr2862
urn:nbn:de:bvb:20-opus-169119
Breast Cancer Research 2011 13:R40
Griselda Martrat
Christopher A. Maxwell
Emiko Tominaga
Montserrat Porta-de-la-Riva
Núria Bonifaci
Laia Gómez-Baldó
Massimo Bogliolo
Conxi Lázaro
Ignacio Blanco
Joan Brunet
Kornelia Neveling
et al
eng
uncontrolled
breast cancer
Krankheiten
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16911/047_Martrat_Breast-Cancer-Research.pdf
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