Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

KConFab Investigators; HEBON Investigators; GEMO Study Collaborators; EMBRACE Collaborators; Frank Qian; Matti A. Rookus; Goska Leslie; Harvey A. Risch; Mark H. Greene; Cora M. Aalfs; Muriel A. Adank; Julian Adlard; Bjarni A. Agnarsson; Munaza Ahmed; Kristiina Aittomäki; Irene L. Andrulis; Norbert Arnold; Banu K. Arun; Margreet G.E.M. Ausems; Jacopo Azzollini; Daniel Barrowdale; Julian Barwell; Javier Benitez; Katarzyna Białkowska; Valérie Bonadona; Julika Borde; Ake Borg; Angela R. Bradbury; Joan Brunet; Saundra S. Buys; Trinidad Caldés; Maria A. Caligo; Ian Campbell; Jonathan Carter; Jocelyne Chiquette; Wendy K. Chung; Kathleen B.M. Claes; J. Margriet Collée; Marie Agnès Collonge-Rame; Fergus J. Couch; Mary B. Daly; Capucine Delnatte; Orland Diez; Susan M. Domchek; Cecilia M. Dorfling; Jacqueline Eason; Douglas F. Easton; Ros Eeles; Christoph Engel; D. Gareth Evans; Laurence Faivre; Marco Montagna; Paolo Radice; Silvia Tognazzo; Amanda Toland; CIMBA CIMBA

doi:10.1038/s41416-019-0492-8

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

KConFab Investigators, HEBON Investigators, GEMO Study Collaborators, EMBRACE Collaborators, Frank Qian, Matti A. Rookus, Goska Leslie, Harvey A. Risch, Mark H. Greene, Cora M. Aalfs, Muriel A. Adank, Julian Adlard, Bjarni A. Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Margreet G.E.M. Ausems, Jacopo AzzolliniDaniel Barrowdale, Julian Barwell, Javier Benitez, Katarzyna Białkowska, Valérie Bonadona, Julika Borde, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Jonathan Carter, Jocelyne Chiquette, Wendy K. Chung, Kathleen B.M. Claes, J. Margriet Collée, Marie Agnès Collonge-Rame, Fergus J. Couch, Mary B. Daly, Capucine Delnatte, Orland Diez, Susan M. Domchek, Cecilia M. Dorfling, Jacqueline Eason, Douglas F. Easton, Ros Eeles, Christoph Engel, D. Gareth Evans, Laurence Faivre, Marco Montagna, Paolo Radice, Silvia Tognazzo, Amanda Toland, CIMBA CIMBA

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Abstract

Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction <0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Original language	English
Pages (from-to)	180-192
Number of pages	13
Journal	British Journal of Cancer
Volume	121
Issue number	2
DOIs	https://doi.org/10.1038/s41416-019-0492-8
Publication status	Published - Jul 16 2019

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Investigators, KC., Investigators, HEBON., Collaborators, GEMO. S., Collaborators, EMBRACE., Qian, F., Rookus, M. A., Leslie, G., Risch, H. A., Greene, M. H., Aalfs, C. M., Adank, M. A., Adlard, J., Agnarsson, B. A., Ahmed, M., Aittomäki, K., Andrulis, I. L., Arnold, N., Arun, B. K., Ausems, M. G. E. M., ... CIMBA, CIMBA. (2019). Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. British Journal of Cancer, 121(2), 180-192. https://doi.org/10.1038/s41416-019-0492-8

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. / Investigators, KConFab; Investigators, HEBON; Collaborators, GEMO Study; Collaborators, EMBRACE; Qian, Frank; Rookus, Matti A.; Leslie, Goska; Risch, Harvey A.; Greene, Mark H.; Aalfs, Cora M.; Adank, Muriel A.; Adlard, Julian; Agnarsson, Bjarni A.; Ahmed, Munaza; Aittomäki, Kristiina; Andrulis, Irene L.; Arnold, Norbert; Arun, Banu K.; Ausems, Margreet G.E.M.; Azzollini, Jacopo; Barrowdale, Daniel; Barwell, Julian; Benitez, Javier; Białkowska, Katarzyna; Bonadona, Valérie; Borde, Julika; Borg, Ake; Bradbury, Angela R.; Brunet, Joan; Buys, Saundra S.; Caldés, Trinidad; Caligo, Maria A.; Campbell, Ian; Carter, Jonathan; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B.M.; Collée, J. Margriet; Collonge-Rame, Marie Agnès; Couch, Fergus J.; Daly, Mary B.; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dorfling, Cecilia M.; Eason, Jacqueline; Easton, Douglas F.; Eeles, Ros; Engel, Christoph; Evans, D. Gareth; Faivre, Laurence; Montagna, Marco ; Radice, Paolo ; Tognazzo, Silvia; Toland, Amanda; CIMBA, CIMBA.

In: British Journal of Cancer, Vol. 121, No. 2, 16.07.2019, p. 180-192.

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

Investigators, KC, Investigators, HEBON, Collaborators, GEMOS, Collaborators, EMBRACE, Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomäki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Białkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldés, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collée, JM, Collonge-Rame, MA, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Montagna, M , Radice, P , Tognazzo, S, Toland, A & CIMBA, CIMBA 2019, 'Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers', British Journal of Cancer, vol. 121, no. 2, pp. 180-192. https://doi.org/10.1038/s41416-019-0492-8

Investigators, KConFab ; Investigators, HEBON ; Collaborators, GEMO Study ; Collaborators, EMBRACE ; Qian, Frank ; Rookus, Matti A. ; Leslie, Goska ; Risch, Harvey A. ; Greene, Mark H. ; Aalfs, Cora M. ; Adank, Muriel A. ; Adlard, Julian ; Agnarsson, Bjarni A. ; Ahmed, Munaza ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Arnold, Norbert ; Arun, Banu K. ; Ausems, Margreet G.E.M. ; Azzollini, Jacopo ; Barrowdale, Daniel ; Barwell, Julian ; Benitez, Javier ; Białkowska, Katarzyna ; Bonadona, Valérie ; Borde, Julika ; Borg, Ake ; Bradbury, Angela R. ; Brunet, Joan ; Buys, Saundra S. ; Caldés, Trinidad ; Caligo, Maria A. ; Campbell, Ian ; Carter, Jonathan ; Chiquette, Jocelyne ; Chung, Wendy K. ; Claes, Kathleen B.M. ; Collée, J. Margriet ; Collonge-Rame, Marie Agnès ; Couch, Fergus J. ; Daly, Mary B. ; Delnatte, Capucine ; Diez, Orland ; Domchek, Susan M. ; Dorfling, Cecilia M. ; Eason, Jacqueline ; Easton, Douglas F. ; Eeles, Ros ; Engel, Christoph ; Evans, D. Gareth ; Faivre, Laurence ; Montagna, Marco ; Radice, Paolo ; Tognazzo, Silvia ; Toland, Amanda ; CIMBA, CIMBA. / Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. In: British Journal of Cancer. 2019 ; Vol. 121, No. 2. pp. 180-192.

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title = "Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers",

abstract = "Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction <0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.",

author = "KConFab Investigators and HEBON Investigators and Collaborators, {GEMO Study} and EMBRACE Collaborators and Frank Qian and Rookus, {Matti A.} and Goska Leslie and Risch, {Harvey A.} and Greene, {Mark H.} and Aalfs, {Cora M.} and Adank, {Muriel A.} and Julian Adlard and Agnarsson, {Bjarni A.} and Munaza Ahmed and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Norbert Arnold and Arun, {Banu K.} and Ausems, {Margreet G.E.M.} and Jacopo Azzollini and Daniel Barrowdale and Julian Barwell and Javier Benitez and Katarzyna Bia{\l}kowska and Val{\'e}rie Bonadona and Julika Borde and Ake Borg and Bradbury, {Angela R.} and Joan Brunet and Buys, {Saundra S.} and Trinidad Cald{\'e}s and Caligo, {Maria A.} and Ian Campbell and Jonathan Carter and Jocelyne Chiquette and Chung, {Wendy K.} and Claes, {Kathleen B.M.} and Coll{\'e}e, {J. Margriet} and Collonge-Rame, {Marie Agn{\`e}s} and Couch, {Fergus J.} and Daly, {Mary B.} and Capucine Delnatte and Orland Diez and Domchek, {Susan M.} and Dorfling, {Cecilia M.} and Jacqueline Eason and Easton, {Douglas F.} and Ros Eeles and Christoph Engel and Evans, {D. Gareth} and Laurence Faivre and Marco Montagna and Paolo Radice and Silvia Tognazzo and Amanda Toland and CIMBA CIMBA",

year = "2019",

month = jul,

day = "16",

doi = "10.1038/s41416-019-0492-8",

language = "English",

volume = "121",

pages = "180--192",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "2",

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TY - JOUR

T1 - Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

AU - Investigators, KConFab

AU - Investigators, HEBON

AU - Collaborators, GEMO Study

AU - Collaborators, EMBRACE

AU - Qian, Frank

AU - Rookus, Matti A.

AU - Leslie, Goska

AU - Risch, Harvey A.

AU - Greene, Mark H.

AU - Aalfs, Cora M.

AU - Adank, Muriel A.

AU - Adlard, Julian

AU - Agnarsson, Bjarni A.

AU - Ahmed, Munaza

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Arnold, Norbert

AU - Arun, Banu K.

AU - Ausems, Margreet G.E.M.

AU - Azzollini, Jacopo

AU - Barrowdale, Daniel

AU - Barwell, Julian

AU - Benitez, Javier

AU - Białkowska, Katarzyna

AU - Bonadona, Valérie

AU - Borde, Julika

AU - Borg, Ake

AU - Bradbury, Angela R.

AU - Brunet, Joan

AU - Buys, Saundra S.

AU - Caldés, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Carter, Jonathan

AU - Chiquette, Jocelyne

AU - Chung, Wendy K.

AU - Claes, Kathleen B.M.

AU - Collée, J. Margriet

AU - Collonge-Rame, Marie Agnès

AU - Couch, Fergus J.

AU - Daly, Mary B.

AU - Delnatte, Capucine

AU - Diez, Orland

AU - Domchek, Susan M.

AU - Dorfling, Cecilia M.

AU - Eason, Jacqueline

AU - Easton, Douglas F.

AU - Eeles, Ros

AU - Engel, Christoph

AU - Evans, D. Gareth

AU - Faivre, Laurence

AU - Montagna, Marco

AU - Radice, Paolo

AU - Tognazzo, Silvia

AU - Toland, Amanda

AU - CIMBA, CIMBA

PY - 2019/7/16

Y1 - 2019/7/16

N2 - Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction <0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

AB - Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction <0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

U2 - 10.1038/s41416-019-0492-8

DO - 10.1038/s41416-019-0492-8

M3 - Article

VL - 121

SP - 180

EP - 192

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 2

ER -

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

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