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

Paolo Peterlongo; Jenny Chang-Claude; Kirsten B. Moysich; Anja Rudolph; Rita K. Schmutzler; Jacques Simard; Penny Soucy; Rosalind A. Eeles; Douglas F. Easton; Ute Hamann; Stefan Wilkening; Bowang Chen; Matti A. Rookus; MarjankaK. Schmidt; Frederieke H. van der Baan; Amanda B. Spurdle; Logan C. Walker; Felicity Lose; Ana-Teresa Maia; Marco Montagna; Laura Matricardi; Jan Lubinski; Anna Jakubowska; Encarna B. Gomez Garcia; Olufunmilayo I. Olopade; Robert L. Nussbaum; Katherine L. Nathanson; Susan M. Domchek; Timothy R. Rebbeck; Banu K. Arun; Beth Y. Karlan; Sandra Orsulic; Jenny Lester; Wendy K. Chung; Alex Miron; Melissa C. Southey; David E. Goldgar; Saundra S. Buys; Ramunas Janavicius; Cecilia M. Dorfling; Elizabeth J. van Rensburg; Yuan Chun Ding; Susan L. Neuhausen; Thomas V. O. Hansen; Anne-Marie Gerdes; Bent Ejlertsen; Lars Jonson; Ana Osorio; Cristina Martinez-Bouzas; Javier Benitez; Author collaboration

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

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

Paolo Peterlongo^*, Jenny Chang-Claude, Kirsten B. Moysich, Anja Rudolph, Rita K. Schmutzler, Jacques Simard, Penny Soucy, Rosalind A. Eeles, Douglas F. Easton, Ute Hamann, Stefan Wilkening, Bowang Chen, Matti A. Rookus, MarjankaK. Schmidt, Frederieke H. van der Baan, Amanda B. Spurdle, Logan C. Walker, Felicity Lose, Ana-Teresa Maia, Marco MontagnaLaura Matricardi, Jan Lubinski, Anna Jakubowska, Encarna B. Gomez Garcia, Olufunmilayo I. Olopade, Robert L. Nussbaum, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Banu K. Arun, Beth Y. Karlan, Sandra Orsulic, Jenny Lester, Wendy K. Chung, Alex Miron, Melissa C. Southey, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Yuan Chun Ding, Susan L. Neuhausen, Thomas V. O. Hansen, Anne-Marie Gerdes, Bent Ejlertsen, Lars Jonson, Ana Osorio, Cristina Martinez-Bouzas, Javier Benitez, Author collaboration

^*Corresponding author for this work

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

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	English
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 - Jan 2015

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Peterlongo, P., Chang-Claude, J., Moysich, K. B., Rudolph, A., Schmutzler, R. K., Simard, J., Soucy, P., Eeles, R. A., Easton, D. F., Hamann, U., Wilkening, S., Chen, B., Rookus, M. A., Schmidt, M., van der Baan, F. H., Spurdle, A. B., Walker, L. C., Lose, F., Maia, A.-T., ... Author collaboration (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

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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.",

keywords = "Association",

author = "Paolo Peterlongo and Jenny Chang-Claude and Moysich, {Kirsten B.} and Anja Rudolph and Schmutzler, {Rita K.} and Jacques Simard and Penny Soucy and Eeles, {Rosalind A.} and Easton, {Douglas F.} and Ute Hamann and Stefan Wilkening and Bowang Chen and Rookus, {Matti A.} and MarjankaK. Schmidt and {van der Baan}, {Frederieke H.} and Spurdle, {Amanda B.} and Walker, {Logan C.} and Felicity Lose and Ana-Teresa Maia and Marco Montagna and Laura Matricardi and Jan Lubinski and Anna Jakubowska and Garcia, {Encarna B. Gomez} and Olopade, {Olufunmilayo I.} and Nussbaum, {Robert L.} and Nathanson, {Katherine L.} and Domchek, {Susan M.} and Rebbeck, {Timothy R.} and Arun, {Banu K.} and Karlan, {Beth Y.} and Sandra Orsulic and Jenny Lester and Chung, {Wendy K.} and Alex Miron and Southey, {Melissa C.} and Goldgar, {David E.} and Buys, {Saundra S.} and Ramunas Janavicius and Dorfling, {Cecilia M.} and {van Rensburg}, {Elizabeth J.} and Ding, {Yuan Chun} and Neuhausen, {Susan L.} and Hansen, {Thomas V. O.} and Anne-Marie Gerdes and Bent Ejlertsen and Lars Jonson and Ana Osorio and Cristina Martinez-Bouzas and Javier Benitez and {Author collaboration}",

year = "2015",

month = jan,

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

language = "English",

volume = "24",

pages = "308--316",

journal = "Cancer Epidemiology Biomarkers & Prevention",

issn = "1055-9965",

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

number = "1",

}

Peterlongo, P, Chang-Claude, J, Moysich, KB, Rudolph, A, Schmutzler, RK, Simard, J, Soucy, P, Eeles, RA, Easton, DF, Hamann, U, Wilkening, S, Chen, B, Rookus, MA, Schmidt, M, van der Baan, FH, Spurdle, AB, Walker, LC, Lose, F, Maia, A-T, 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, A-M, Ejlertsen, B, Jonson, L, Osorio, A, Martinez-Bouzas, C, Benitez, J & Author collaboration 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, Paolo

AU - Chang-Claude, Jenny

AU - Moysich, Kirsten B.

AU - Rudolph, Anja

AU - Schmutzler, Rita K.

AU - Simard, Jacques

AU - Soucy, Penny

AU - Eeles, Rosalind A.

AU - Easton, Douglas F.

AU - Hamann, Ute

AU - Wilkening, Stefan

AU - Chen, Bowang

AU - Rookus, Matti A.

AU - Schmidt, MarjankaK.

AU - van der Baan, Frederieke H.

AU - Spurdle, Amanda B.

AU - Walker, Logan C.

AU - Lose, Felicity

AU - Maia, Ana-Teresa

AU - Montagna, Marco

AU - Matricardi, Laura

AU - Lubinski, Jan

AU - Jakubowska, Anna

AU - Garcia, Encarna B. Gomez

AU - Olopade, Olufunmilayo I.

AU - Nussbaum, Robert L.

AU - Nathanson, Katherine L.

AU - Domchek, Susan M.

AU - Rebbeck, Timothy R.

AU - Arun, Banu K.

AU - Karlan, Beth Y.

AU - Orsulic, Sandra

AU - Lester, Jenny

AU - Chung, Wendy K.

AU - Miron, Alex

AU - Southey, Melissa C.

AU - Goldgar, David E.

AU - Buys, Saundra S.

AU - Janavicius, Ramunas

AU - Dorfling, Cecilia M.

AU - van Rensburg, Elizabeth J.

AU - Ding, Yuan Chun

AU - Neuhausen, Susan L.

AU - Hansen, Thomas V. O.

AU - Gerdes, Anne-Marie

AU - Ejlertsen, Bent

AU - Jonson, Lars

AU - Osorio, Ana

AU - Martinez-Bouzas, Cristina

AU - Benitez, Javier

AU - Author collaboration

PY - 2015/1

Y1 - 2015/1

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.

KW - Association

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

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

M3 - Article

C2 - 25336561

SN - 1055-9965

VL - 24

SP - 308

EP - 316

JO - Cancer Epidemiology Biomarkers & Prevention

JF - Cancer Epidemiology Biomarkers & Prevention

IS - 1

ER -

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

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