Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

P Peterlongo; J Chang-Claude; KB Moysich; A Rudolph; RK Schmutzler; J Simard; P Soucy; RA Eeles; DF Easton; U Hamann; S Wilkening; BW Chen; MA Rookus; MK Schmidt; FH van der Baan; AB Spurdle; LC Walker; F Lose; AT Maia; M Montagna; L Matricardi; J Lubinski; A Jakubowska; EBG Garcia; OI Olopade; RL Nussbaum; KL Nathanson; SM Domchek; TR Rebbeck; BK Arun; BY Karlan; S Orsulic; J Lester; WK Chung; A Miron; MC Southey; DE Goldgar; SS Buys; R Janavicius; CM Dorfling; EJ van Rensburg; YC Ding; SL Neuhausen; TVO Hansen; AM Gerdes; B Ejlertsen; L Jonson; A Osorio; C Martinez-Bouzas; J Benitez; EE Conway; KR Blazer; JN Weitzel; S Manoukian; B Peissel; D Zaffaroni; G Scuvera; M Barile; F Ficarazzi; F Mariette; S Fortuzzi; A Viel; G Giannini; L Papi; A Martayan; MG Tibiletti; P Radice; A Vratimos; F Fostira; JE Garber; A Donaldson; C Brewer; C Foo; DGR Evans; D Frost; D Eccles; A Brady; J Cook; M Tischkowitz; J Adlard; J Barwell; L Walker; L Izatt; LE Side; MJ Kennedy; MT Rogers; ME Porteous; PJ Morrison; R Platte; R Davidson; SV Hodgson; S Ellis; T Cole; AK Godwin; K Claes; T Van Maerken; A Meindl; A Gehrig; C Sutter; C Engel; D Niederacher; D Steinemann; H Plendl; K Kast; K Rhiem; N Ditsch; N Arnold; R Varon-Mateeva; B Wappenschmidt; S Wang-Gohrke; B Bressac-de Paillerets; B Buecher; C Delnatte; C Houdayer; D Stoppa-Lyonnet; F Damiola; I Coupier; L Barjhoux; L Venat-Bouvet; L Golmard; N Boutry-Kryza; OM Sinilnikova; O (Olivier) Caron; P Pujol; S Mazoyer; M Belotti; M Piedmonte; ML Friedlander; GC Rodriguez; LJ Copeland; M de la Hoya; PP Segura; H Nevanlinna; K Aittomaki; TAM van Os; HEJ Meijers-Heijboer; AH van der Hout; MPG Vreeswijk; N Hoogerbrugge; MGEM Ausems; Lena van Doorn; Margriet Collee; E Olah; O Diez; I Blanco; C (Conxi) Lazaro; J Brunet; L Feliubadalo; C Cybulski; J Gronwald; K Durda; K Jaworska-Bieniek; G Sukiennicki; A Arason; J Chiquette; MR Teixeira; C Olswold; FJ Couch; NM Lindor; XS Wang; CI Szabo; K Offit; M Corines; L Jacobs; ME Robson; LY Zhang; V Joseph; A Berger; CF Singer; C Rappaport; DG Kaulich; G Pfeiler; MKM Tea; CM Phelan; MH Greene; PL Mai; G Rennert; AM Mulligan; G Glendon; S Tchatchou; IL Andrulis; AE Toland; A Bojesen; IS Pedersen; Marga Thomassen; UB Jensen; Y Laitman; J Rantala; A von Wachenfeldt; H Ehrencrona; MS Askmalm; A Borg; KB Kuchenbaecker; L McGuffog; D Barrowdale; S Healey; A van der Lee; PDP Pharoah; G Chenevix-Trench; AC Antoniou; E Friedman

doi:10.1158/1055-9965.EPI-14-0532

Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

P Peterlongo, J Chang-Claude, KB Moysich, A Rudolph, RK Schmutzler, J Simard, P Soucy, RA Eeles, DF Easton, U Hamann, S Wilkening, BW Chen, MA Rookus, MK Schmidt, FH van der Baan, AB Spurdle, LC Walker, F Lose, AT Maia, M MontagnaL Matricardi, J Lubinski, A Jakubowska, EBG Garcia, OI Olopade, RL Nussbaum, KL Nathanson, SM Domchek, TR Rebbeck, BK Arun, BY Karlan, S Orsulic, J Lester, WK Chung, A Miron, MC Southey, DE Goldgar, SS Buys, R Janavicius, CM Dorfling, EJ van Rensburg, YC Ding, SL Neuhausen, TVO Hansen, AM Gerdes, B Ejlertsen, L Jonson, A Osorio, C Martinez-Bouzas, J Benitez, EE Conway, KR Blazer, JN Weitzel, S Manoukian, B Peissel, D Zaffaroni, G Scuvera, M Barile, F Ficarazzi, F Mariette, S Fortuzzi, A Viel, G Giannini, L Papi, A Martayan, MG Tibiletti, P Radice, A Vratimos, F Fostira, JE Garber, A Donaldson, C Brewer, C Foo, DGR Evans, D Frost, D Eccles, A Brady, J Cook, M Tischkowitz, J Adlard, J Barwell, L Walker, L Izatt, LE Side, MJ Kennedy, MT Rogers, ME Porteous, PJ Morrison, R Platte, R Davidson, SV Hodgson, S Ellis, T Cole, AK Godwin, K Claes, T Van Maerken, A Meindl, A Gehrig, C Sutter, C Engel, D Niederacher, D Steinemann, H Plendl, K Kast, K Rhiem, N Ditsch, N Arnold, R Varon-Mateeva, B Wappenschmidt, S Wang-Gohrke, B Bressac-de Paillerets, B Buecher, C Delnatte, C Houdayer, D Stoppa-Lyonnet, F Damiola, I Coupier, L Barjhoux, L Venat-Bouvet, L Golmard, N Boutry-Kryza, OM Sinilnikova, O (Olivier) Caron, P Pujol, S Mazoyer, M Belotti, M Piedmonte, ML Friedlander, GC Rodriguez, LJ Copeland, M de la Hoya, PP Segura, H Nevanlinna, K Aittomaki, TAM van Os, HEJ Meijers-Heijboer, AH van der Hout, MPG Vreeswijk, N Hoogerbrugge, MGEM Ausems, Lena van Doorn, Margriet Collee, E Olah, O Diez, I Blanco, C (Conxi) Lazaro, J Brunet, L Feliubadalo, C Cybulski, J Gronwald, K Durda, K Jaworska-Bieniek, G Sukiennicki, A Arason, J Chiquette, MR Teixeira, C Olswold, FJ Couch, NM Lindor, XS Wang, CI Szabo, K Offit, M Corines, L Jacobs, ME Robson, LY Zhang, V Joseph, A Berger, CF Singer, C Rappaport, DG Kaulich, G Pfeiler, MKM Tea, CM Phelan, MH Greene, PL Mai, G Rennert, AM Mulligan, G Glendon, S Tchatchou, IL Andrulis, AE Toland, A Bojesen, IS Pedersen, Marga Thomassen, UB Jensen, Y Laitman, J Rantala, A von Wachenfeldt, H Ehrencrona, MS Askmalm, A Borg, KB Kuchenbaecker, L McGuffog, D Barrowdale, S Healey, A van der Lee, PDP Pharoah, G Chenevix-Trench, AC Antoniou, E Friedman

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

18 Citations (Scopus)

Abstract

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR.

Original language	Undefined/Unknown
Pages (from-to)	308-316
Number of pages	9
Journal	Cancer Epidemiology Biomarkers & Prevention
Volume	24
Issue number	1
DOIs	https://doi.org/10.1158/1055-9965.EPI-14-0532
Publication status	Published - 2015

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10.1158/1055-9965.EPI-14-0532

Cite this

Peterlongo, P., Chang-Claude, J., Moysich, KB., Rudolph, A., Schmutzler, RK., Simard, J., Soucy, P., Eeles, RA., Easton, DF., Hamann, U., Wilkening, S., Chen, BW., Rookus, MA., Schmidt, MK., van der Baan, FH., Spurdle, AB., Walker, LC., Lose, F., Maia, AT., ... Friedman, E. (2015). Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. Cancer Epidemiology Biomarkers & Prevention, 24(1), 308-316. https://doi.org/10.1158/1055-9965.EPI-14-0532

@article{e2ca3ab649e740b18b1afe4eb2fa9aab,

title = "Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers",

abstract = "Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR.",

author = "P Peterlongo and J Chang-Claude and KB Moysich and A Rudolph and RK Schmutzler and J Simard and P Soucy and RA Eeles and DF Easton and U Hamann and S Wilkening and BW Chen and MA Rookus and MK Schmidt and {van der Baan}, FH and AB Spurdle and LC Walker and F Lose and AT Maia and M Montagna and L Matricardi and J Lubinski and A Jakubowska and EBG Garcia and OI Olopade and RL Nussbaum and KL Nathanson and SM Domchek and TR Rebbeck and BK Arun and BY Karlan and S Orsulic and J Lester and WK Chung and A Miron and MC Southey and DE Goldgar and SS Buys and R Janavicius and CM Dorfling and {van Rensburg}, EJ and YC Ding and SL Neuhausen and TVO Hansen and AM Gerdes and B Ejlertsen and L Jonson and A Osorio and C Martinez-Bouzas and J Benitez and EE Conway and KR Blazer and JN Weitzel and S Manoukian and B Peissel and D Zaffaroni and G Scuvera and M Barile and F Ficarazzi and F Mariette and S Fortuzzi and A Viel and G Giannini and L Papi and A Martayan and MG Tibiletti and P Radice and A Vratimos and F Fostira and JE Garber and A Donaldson and C Brewer and C Foo and DGR Evans and D Frost and D Eccles and A Brady and J Cook and M Tischkowitz and J Adlard and J Barwell and L Walker and L Izatt and LE Side and MJ Kennedy and MT Rogers and ME Porteous and PJ Morrison and R Platte and R Davidson and SV Hodgson and S Ellis and T Cole and AK Godwin and K Claes and {Van Maerken}, T and A Meindl and A Gehrig and C Sutter and C Engel and D Niederacher and D Steinemann and H Plendl and K Kast and K Rhiem and N Ditsch and N Arnold and R Varon-Mateeva and B Wappenschmidt and S Wang-Gohrke and {Bressac-de Paillerets}, B and B Buecher and C Delnatte and C Houdayer and D Stoppa-Lyonnet and F Damiola and I Coupier and L Barjhoux and L Venat-Bouvet and L Golmard and N Boutry-Kryza and OM Sinilnikova and Caron, {O (Olivier)} and P Pujol and S Mazoyer and M Belotti and M Piedmonte and ML Friedlander and GC Rodriguez and LJ Copeland and {de la Hoya}, M and PP Segura and H Nevanlinna and K Aittomaki and {van Os}, TAM and HEJ Meijers-Heijboer and {van der Hout}, AH and MPG Vreeswijk and N Hoogerbrugge and MGEM Ausems and {van Doorn}, Lena and Margriet Collee and E Olah and O Diez and I Blanco and Lazaro, {C (Conxi)} and J Brunet and L Feliubadalo and C Cybulski and J Gronwald and K Durda and K Jaworska-Bieniek and G Sukiennicki and A Arason and J Chiquette and MR Teixeira and C Olswold and FJ Couch and NM Lindor and XS Wang and CI Szabo and K Offit and M Corines and L Jacobs and ME Robson and LY Zhang and V Joseph and A Berger and CF Singer and C Rappaport and DG Kaulich and G Pfeiler and MKM Tea and CM Phelan and MH Greene and PL Mai and G Rennert and AM Mulligan and G Glendon and S Tchatchou and IL Andrulis and AE Toland and A Bojesen and IS Pedersen and Marga Thomassen and UB Jensen and Y Laitman and J Rantala and {von Wachenfeldt}, A and H Ehrencrona and MS Askmalm and A Borg and KB Kuchenbaecker and L McGuffog and D Barrowdale and S Healey and {van der Lee}, A and PDP Pharoah and G Chenevix-Trench and AC Antoniou and E Friedman",

year = "2015",

doi = "10.1158/1055-9965.EPI-14-0532",

language = "Undefined/Unknown",

volume = "24",

pages = "308--316",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "1",

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Peterlongo, P, Chang-Claude, J, Moysich, KB, Rudolph, A, Schmutzler, RK, Simard, J, Soucy, P, Eeles, RA, Easton, DF, Hamann, U, Wilkening, S, Chen, BW, Rookus, MA, Schmidt, MK, van der Baan, FH, Spurdle, AB, Walker, LC, Lose, F, Maia, AT, Montagna, M, Matricardi, L, Lubinski, J, Jakubowska, A, Garcia, EBG, Olopade, OI, Nussbaum, RL, Nathanson, KL, Domchek, SM, Rebbeck, TR, Arun, BK, Karlan, BY, Orsulic, S, Lester, J, Chung, WK, Miron, A, Southey, MC, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Ding, YC, Neuhausen, SL, Hansen, TVO, Gerdes, AM, Ejlertsen, B, Jonson, L, Osorio, A, Martinez-Bouzas, C, Benitez, J, Conway, EE, Blazer, KR, Weitzel, JN, Manoukian, S, Peissel, B, Zaffaroni, D, Scuvera, G, Barile, M, Ficarazzi, F, Mariette, F, Fortuzzi, S, Viel, A, Giannini, G, Papi, L, Martayan, A, Tibiletti, MG, Radice, P, Vratimos, A, Fostira, F, Garber, JE, Donaldson, A, Brewer, C, Foo, C, Evans, DGR, Frost, D, Eccles, D, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Davidson, R, Hodgson, SV, Ellis, S, Cole, T, Godwin, AK, Claes, K, Van Maerken, T, Meindl, A, Gehrig, A, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Wappenschmidt, B, Wang-Gohrke, S, Bressac-de Paillerets, B, Buecher, B, Delnatte, C, Houdayer, C, Stoppa-Lyonnet, D, Damiola, F, Coupier, I, Barjhoux, L, Venat-Bouvet, L, Golmard, L, Boutry-Kryza, N, Sinilnikova, OM, Caron, O, Pujol, P, Mazoyer, S, Belotti, M, Piedmonte, M, Friedlander, ML, Rodriguez, GC, Copeland, LJ, de la Hoya, M, Segura, PP, Nevanlinna, H, Aittomaki, K, van Os, TAM, Meijers-Heijboer, HEJ, van der Hout, AH, Vreeswijk, MPG, Hoogerbrugge, N, Ausems, MGEM, van Doorn, L , Collee, M, Olah, E, Diez, O, Blanco, I, Lazaro, C, Brunet, J, Feliubadalo, L, Cybulski, C, Gronwald, J, Durda, K, Jaworska-Bieniek, K, Sukiennicki, G, Arason, A, Chiquette, J, Teixeira, MR, Olswold, C, Couch, FJ, Lindor, NM, Wang, XS, Szabo, CI, Offit, K, Corines, M, Jacobs, L, Robson, ME, Zhang, LY, Joseph, V, Berger, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, MKM, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Glendon, G, Tchatchou, S, Andrulis, IL, Toland, AE, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Laitman, Y, Rantala, J, von Wachenfeldt, A, Ehrencrona, H, Askmalm, MS, Borg, A, Kuchenbaecker, KB, McGuffog, L, Barrowdale, D, Healey, S, van der Lee, A, Pharoah, PDP, Chenevix-Trench, G, Antoniou, AC & Friedman, E 2015, 'Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers', Cancer Epidemiology Biomarkers & Prevention, vol. 24, no. 1, pp. 308-316. https://doi.org/10.1158/1055-9965.EPI-14-0532

TY - JOUR

T1 - Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

AU - Peterlongo, P

AU - Chang-Claude, J

AU - Moysich, KB

AU - Rudolph, A

AU - Schmutzler, RK

AU - Simard, J

AU - Soucy, P

AU - Eeles, RA

AU - Easton, DF

AU - Hamann, U

AU - Wilkening, S

AU - Chen, BW

AU - Rookus, MA

AU - Schmidt, MK

AU - van der Baan, FH

AU - Spurdle, AB

AU - Walker, LC

AU - Lose, F

AU - Maia, AT

AU - Montagna, M

AU - Matricardi, L

AU - Lubinski, J

AU - Jakubowska, A

AU - Garcia, EBG

AU - Olopade, OI

AU - Nussbaum, RL

AU - Nathanson, KL

AU - Domchek, SM

AU - Rebbeck, TR

AU - Arun, BK

AU - Karlan, BY

AU - Orsulic, S

AU - Lester, J

AU - Chung, WK

AU - Miron, A

AU - Southey, MC

AU - Goldgar, DE

AU - Buys, SS

AU - Janavicius, R

AU - Dorfling, CM

AU - van Rensburg, EJ

AU - Ding, YC

AU - Neuhausen, SL

AU - Hansen, TVO

AU - Gerdes, AM

AU - Ejlertsen, B

AU - Jonson, L

AU - Osorio, A

AU - Martinez-Bouzas, C

AU - Benitez, J

AU - Conway, EE

AU - Blazer, KR

AU - Weitzel, JN

AU - Manoukian, S

AU - Peissel, B

AU - Zaffaroni, D

AU - Scuvera, G

AU - Barile, M

AU - Ficarazzi, F

AU - Mariette, F

AU - Fortuzzi, S

AU - Viel, A

AU - Giannini, G

AU - Papi, L

AU - Martayan, A

AU - Tibiletti, MG

AU - Radice, P

AU - Vratimos, A

AU - Fostira, F

AU - Garber, JE

AU - Donaldson, A

AU - Brewer, C

AU - Foo, C

AU - Evans, DGR

AU - Frost, D

AU - Eccles, D

AU - Brady, A

AU - Cook, J

AU - Tischkowitz, M

AU - Adlard, J

AU - Barwell, J

AU - Walker, L

AU - Izatt, L

AU - Side, LE

AU - Kennedy, MJ

AU - Rogers, MT

AU - Porteous, ME

AU - Morrison, PJ

AU - Platte, R

AU - Davidson, R

AU - Hodgson, SV

AU - Ellis, S

AU - Cole, T

AU - Godwin, AK

AU - Claes, K

AU - Van Maerken, T

AU - Meindl, A

AU - Gehrig, A

AU - Sutter, C

AU - Engel, C

AU - Niederacher, D

AU - Steinemann, D

AU - Plendl, H

AU - Kast, K

AU - Rhiem, K

AU - Ditsch, N

AU - Arnold, N

AU - Varon-Mateeva, R

AU - Wappenschmidt, B

AU - Wang-Gohrke, S

AU - Bressac-de Paillerets, B

AU - Buecher, B

AU - Delnatte, C

AU - Houdayer, C

AU - Stoppa-Lyonnet, D

AU - Damiola, F

AU - Coupier, I

AU - Barjhoux, L

AU - Venat-Bouvet, L

AU - Golmard, L

AU - Boutry-Kryza, N

AU - Sinilnikova, OM

AU - Caron, O (Olivier)

AU - Pujol, P

AU - Mazoyer, S

AU - Belotti, M

AU - Piedmonte, M

AU - Friedlander, ML

AU - Rodriguez, GC

AU - Copeland, LJ

AU - de la Hoya, M

AU - Segura, PP

AU - Nevanlinna, H

AU - Aittomaki, K

AU - van Os, TAM

AU - Meijers-Heijboer, HEJ

AU - van der Hout, AH

AU - Vreeswijk, MPG

AU - Hoogerbrugge, N

AU - Ausems, MGEM

AU - van Doorn, Lena

AU - Collee, Margriet

AU - Olah, E

AU - Diez, O

AU - Blanco, I

AU - Lazaro, C (Conxi)

AU - Brunet, J

AU - Feliubadalo, L

AU - Cybulski, C

AU - Gronwald, J

AU - Durda, K

AU - Jaworska-Bieniek, K

AU - Sukiennicki, G

AU - Arason, A

AU - Chiquette, J

AU - Teixeira, MR

AU - Olswold, C

AU - Couch, FJ

AU - Lindor, NM

AU - Wang, XS

AU - Szabo, CI

AU - Offit, K

AU - Corines, M

AU - Jacobs, L

AU - Robson, ME

AU - Zhang, LY

AU - Joseph, V

AU - Berger, A

AU - Singer, CF

AU - Rappaport, C

AU - Kaulich, DG

AU - Pfeiler, G

AU - Tea, MKM

AU - Phelan, CM

AU - Greene, MH

AU - Mai, PL

AU - Rennert, G

AU - Mulligan, AM

AU - Glendon, G

AU - Tchatchou, S

AU - Andrulis, IL

AU - Toland, AE

AU - Bojesen, A

AU - Pedersen, IS

AU - Thomassen, Marga

AU - Jensen, UB

AU - Laitman, Y

AU - Rantala, J

AU - von Wachenfeldt, A

AU - Ehrencrona, H

AU - Askmalm, MS

AU - Borg, A

AU - Kuchenbaecker, KB

AU - McGuffog, L

AU - Barrowdale, D

AU - Healey, S

AU - van der Lee, A

AU - Pharoah, PDP

AU - Chenevix-Trench, G

AU - Antoniou, AC

AU - Friedman, E

PY - 2015

Y1 - 2015

N2 - Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR.

AB - Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR.

U2 - 10.1158/1055-9965.EPI-14-0532

DO - 10.1158/1055-9965.EPI-14-0532

M3 - Article

VL - 24

SP - 308

EP - 316

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 1

ER -