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

A Osorio; RL Milne; K Kuchenbaecker; T Vaclova; G Pita; R Alonso; P Peterlongo; I Blanco; M de la Hoya; M (Mercedes) Duran; O Diez; TRY Cajal; I Konstantopoulou; C Martinez-Bouzas; RA Conejero; P Soucy; L McGuffog; D Barrowdale; A van der Lee; B Arver; J Rantala; N Loman; H Ehrencrona; OI Olopade; MS Beattie; SM Domchek; K Nathanson; TR Rebbeck; BK Arun; BY Karlan; C Walsh; J Lester; EM John; AS Whittemore; MB Daly; M Southey; J Hopper; MB Terry; SS Buys; R Janavicius; CM Dorfling; EJ van Rensburg; L Steele; SL Neuhausen; YC Ding; TVO Hansen; L Jonson; B Ejlertsen; AM Gerdes; M Infante; B Herraez; LT Moreno; JN Weitzel; J Herzog; K Weeman; S Manoukian; B Peissel; D Zaffaroni; G Scuvera; B Bonanni; F Mariette; S Volorio; A Viel; L Varesco; L Papi; L Ottini; MG Tibiletti; P Radice; D Yannoukakos; J Garber; S Ellis; D Frost; R Platte; E Fineberg; G Evans; F Lalloo; L Izatt; R Eeles; J Adlard; R Davidson; T Cole; D Eccles; J Cook; S Hodgson; C Brewer; M Tischkowitz; F Douglas; M Porteous; L Side; L Walker; P Morrison; A Donaldson; J Kennedy; C Foo; AK Godwin; RK Schmutzler; B Wappenschmidt; K Rhiem; C Engel; A Meindl; N Ditsch; N Arnold; HJ Plendl; D Niederacher; C Sutter; S Wang-Gohrke; D Steinemann; S Preisler-Adams; K Kast; R Varon-Mateeva; A Gehrig; D Stoppa-Lyonnet; OM Sinilnikova; S Mazoyer; F Damiola; B Poppe; K Claes; M Piedmonte; K Tucker; F Backes; G Rodriguez; W Brewster; K Wakeley; T Rutherford; T Caldes; H Nevanlinna; K Aittomaki; MA Rookus; TAM van Os; L van der Kolk; JL de Lange; HEJ Meijers-Heijboer; AH van der Hout; CJ van Asperen; EBG Garcia; N Hoogerbrugge; Margriet Collee; Carolien van Deurzen; RB van der Luijt; P Devilee; E Olah; C (Conxi) Lazaro; A Teule; M Menendez; A Jakubowska; C Cybulski; J Gronwald; J Lubinski; K Durda; K Jaworska-Bieniek; OT Johannsson; C Maugard; M Montagna; S Tognazzo; MR Teixeira; S Healey; C Olswold; L Guidugli; N Lindor; S Slager; CI Szabo; J Vijai; M Robson; N Kauff; LY Zhang; R Rau-Murthy; A Fink-Retter; CF Singer; C Rappaport; DG Kaulich; G Pfeiler; MK Tea; A Berger; CM Phelan; MH Greene; PL Mai; F Lejbkowicz; I Andrulis; AM Mulligan; G Glendon; AE Toland; A Bojesen; IS Pedersen; L Sunde; Marga Thomassen; TA Kruse; UB Jensen; E Friedman; Y Laitman; SP Shimon; J Simard; DF Easton; K Offit; FJ Couch; G Chenevix-Trench; AC Antoniou; J Benitez

doi:10.1371/journal.pgen.1004256

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

A Osorio, RL Milne, K Kuchenbaecker, T Vaclova, G Pita, R Alonso, P Peterlongo, I Blanco, M de la Hoya, M (Mercedes) Duran, O Diez, TRY Cajal, I Konstantopoulou, C Martinez-Bouzas, RA Conejero, P Soucy, L McGuffog, D Barrowdale, A van der Lee, B ArverJ Rantala, N Loman, H Ehrencrona, OI Olopade, MS Beattie, SM Domchek, K Nathanson, TR Rebbeck, BK Arun, BY Karlan, C Walsh, J Lester, EM John, AS Whittemore, MB Daly, M Southey, J Hopper, MB Terry, SS Buys, R Janavicius, CM Dorfling, EJ van Rensburg, L Steele, SL Neuhausen, YC Ding, TVO Hansen, L Jonson, B Ejlertsen, AM Gerdes, M Infante, B Herraez, LT Moreno, JN Weitzel, J Herzog, K Weeman, S Manoukian, B Peissel, D Zaffaroni, G Scuvera, B Bonanni, F Mariette, S Volorio, A Viel, L Varesco, L Papi, L Ottini, MG Tibiletti, P Radice, D Yannoukakos, J Garber, S Ellis, D Frost, R Platte, E Fineberg, G Evans, F Lalloo, L Izatt, R Eeles, J Adlard, R Davidson, T Cole, D Eccles, J Cook, S Hodgson, C Brewer, M Tischkowitz, F Douglas, M Porteous, L Side, L Walker, P Morrison, A Donaldson, J Kennedy, C Foo, AK Godwin, RK Schmutzler, B Wappenschmidt, K Rhiem, C Engel, A Meindl, N Ditsch, N Arnold, HJ Plendl, D Niederacher, C Sutter, S Wang-Gohrke, D Steinemann, S Preisler-Adams, K Kast, R Varon-Mateeva, A Gehrig, D Stoppa-Lyonnet, OM Sinilnikova, S Mazoyer, F Damiola, B Poppe, K Claes, M Piedmonte, K Tucker, F Backes, G Rodriguez, W Brewster, K Wakeley, T Rutherford, T Caldes, H Nevanlinna, K Aittomaki, MA Rookus, TAM van Os, L van der Kolk, JL de Lange, HEJ Meijers-Heijboer, AH van der Hout, CJ van Asperen, EBG Garcia, N Hoogerbrugge, Margriet Collee, Carolien van Deurzen, RB van der Luijt, P Devilee, E Olah, C (Conxi) Lazaro, A Teule, M Menendez, A Jakubowska, C Cybulski, J Gronwald, J Lubinski, K Durda, K Jaworska-Bieniek, OT Johannsson, C Maugard, M Montagna, S Tognazzo, MR Teixeira, S Healey, C Olswold, L Guidugli, N Lindor, S Slager, CI Szabo, J Vijai, M Robson, N Kauff, LY Zhang, R Rau-Murthy, A Fink-Retter, CF Singer, C Rappaport, DG Kaulich, G Pfeiler, MK Tea, A Berger, CM Phelan, MH Greene, PL Mai, F Lejbkowicz, I Andrulis, AM Mulligan, G Glendon, AE Toland, A Bojesen, IS Pedersen, L Sunde, Marga Thomassen, TA Kruse, UB Jensen, E Friedman, Y Laitman, SP Shimon, J Simard, DF Easton, K Offit, FJ Couch, G Chenevix-Trench, AC Antoniou, J Benitez

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

45 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 = 2.7x10(-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.

Original language	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	10
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1004256
Publication status	Published - 2014

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10.1371/journal.pgen.1004256

http://hdl.handle.net/1765/60413

Cite this

Osorio, A., Milne, RL., Kuchenbaecker, K., Vaclova, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., de la Hoya, M., Duran, M., Diez, O., Cajal, TRY., Konstantopoulou, I., Martinez-Bouzas, C., Conejero, RA., Soucy, P., McGuffog, L., Barrowdale, D., van der Lee, A., ... Benitez, J. (2014). DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. PLoS Genetics (print), 10(4). https://doi.org/10.1371/journal.pgen.1004256

@article{52d6367d255a4245b7348eca5a8c0efe,

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 = 2.7x10(-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.",

author = "A Osorio and RL Milne and K Kuchenbaecker and T Vaclova and G Pita and R Alonso and P Peterlongo and I Blanco and {de la Hoya}, M and Duran, {M (Mercedes)} and O Diez and TRY Cajal and I Konstantopoulou and C Martinez-Bouzas and RA Conejero and P Soucy and L McGuffog and D Barrowdale and {van der Lee}, A and B Arver and J Rantala and N Loman and H Ehrencrona and OI Olopade and MS Beattie and SM Domchek and K Nathanson and TR Rebbeck and BK Arun and BY Karlan and C Walsh and J Lester and EM John and AS Whittemore and MB Daly and M Southey and J Hopper and MB Terry and SS Buys and R Janavicius and CM Dorfling and {van Rensburg}, EJ and L Steele and SL Neuhausen and YC Ding and TVO Hansen and L Jonson and B Ejlertsen and AM Gerdes and M Infante and B Herraez and LT Moreno and JN Weitzel and J Herzog and K Weeman and S Manoukian and B Peissel and D Zaffaroni and G Scuvera and B Bonanni and F Mariette and S Volorio and A Viel and L Varesco and L Papi and L Ottini and MG Tibiletti and P Radice and D Yannoukakos and J Garber and S Ellis and D Frost and R Platte and E Fineberg and G Evans and F Lalloo and L Izatt and R Eeles and J Adlard and R Davidson and T Cole and D Eccles and J Cook and S Hodgson and C Brewer and M Tischkowitz and F Douglas and M Porteous and L Side and L Walker and P Morrison and A Donaldson and J Kennedy and C Foo and AK Godwin and RK Schmutzler and B Wappenschmidt and K Rhiem and C Engel and A Meindl and N Ditsch and N Arnold and HJ Plendl and D Niederacher and C Sutter and S Wang-Gohrke and D Steinemann and S Preisler-Adams and K Kast and R Varon-Mateeva and A Gehrig and D Stoppa-Lyonnet and OM Sinilnikova and S Mazoyer and F Damiola and B Poppe and K Claes and M Piedmonte and K Tucker and F Backes and G Rodriguez and W Brewster and K Wakeley and T Rutherford and T Caldes and H Nevanlinna and K Aittomaki and MA Rookus and {van Os}, TAM and {van der Kolk}, L and {de Lange}, JL and HEJ Meijers-Heijboer and {van der Hout}, AH and {van Asperen}, CJ and EBG Garcia and N Hoogerbrugge and Margriet Collee and {van Deurzen}, Carolien and {van der Luijt}, RB and P Devilee and E Olah and Lazaro, {C (Conxi)} and A Teule and M Menendez and A Jakubowska and C Cybulski and J Gronwald and J Lubinski and K Durda and K Jaworska-Bieniek and OT Johannsson and C Maugard and M Montagna and S Tognazzo and MR Teixeira and S Healey and C Olswold and L Guidugli and N Lindor and S Slager and CI Szabo and J Vijai and M Robson and N Kauff and LY Zhang and R Rau-Murthy and A Fink-Retter and CF Singer and C Rappaport and DG Kaulich and G Pfeiler and MK Tea and A Berger and CM Phelan and MH Greene and PL Mai and F Lejbkowicz and I Andrulis and AM Mulligan and G Glendon and AE Toland and A Bojesen and IS Pedersen and L Sunde and Marga Thomassen and TA Kruse and UB Jensen and E Friedman and Y Laitman and SP Shimon and J Simard and DF Easton and K Offit and FJ Couch and G Chenevix-Trench and AC Antoniou and J Benitez",

year = "2014",

doi = "10.1371/journal.pgen.1004256",

language = "Undefined/Unknown",

volume = "10",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

Osorio, A, Milne, RL, Kuchenbaecker, K, Vaclova, T, Pita, G, Alonso, R, Peterlongo, P, Blanco, I, de la Hoya, M, Duran, M, Diez, O, Cajal, TRY, Konstantopoulou, I, Martinez-Bouzas, C, Conejero, RA, Soucy, P, McGuffog, L, Barrowdale, D, van der 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, Jonson, L, Ejlertsen, B, Gerdes, AM, Infante, M, Herraez, 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, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Stoppa-Lyonnet, D, Sinilnikova, OM, Mazoyer, S, Damiola, F, Poppe, B, Claes, K, Piedmonte, M, Tucker, K, Backes, F, Rodriguez, G, Brewster, W, Wakeley, K, Rutherford, T, Caldes, T, Nevanlinna, H, Aittomaki, K, Rookus, MA, van Os, TAM, van der Kolk, L, de Lange, JL, Meijers-Heijboer, HEJ, van der Hout, AH, van Asperen, CJ, Garcia, EBG, Hoogerbrugge, N, Collee, M , van Deurzen, C, van der Luijt, RB, Devilee, P, Olah, E, Lazaro, C, Teule, A, Menendez, M, Jakubowska, A, Cybulski, C, Gronwald, J, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Johannsson, OT, Maugard, C, Montagna, M, Tognazzo, S, Teixeira, MR, Healey, S, Olswold, C, Guidugli, L, Lindor, N, Slager, S, Szabo, CI, Vijai, J, Robson, M, Kauff, N, Zhang, LY, Rau-Murthy, R, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, MK, Berger, A, Phelan, CM, Greene, MH, Mai, PL, Lejbkowicz, F, Andrulis, I, Mulligan, AM, Glendon, G, Toland, AE, Bojesen, A, Pedersen, IS, Sunde, L, Thomassen, M, Kruse, TA, Jensen, UB, Friedman, E, Laitman, Y, Shimon, SP, Simard, J, Easton, DF, Offit, K, Couch, FJ, Chenevix-Trench, G, Antoniou, AC & Benitez, J 2014, 'DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers', PLoS Genetics (print), vol. 10, no. 4. https://doi.org/10.1371/journal.pgen.1004256

TY - JOUR

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

AU - Osorio, A

AU - Milne, RL

AU - Kuchenbaecker, K

AU - Vaclova, T

AU - Pita, G

AU - Alonso, R

AU - Peterlongo, P

AU - Blanco, I

AU - de la Hoya, M

AU - Duran, M (Mercedes)

AU - Diez, O

AU - Cajal, TRY

AU - Konstantopoulou, I

AU - Martinez-Bouzas, C

AU - Conejero, RA

AU - Soucy, P

AU - McGuffog, L

AU - Barrowdale, D

AU - van der Lee, A

AU - Arver, B

AU - Rantala, J

AU - Loman, N

AU - Ehrencrona, H

AU - Olopade, OI

AU - Beattie, MS

AU - Domchek, SM

AU - Nathanson, K

AU - Rebbeck, TR

AU - Arun, BK

AU - Karlan, BY

AU - Walsh, C

AU - Lester, J

AU - John, EM

AU - Whittemore, AS

AU - Daly, MB

AU - Southey, M

AU - Hopper, J

AU - Terry, MB

AU - Buys, SS

AU - Janavicius, R

AU - Dorfling, CM

AU - van Rensburg, EJ

AU - Steele, L

AU - Neuhausen, SL

AU - Ding, YC

AU - Hansen, TVO

AU - Jonson, L

AU - Ejlertsen, B

AU - Gerdes, AM

AU - Infante, M

AU - Herraez, B

AU - Moreno, LT

AU - Weitzel, JN

AU - Herzog, J

AU - Weeman, K

AU - Manoukian, S

AU - Peissel, B

AU - Zaffaroni, D

AU - Scuvera, G

AU - Bonanni, B

AU - Mariette, F

AU - Volorio, S

AU - Viel, A

AU - Varesco, L

AU - Papi, L

AU - Ottini, L

AU - Tibiletti, MG

AU - Radice, P

AU - Yannoukakos, D

AU - Garber, J

AU - Ellis, S

AU - Frost, D

AU - Platte, R

AU - Fineberg, E

AU - Evans, G

AU - Lalloo, F

AU - Izatt, L

AU - Eeles, R

AU - Adlard, J

AU - Davidson, R

AU - Cole, T

AU - Eccles, D

AU - Cook, J

AU - Hodgson, S

AU - Brewer, C

AU - Tischkowitz, M

AU - Douglas, F

AU - Porteous, M

AU - Side, L

AU - Walker, L

AU - Morrison, P

AU - Donaldson, A

AU - Kennedy, J

AU - Foo, C

AU - Godwin, AK

AU - Schmutzler, RK

AU - Wappenschmidt, B

AU - Rhiem, K

AU - Engel, C

AU - Meindl, A

AU - Ditsch, N

AU - Arnold, N

AU - Plendl, HJ

AU - Niederacher, D

AU - Sutter, C

AU - Wang-Gohrke, S

AU - Steinemann, D

AU - Preisler-Adams, S

AU - Kast, K

AU - Varon-Mateeva, R

AU - Gehrig, A

AU - Stoppa-Lyonnet, D

AU - Sinilnikova, OM

AU - Mazoyer, S

AU - Damiola, F

AU - Poppe, B

AU - Claes, K

AU - Piedmonte, M

AU - Tucker, K

AU - Backes, F

AU - Rodriguez, G

AU - Brewster, W

AU - Wakeley, K

AU - Rutherford, T

AU - Caldes, T

AU - Nevanlinna, H

AU - Aittomaki, K

AU - Rookus, MA

AU - van Os, TAM

AU - van der Kolk, L

AU - de Lange, JL

AU - Meijers-Heijboer, HEJ

AU - van der Hout, AH

AU - van Asperen, CJ

AU - Garcia, EBG

AU - Hoogerbrugge, N

AU - Collee, Margriet

AU - van Deurzen, Carolien

AU - van der Luijt, RB

AU - Devilee, P

AU - Olah, E

AU - Lazaro, C (Conxi)

AU - Teule, A

AU - Menendez, M

AU - Jakubowska, A

AU - Cybulski, C

AU - Gronwald, J

AU - Lubinski, J

AU - Durda, K

AU - Jaworska-Bieniek, K

AU - Johannsson, OT

AU - Maugard, C

AU - Montagna, M

AU - Tognazzo, S

AU - Teixeira, MR

AU - Healey, S

AU - Olswold, C

AU - Guidugli, L

AU - Lindor, N

AU - Slager, S

AU - Szabo, CI

AU - Vijai, J

AU - Robson, M

AU - Kauff, N

AU - Zhang, LY

AU - Rau-Murthy, R

AU - Fink-Retter, A

AU - Singer, CF

AU - Rappaport, C

AU - Kaulich, DG

AU - Pfeiler, G

AU - Tea, MK

AU - Berger, A

AU - Phelan, CM

AU - Greene, MH

AU - Mai, PL

AU - Lejbkowicz, F

AU - Andrulis, I

AU - Mulligan, AM

AU - Glendon, G

AU - Toland, AE

AU - Bojesen, A

AU - Pedersen, IS

AU - Sunde, L

AU - Thomassen, Marga

AU - Kruse, TA

AU - Jensen, UB

AU - Friedman, E

AU - Laitman, Y

AU - Shimon, SP

AU - Simard, J

AU - Easton, DF

AU - Offit, K

AU - Couch, FJ

AU - Chenevix-Trench, G

AU - Antoniou, AC

AU - Benitez, J

PY - 2014

Y1 - 2014

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 = 2.7x10(-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.

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 = 2.7x10(-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.

U2 - 10.1371/journal.pgen.1004256

DO - 10.1371/journal.pgen.1004256

M3 - Article

C2 - 24698998

SN - 1553-7390

VL - 10

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 4

ER -