Exploring the link between MORF4L1 and risk of breast cancer

G Martrat; CA Maxwell; E Tominaga; M Porta-de-la-Riva; N Bonifaci; L Gomez-Baldo; M Bogliolo; C (Conxi) Lazaro; I Blanco; J Brunet; H Aguilar; J Fernandez-Rodriguez; S Seal; A Renwick; N Rahman; J Kuhl; K Neveling; D Schindler; MJ Ramirez; M Castella; G Hernandez; DF Easton; S Peock; M Cook; CT Oliver; D Frost; R Platte; DG Evans; F Lalloo; R Eeles; L Izatt; C Chu; R Davidson; KR Ong; J Cook; F Douglas; S Hodgson; C Brewer; PJ Morrison; M Porteous; P Peterlongo; S Manoukian; B Peissel; D Zaffaroni; G Roversi; M Barile; A Viel; B pasini; L Ottini; AL Putignano; A Savarese; L Bernard; P Radice; S Healey; A Spurdle; XQ Chen; J Beesley; MA Rookus; S Verhoef; MA Tilanus-Linthorst; MP Vreeswijk; CJ van Asperen; D Bodmer; MGEM Ausems; TA van Os; MJ Blok; HEJ Meijers-Heijboer; FBL Hogervorst; DE Goldgar; S Buys; EM John; A Miron; M Southey; MB Daly; K Harbst; A Borg; J Rantala; G Barbany-Bustinza; H Ehrencrona; M Stenmark-Askmalm; B Kaufman; Y Laitman; R Milgrom; E Friedman; SM Domchek; KL Nathanson; TR Rebbeck; T Oskar; FJ Couch; XS Wang; Z Fredericksen; D Cuadras; V Moreno; FK Pientka; R Depping; T Caldes; A Osorio; J Benitez; J Bueren; T Heikkinen; H Nevanlinna; U Hamann; D Torres; MA Caligo; AK Godwin; EN Imyanitov; R Janavicius; OM Sinilnikova; D Stoppa-Lyonnet; S Mazoyer; C Verny-Pierre; L Castera; A de Pauw; YJ Bignon; N Uhrhammer; JP Peyrat; P Vennin; SF Ferrer; MA Collonge-Rame; I Mortemousque; L McGuffog; G Chenevix-Trench; OM Pereira-Smith; AC Antoniou; J Ceron; K Tominaga; J Surralles; MA Pujana

doi:10.1186/bcr2862

Exploring the link between MORF4L1 and risk of breast cancer

G Martrat, CA Maxwell, E Tominaga, M Porta-de-la-Riva, N Bonifaci, L Gomez-Baldo, M Bogliolo, C (Conxi) Lazaro, I Blanco, J Brunet, H Aguilar, J Fernandez-Rodriguez, S Seal, A Renwick, N Rahman, J Kuhl, K Neveling, D Schindler, MJ Ramirez, M CastellaG Hernandez, DF Easton, S Peock, M Cook, CT Oliver, D Frost, R Platte, DG Evans, F Lalloo, R Eeles, L Izatt, C Chu, R Davidson, KR Ong, J Cook, F Douglas, S Hodgson, C Brewer, PJ Morrison, M Porteous, P Peterlongo, S Manoukian, B Peissel, D Zaffaroni, G Roversi, M Barile, A Viel, B pasini, L Ottini, AL Putignano, A Savarese, L Bernard, P Radice, S Healey, A Spurdle, XQ Chen, J Beesley, MA Rookus, S Verhoef, MA Tilanus-Linthorst, MP Vreeswijk, CJ van Asperen, D Bodmer, MGEM Ausems, TA van Os, MJ Blok, HEJ Meijers-Heijboer, FBL Hogervorst, DE Goldgar, S Buys, EM John, A Miron, M Southey, MB Daly, K Harbst, A Borg, J Rantala, G Barbany-Bustinza, H Ehrencrona, M Stenmark-Askmalm, B Kaufman, Y Laitman, R Milgrom, E Friedman, SM Domchek, KL Nathanson, TR Rebbeck, T Oskar, FJ Couch, XS Wang, Z Fredericksen, D Cuadras, V Moreno, FK Pientka, R Depping, T Caldes, A Osorio, J Benitez, J Bueren, T Heikkinen, H Nevanlinna, U Hamann, D Torres, MA Caligo, AK Godwin, EN Imyanitov, R Janavicius, OM Sinilnikova, D Stoppa-Lyonnet, S Mazoyer, C Verny-Pierre, L Castera, A de Pauw, YJ Bignon, N Uhrhammer, JP Peyrat, P Vennin, SF Ferrer, MA Collonge-Rame, I Mortemousque, L McGuffog, G Chenevix-Trench, OM Pereira-Smith, AC Antoniou, J Ceron, K Tominaga, J Surralles, MA Pujana

Clinical Genetics

Research output: Contribution to journal › Article › Academic › peer-review

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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. 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, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 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.

Original language	Undefined/Unknown
Journal	Breast Cancer Research
Volume	13
Issue number	2
DOIs	https://doi.org/10.1186/bcr2862
Publication status	Published - 2011

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Cite this

Martrat, G., Maxwell, CA., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, MJ., ... Pujana, MA. (2011). Exploring the link between MORF4L1 and risk of breast cancer. Breast Cancer Research, 13(2). https://doi.org/10.1186/bcr2862

@article{eca3f792907241f2baa3fa52366224d2,

title = "Exploring the link between MORF4L1 and risk of breast cancer",

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. 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, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 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.",

author = "G Martrat and CA Maxwell and E Tominaga and M Porta-de-la-Riva and N Bonifaci and L Gomez-Baldo and M Bogliolo and Lazaro, {C (Conxi)} and I Blanco and J Brunet and H Aguilar and J Fernandez-Rodriguez and S Seal and A Renwick and N Rahman and J Kuhl and K Neveling and D Schindler and MJ Ramirez and M Castella and G Hernandez and DF Easton and S Peock and M Cook and CT Oliver and D Frost and R Platte and DG Evans and F Lalloo and R Eeles and L Izatt and C Chu and R Davidson and KR Ong and J Cook and F Douglas and S Hodgson and C Brewer and PJ Morrison and M Porteous and P Peterlongo and S Manoukian and B Peissel and D Zaffaroni and G Roversi and M Barile and A Viel and B pasini and L Ottini and AL Putignano and A Savarese and L Bernard and P Radice and S Healey and A Spurdle and XQ Chen and J Beesley and MA Rookus and S Verhoef and MA Tilanus-Linthorst and MP Vreeswijk and {van Asperen}, CJ and D Bodmer and MGEM Ausems and {van Os}, TA and MJ Blok and HEJ Meijers-Heijboer and FBL Hogervorst and DE Goldgar and S Buys and EM John and A Miron and M Southey and MB Daly and K Harbst and A Borg and J Rantala and G Barbany-Bustinza and H Ehrencrona and M Stenmark-Askmalm and B Kaufman and Y Laitman and R Milgrom and E Friedman and SM Domchek and KL Nathanson and TR Rebbeck and T Oskar and FJ Couch and XS Wang and Z Fredericksen and D Cuadras and V Moreno and FK Pientka and R Depping and T Caldes and A Osorio and J Benitez and J Bueren and T Heikkinen and H Nevanlinna and U Hamann and D Torres and MA Caligo and AK Godwin and EN Imyanitov and R Janavicius and OM Sinilnikova and D Stoppa-Lyonnet and S Mazoyer and C Verny-Pierre and L Castera and {de Pauw}, A and YJ Bignon and N Uhrhammer and JP Peyrat and P Vennin and SF Ferrer and MA Collonge-Rame and I Mortemousque and L McGuffog and G Chenevix-Trench and OM Pereira-Smith and AC Antoniou and J Ceron and K Tominaga and J Surralles and MA Pujana",

year = "2011",

doi = "10.1186/bcr2862",

language = "Undefined/Unknown",

volume = "13",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

number = "2",

}

Martrat, G, Maxwell, CA, Tominaga, E, Porta-de-la-Riva, M, Bonifaci, N, Gomez-Baldo, L, Bogliolo, M, Lazaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernandez-Rodriguez, J, Seal, S, Renwick, A, Rahman, N, Kuhl, J, Neveling, K, Schindler, D, Ramirez, MJ, Castella, M, Hernandez, 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, XQ, Beesley, J, Rookus, MA, Verhoef, S, Tilanus-Linthorst, MA, Vreeswijk, MP, van Asperen, CJ, Bodmer, D, Ausems, MGEM, van Os, TA, Blok, MJ, Meijers-Heijboer, HEJ, Hogervorst, FBL, 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, Oskar, T, Couch, FJ, Wang, XS, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, FK, Depping, R, Caldes, T, Osorio, A, Benitez, 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, Ceron, J, Tominaga, K, Surralles, J & Pujana, MA 2011, 'Exploring the link between MORF4L1 and risk of breast cancer', Breast Cancer Research, vol. 13, no. 2. https://doi.org/10.1186/bcr2862

TY - JOUR

T1 - Exploring the link between MORF4L1 and risk of breast cancer

AU - Martrat, G

AU - Maxwell, CA

AU - Tominaga, E

AU - Porta-de-la-Riva, M

AU - Bonifaci, N

AU - Gomez-Baldo, L

AU - Bogliolo, M

AU - Lazaro, C (Conxi)

AU - Blanco, I

AU - Brunet, J

AU - Aguilar, H

AU - Fernandez-Rodriguez, J

AU - Seal, S

AU - Renwick, A

AU - Rahman, N

AU - Kuhl, J

AU - Neveling, K

AU - Schindler, D

AU - Ramirez, MJ

AU - Castella, M

AU - Hernandez, G

AU - Easton, DF

AU - Peock, S

AU - Cook, M

AU - Oliver, CT

AU - Frost, D

AU - Platte, R

AU - Evans, DG

AU - Lalloo, F

AU - Eeles, R

AU - Izatt, L

AU - Chu, C

AU - Davidson, R

AU - Ong, KR

AU - Cook, J

AU - Douglas, F

AU - Hodgson, S

AU - Brewer, C

AU - Morrison, PJ

AU - Porteous, M

AU - Peterlongo, P

AU - Manoukian, S

AU - Peissel, B

AU - Zaffaroni, D

AU - Roversi, G

AU - Barile, M

AU - Viel, A

AU - pasini, B

AU - Ottini, L

AU - Putignano, AL

AU - Savarese, A

AU - Bernard, L

AU - Radice, P

AU - Healey, S

AU - Spurdle, A

AU - Chen, XQ

AU - Beesley, J

AU - Rookus, MA

AU - Verhoef, S

AU - Tilanus-Linthorst, MA

AU - Vreeswijk, MP

AU - van Asperen, CJ

AU - Bodmer, D

AU - Ausems, MGEM

AU - van Os, TA

AU - Blok, MJ

AU - Meijers-Heijboer, HEJ

AU - Hogervorst, FBL

AU - Goldgar, DE

AU - Buys, S

AU - John, EM

AU - Miron, A

AU - Southey, M

AU - Daly, MB

AU - Harbst, K

AU - Borg, A

AU - Rantala, J

AU - Barbany-Bustinza, G

AU - Ehrencrona, H

AU - Stenmark-Askmalm, M

AU - Kaufman, B

AU - Laitman, Y

AU - Milgrom, R

AU - Friedman, E

AU - Domchek, SM

AU - Nathanson, KL

AU - Rebbeck, TR

AU - Oskar, T

AU - Couch, FJ

AU - Wang, XS

AU - Fredericksen, Z

AU - Cuadras, D

AU - Moreno, V

AU - Pientka, FK

AU - Depping, R

AU - Caldes, T

AU - Osorio, A

AU - Benitez, J

AU - Bueren, J

AU - Heikkinen, T

AU - Nevanlinna, H

AU - Hamann, U

AU - Torres, D

AU - Caligo, MA

AU - Godwin, AK

AU - Imyanitov, EN

AU - Janavicius, R

AU - Sinilnikova, OM

AU - Stoppa-Lyonnet, D

AU - Mazoyer, S

AU - Verny-Pierre, C

AU - Castera, L

AU - de Pauw, A

AU - Bignon, YJ

AU - Uhrhammer, N

AU - Peyrat, JP

AU - Vennin, P

AU - Ferrer, SF

AU - Collonge-Rame, MA

AU - Mortemousque, I

AU - McGuffog, L

AU - Chenevix-Trench, G

AU - Pereira-Smith, OM

AU - Antoniou, AC

AU - Ceron, J

AU - Tominaga, K

AU - Surralles, J

AU - Pujana, MA

PY - 2011

Y1 - 2011

N2 - 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, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 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.

AB - 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, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 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.

U2 - 10.1186/bcr2862

DO - 10.1186/bcr2862

M3 - Article

C2 - 21466675

SN - 1465-5411

VL - 13

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 2

ER -