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; Marjanka K 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 Gómez 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 Jønson; Ana Osorio; Cristina Martínez-Bouzas; Javier Benitez; EMBRACE

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, Marjanka K 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 Gómez 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 Jønson, Ana Osorio, Cristina Martínez-Bouzas, Javier Benitez, EMBRACE

16 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.

Original language	English
Journal	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume	24
Issue number	1
Pages (from-to)	308-16
Number of pages	9
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.epi-14-0532
Publication status	Published - 1 Jan 2015

Keywords

Adult
Breast Neoplasms
Cohort Studies
Female
Genes, BRCA1
Genes, BRCA2
Humans
Mutation
Ovarian Neoplasms
Polymorphism, Single Nucleotide
Retrospective Studies
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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. K., van der Baan, F. H., Spurdle, A. B., Walker, L. C., Lose, F., Maia, A-T., ... EMBRACE (2015). Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 24(1), 308-16. https://doi.org/10.1158/1055-9965.epi-14-0532

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. / Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B et al.

In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Vol. 24, No. 1, 01.01.2015, p. 308-16.

Research output: Contribution to journal › Journal article › Research › peer-review

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, MK, van der Baan, FH, Spurdle, AB, Walker, LC, Lose, F, Maia, A-T, Montagna, M, Matricardi, L, Lubinski, J, Jakubowska, A, Gómez Garcia, EB, 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, Jønson, L, Osorio, A, Martínez-Bouzas, C, Benitez, J & EMBRACE 2015, 'Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers', Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, vol. 24, no. 1, pp. 308-16. https://doi.org/10.1158/1055-9965.epi-14-0532

Peterlongo P, Chang-Claude J, Moysich KB, Rudolph A, Schmutzler RK, Simard J et al. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015 Jan 1;24(1):308-16. doi: 10.1158/1055-9965.epi-14-0532

Peterlongo, Paolo ; Chang-Claude, Jenny ; Moysich, Kirsten B et al. / Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015 ; Vol. 24, No. 1. pp. 308-16.

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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.",

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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, Marjanka K

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 - Gómez Garcia, Encarna B

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 - Jønson, Lars

AU - Osorio, Ana

AU - Martínez-Bouzas, Cristina

AU - Benitez, Javier

AU - EMBRACE

PY - 2015/1/1

Y1 - 2015/1/1

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.

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.

KW - Adult

KW - Breast Neoplasms

KW - Cohort Studies

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Humans

KW - Mutation

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Retrospective Studies

KW - Young Adult

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

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

M3 - Journal 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

Abstract

Keywords

UN SDGs

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