DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Ana Osorio; Roger L. Milne; Karoline Kuchenbaecker; Tereza Vaclová; Guillermo Pita; Rosario Alonso; Paolo Peterlongo; Ignacio Blanco; Miguel de la Hoya; Mercedes Duran; Orland Díez; Teresa Ramón y Cajal; Irene Konstantopoulou; Cristina 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; Giulietta 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; Alfons Meindl

doi:https://doi.org/10.1371/journal.pgen.1004256

DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Ana Osorio, Roger L. Milne, Karoline Kuchenbaecker, Tereza Vaclová, Guillermo Pita, Rosario Alonso, Paolo Peterlongo, Ignacio Blanco, Miguel de la Hoya, Mercedes Duran, Orland Díez, Teresa Ramón y Cajal, Irene Konstantopoulou, Cristina Martínez-Bouzas, Raquel Andrés Conejero, Penny Soucy, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Brita ArverJohanna 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, Giulietta 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, Alfons Meindl

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

25 Citations (Scopus)

Abstract

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 = 2.7×10-3) 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 = 4.8×10-3). 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. © 2014.

Original language	English
Article number	e1004256
Journal	PLoS Genetics
Volume	10
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1004256
Publication status	Published - 1 Jan 2014

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Osorio, A., Milne, R. L., Kuchenbaecker, K., Vaclová, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., de la Hoya, M., Duran, M., Díez, O., Ramón y Cajal, T., Konstantopoulou, I., Martínez-Bouzas, C., Andrés Conejero, R., Soucy, P., McGuffog, L., Barrowdale, D., Lee, A., ... Meindl, A. (2014). DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. PLoS Genetics, 10(4), [e1004256]. https://doi.org/10.1371/journal.pgen.1004256

Osorio, Ana ; Milne, Roger L. ; Kuchenbaecker, Karoline ; Vaclová, Tereza ; Pita, Guillermo ; Alonso, Rosario ; Peterlongo, Paolo ; Blanco, Ignacio ; de la Hoya, Miguel ; Duran, Mercedes ; Díez, Orland ; Ramón y Cajal, Teresa ; Konstantopoulou, Irene ; Martínez-Bouzas, Cristina ; Andrés Conejero, Raquel ; Soucy, Penny ; McGuffog, Lesley ; Barrowdale, Daniel ; Lee, Andrew ; Arver, Brita ; Rantala, Johanna ; Loman, Niklas ; Ehrencrona, Hans ; Olopade, Olufunmilayo I. ; Beattie, Mary S. ; Domchek, Susan M. ; Nathanson, Katherine ; Rebbeck, Timothy R. ; Arun, Banu K. ; Karlan, Beth Y. ; Walsh, Christine ; Lester, Jenny ; John, Esther M. ; Whittemore, Alice S. ; Daly, Mary B. ; Southey, Melissa ; Hopper, John ; Terry, Mary B. ; Buys, Saundra S. ; Janavicius, Ramunas ; Dorfling, Cecilia M. ; van Rensburg, Elizabeth J. ; Steele, Linda ; Neuhausen, Susan L. ; Ding, Yuan Chun ; Hansen, Thomas v.O. ; Jønson, Lars ; Ejlertsen, Bent ; Gerdes, Anne Marie ; Infante, Mar ; Herráez, Belén ; Moreno, Leticia Thais ; Weitzel, Jeffrey N. ; Herzog, Josef ; Weeman, Kisa ; Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela ; Scuvera, Giulietta ; Bonanni, Bernardo ; Mariette, Frederique ; Volorio, Sara ; Viel, Alessandra ; Varesco, Liliana ; Papi, Laura ; Ottini, Laura ; Tibiletti, Maria Grazia ; Radice, Paolo ; Yannoukakos, Drakoulis ; Garber, Judy ; Ellis, Steve ; Frost, Debra ; Platte, Radka ; Fineberg, Elena ; Evans, Gareth ; Lalloo, Fiona ; Izatt, Louise ; Eeles, Ros ; Adlard, Julian ; Davidson, Rosemarie ; Cole, Trevor ; Eccles, Diana ; Cook, Jackie ; Hodgson, Shirley ; Brewer, Carole ; Tischkowitz, Marc ; Douglas, Fiona ; Porteous, Mary ; Side, Lucy ; Walker, Lisa ; Morrison, Patrick ; Donaldson, Alan ; Kennedy, John ; Foo, Claire ; Godwin, Andrew K. ; Schmutzler, Rita Katharina ; Wappenschmidt, Barbara ; Rhiem, Kerstin ; Engel, Christoph ; Meindl, Alfons. / DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. In: PLoS Genetics. 2014 ; Vol. 10, No. 4.

@article{87d5f59fb99443f29ef8651ee816a256,

title = "DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers",

abstract = "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 = 2.7×10-3) 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 = 4.8×10-3). 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. {\textcopyright} 2014.",

author = "Ana Osorio and Milne, {Roger L.} and Karoline Kuchenbaecker and Tereza Vaclov{\'a} and Guillermo Pita and Rosario Alonso and Paolo Peterlongo and Ignacio Blanco and {de la Hoya}, Miguel and Mercedes Duran and Orland D{\'i}ez and {Ram{\'o}n y Cajal}, Teresa and Irene Konstantopoulou and Cristina Mart{\'i}nez-Bouzas and {Andr{\'e}s Conejero}, Raquel and Penny Soucy and Lesley McGuffog and Daniel Barrowdale and Andrew Lee and Brita Arver and Johanna Rantala and Niklas Loman and Hans Ehrencrona and Olopade, {Olufunmilayo I.} and Beattie, {Mary S.} and Domchek, {Susan M.} and Katherine Nathanson and Rebbeck, {Timothy R.} and Arun, {Banu K.} and Karlan, {Beth Y.} and Christine Walsh and Jenny Lester and John, {Esther M.} and Whittemore, {Alice S.} and Daly, {Mary B.} and Melissa Southey and John Hopper and Terry, {Mary B.} and Buys, {Saundra S.} and Ramunas Janavicius and Dorfling, {Cecilia M.} and {van Rensburg}, {Elizabeth J.} and Linda Steele and Neuhausen, {Susan L.} and Ding, {Yuan Chun} and Hansen, {Thomas v.O.} and Lars J{\o}nson and Bent Ejlertsen and Gerdes, {Anne Marie} and Mar Infante and Bel{\'e}n Herr{\'a}ez and Moreno, {Leticia Thais} and Weitzel, {Jeffrey N.} and Josef Herzog and Kisa Weeman and Siranoush Manoukian and Bernard Peissel and Daniela Zaffaroni and Giulietta Scuvera and Bernardo Bonanni and Frederique Mariette and Sara Volorio and Alessandra Viel and Liliana Varesco and Laura Papi and Laura Ottini and Tibiletti, {Maria Grazia} and Paolo Radice and Drakoulis Yannoukakos and Judy Garber and Steve Ellis and Debra Frost and Radka Platte and Elena Fineberg and Gareth Evans and Fiona Lalloo and Louise Izatt and Ros Eeles and Julian Adlard and Rosemarie Davidson and Trevor Cole and Diana Eccles and Jackie Cook and Shirley Hodgson and Carole Brewer and Marc Tischkowitz and Fiona Douglas and Mary Porteous and Lucy Side and Lisa Walker and Patrick Morrison and Alan Donaldson and John Kennedy and Claire Foo and Godwin, {Andrew K.} and Schmutzler, {Rita Katharina} and Barbara Wappenschmidt and Kerstin Rhiem and Christoph Engel and Alfons Meindl",

year = "2014",

month = jan,

day = "1",

doi = "https://doi.org/10.1371/journal.pgen.1004256",

language = "English",

volume = "10",

journal = "PLoS Genetics",

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number = "4",

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Osorio, A, Milne, RL, Kuchenbaecker, K, Vaclová, T, Pita, G, Alonso, R, Peterlongo, P, Blanco, I, de la Hoya, M, Duran, M, Díez, O, Ramón y Cajal, T, Konstantopoulou, I, Martínez-Bouzas, C, Andrés Conejero, R, Soucy, P, McGuffog, L, Barrowdale, D, Lee, A, Arver, B, Rantala, J, Loman, N, Ehrencrona, H, Olopade, OI, Beattie, MS, Domchek, SM, Nathanson, K, Rebbeck, TR, Arun, BK, Karlan, BY, Walsh, C, Lester, J, John, EM, Whittemore, AS, Daly, MB, Southey, M, Hopper, J, Terry, MB, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Steele, L, Neuhausen, SL, Ding, YC, Hansen, TVO, Jønson, L, Ejlertsen, B, Gerdes, AM, Infante, M, Herráez, B, Moreno, LT, Weitzel, JN, Herzog, J, Weeman, K, Manoukian, S, Peissel, B, Zaffaroni, D, Scuvera, G, Bonanni, B, Mariette, F, Volorio, S, Viel, A, Varesco, L, Papi, L, Ottini, L, Tibiletti, MG, Radice, P, Yannoukakos, D, Garber, J, Ellis, S, Frost, D, Platte, R, Fineberg, E, Evans, G, Lalloo, F, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Cole, T, Eccles, D, Cook, J, Hodgson, S, Brewer, C, Tischkowitz, M, Douglas, F, Porteous, M, Side, L, Walker, L, Morrison, P, Donaldson, A, Kennedy, J, Foo, C, Godwin, AK, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C & Meindl, A 2014, 'DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers', PLoS Genetics, vol. 10, no. 4, e1004256. https://doi.org/10.1371/journal.pgen.1004256

DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. / Osorio, Ana; Milne, Roger L.; Kuchenbaecker, Karoline; Vaclová, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; Díez, Orland; Ramón y Cajal, Teresa; Konstantopoulou, Irene; Martínez-Bouzas, Cristina; Andrés Conejero, Raquel; Soucy, Penny; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Arver, Brita; Rantala, Johanna; Loman, Niklas; Ehrencrona, Hans; Olopade, Olufunmilayo I.; Beattie, Mary S.; Domchek, Susan M.; Nathanson, Katherine; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; John, Esther M.; Whittemore, Alice S.; Daly, Mary B.; Southey, Melissa; Hopper, John; Terry, Mary B.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Steele, Linda; Neuhausen, Susan L.; Ding, Yuan Chun; Hansen, Thomas v.O.; Jønson, Lars; Ejlertsen, Bent; Gerdes, Anne Marie; Infante, Mar; Herráez, Belén; Moreno, Leticia Thais; Weitzel, Jeffrey N.; Herzog, Josef; Weeman, Kisa; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Bonanni, Bernardo; Mariette, Frederique; Volorio, Sara; Viel, Alessandra; Varesco, Liliana; Papi, Laura; Ottini, Laura; Tibiletti, Maria Grazia; Radice, Paolo; Yannoukakos, Drakoulis; Garber, Judy; Ellis, Steve; Frost, Debra; Platte, Radka; Fineberg, Elena; Evans, Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Eccles, Diana; Cook, Jackie; Hodgson, Shirley; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Porteous, Mary; Side, Lucy; Walker, Lisa; Morrison, Patrick; Donaldson, Alan; Kennedy, John; Foo, Claire; Godwin, Andrew K.; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons.

In: PLoS Genetics, Vol. 10, No. 4, e1004256, 01.01.2014.

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

TY - JOUR

T1 - DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

AU - Osorio, Ana

AU - Milne, Roger L.

AU - Kuchenbaecker, Karoline

AU - Vaclová, Tereza

AU - Pita, Guillermo

AU - Alonso, Rosario

AU - Peterlongo, Paolo

AU - Blanco, Ignacio

AU - de la Hoya, Miguel

AU - Duran, Mercedes

AU - Díez, Orland

AU - Ramón y Cajal, Teresa

AU - Konstantopoulou, Irene

AU - Martínez-Bouzas, Cristina

AU - Andrés Conejero, Raquel

AU - Soucy, Penny

AU - McGuffog, Lesley

AU - Barrowdale, Daniel

AU - Lee, Andrew

AU - Arver, Brita

AU - Rantala, Johanna

AU - Loman, Niklas

AU - Ehrencrona, Hans

AU - Olopade, Olufunmilayo I.

AU - Beattie, Mary S.

AU - Domchek, Susan M.

AU - Nathanson, Katherine

AU - Rebbeck, Timothy R.

AU - Arun, Banu K.

AU - Karlan, Beth Y.

AU - Walsh, Christine

AU - Lester, Jenny

AU - John, Esther M.

AU - Whittemore, Alice S.

AU - Daly, Mary B.

AU - Southey, Melissa

AU - Hopper, John

AU - Terry, Mary B.

AU - Buys, Saundra S.

AU - Janavicius, Ramunas

AU - Dorfling, Cecilia M.

AU - van Rensburg, Elizabeth J.

AU - Steele, Linda

AU - Neuhausen, Susan L.

AU - Ding, Yuan Chun

AU - Hansen, Thomas v.O.

AU - Jønson, Lars

AU - Ejlertsen, Bent

AU - Gerdes, Anne Marie

AU - Infante, Mar

AU - Herráez, Belén

AU - Moreno, Leticia Thais

AU - Weitzel, Jeffrey N.

AU - Herzog, Josef

AU - Weeman, Kisa

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Zaffaroni, Daniela

AU - Scuvera, Giulietta

AU - Bonanni, Bernardo

AU - Mariette, Frederique

AU - Volorio, Sara

AU - Viel, Alessandra

AU - Varesco, Liliana

AU - Papi, Laura

AU - Ottini, Laura

AU - Tibiletti, Maria Grazia

AU - Radice, Paolo

AU - Yannoukakos, Drakoulis

AU - Garber, Judy

AU - Ellis, Steve

AU - Frost, Debra

AU - Platte, Radka

AU - Fineberg, Elena

AU - Evans, Gareth

AU - Lalloo, Fiona

AU - Izatt, Louise

AU - Eeles, Ros

AU - Adlard, Julian

AU - Davidson, Rosemarie

AU - Cole, Trevor

AU - Eccles, Diana

AU - Cook, Jackie

AU - Hodgson, Shirley

AU - Brewer, Carole

AU - Tischkowitz, Marc

AU - Douglas, Fiona

AU - Porteous, Mary

AU - Side, Lucy

AU - Walker, Lisa

AU - Morrison, Patrick

AU - Donaldson, Alan

AU - Kennedy, John

AU - Foo, Claire

AU - Godwin, Andrew K.

AU - Schmutzler, Rita Katharina

AU - Wappenschmidt, Barbara

AU - Rhiem, Kerstin

AU - Engel, Christoph

AU - Meindl, Alfons

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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 = 2.7×10-3) 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 = 4.8×10-3). 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. © 2014.

AB - 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 = 2.7×10-3) 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 = 4.8×10-3). 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. © 2014.

UR - https://ddd.uab.cat/record/185026

U2 - https://doi.org/10.1371/journal.pgen.1004256

DO - https://doi.org/10.1371/journal.pgen.1004256

M3 - Article

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 4

M1 - e1004256

ER -