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Exploring the link between MORF4L1 and risk of breast cancer.

Exploring the link between MORF4L1 and risk of breast cancer.

Authors :
Martrat G
Maxwell CM
Tominaga E
Porta-de-la-Riva M
Bonifaci N
Gómez-Baldó L
Bogliolo M
Lázaro C
Blanco I
Brunet J
Aguilar H
Fernández-Rodríguez J
Seal S
Renwick A
Rahman N
Kühl J
Neveling K
Schindler D
Ramírez MJ
Castellà M
Hernández G
Easton DF
Peock S
Cook M
Oliver CT
Frost D
Platte R
Evans DG
Lalloo F
Eeles R
Izatt L
Chu C
Davidson R
Ong KR
Cook J
Douglas F
Hodgson S
Brewer C
Morrison PJ
Porteous M
Peterlongo P
Manoukian S
Peissel B
Zaffaroni D
Roversi G
Barile M
Viel A
Pasini B
Ottini L
Putignano AL
Savarese A
Bernard L
Radice P
Healey S
Spurdle A
Chen X
Beesley J
Rookus MA
Verhoef S
Tilanus-Linthorst MA
Vreeswijk MP
Asperen CJ
Bodmer D
Ausems MG
van Os TA
Blok MJ
Meijers-Heijboer HE
Hogervorst FB
Goldgar DE
Buys S
John EM
Miron A
Southey M
Daly MB
Harbst K
Borg A
Rantala J
Barbany-Bustinza G
Ehrencrona H
Stenmark-Askmalm M
Kaufman B
Laitman Y
Milgrom R
Friedman E
Domchek SM
Nathanson KL
Rebbeck TR
Johannsson OT
Couch FJ
Wang X
Fredericksen Z
Cuadras D
Moreno V
Pientka FK
Depping R
Caldés T
Osorio A
Benítez J
Bueren J
Heikkinen T
Nevanlinna H
Hamann U
Torres D
Caligo MA
Godwin AK
Imyanitov EN
Janavicius R
Sinilnikova OM
Stoppa-Lyonnet D
Mazoyer S
Verny-Pierre C
Castera L
de Pauw A
Bignon YJ
Uhrhammer N
Peyrat JP
Vennin P
Ferrer SF
Collonge-Rame MA
Mortemousque I
McGuffog L
Chenevix-Trench G
Pereira-Smith OM
Antoniou AC
Cerón J
Tominaga K
Surrallés J
Pujana MA
Source :
Breast cancer research : BCR [Breast Cancer Res] 2011 Apr 05; Vol. 13 (2), pp. R40. Date of Electronic Publication: 2011 Apr 05.
Publication Year :
2011

Abstract

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.<br />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.<br />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 γ-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.<br />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.

Details

Language :
English
ISSN :
1465-542X
Volume :
13
Issue :
2
Database :
MEDLINE
Journal :
Breast cancer research : BCR
Publication Type :
Academic Journal
Accession number :
21466675
Full Text :
https://doi.org/10.1186/bcr2862