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

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 Aittomaki; Irene L. Andrulis; Norbert Arnold; Banu K. Arun; Margreet G. E. M. Ausems; Jacopo Azzollini; Daniel Barrowdale; Julian Barwell; Javier Benitez; Katarzyna Bialkowska; Valerie Bonadona; Julika Borde; Ake Borg; Angela R. Bradbury; Joan Brunet; Saundra S. Buys; Trinidad Caldes; Maria A. Caligo; Ian Campbell; Jonathan Carter; Jocelyne Chiquette; Wendy K. Chung; Kathleen B. M. Claes; J. Margriet Collee; Marie-Agnes 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; Lidia Feliubado; Lenka Foretova; Eitan Friedman; Encarna Gomez Garcia; KConFab Investigators; HEBON Investigators; GEMO Study Collaborators; EMBRACE Collaborators; CIMBA; Dezheng Huo

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

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 Aittomaki, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Margreet G. E. M. Ausems, Jacopo Azzollini, Daniel Barrowdale, Julian Barwell, Javier Benitez, Katarzyna BialkowskaValerie Bonadona, Julika Borde, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Jonathan Carter, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, J. Margriet Collee, Marie-Agnes 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, Lidia Feliubado, Lenka Foretova, Eitan Friedman, Encarna Gomez Garcia, KConFab Investigators, HEBON Investigators, GEMO Study Collaborators, EMBRACE Collaborators, CIMBA, Dezheng Huo^*

^*Corresponding author for this work

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

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/m(2) increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P-interaction <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 - 16 Jul 2019

Keywords

ANTHROPOMETRIC MEASURES
APOPTOSIS
ASSOCIATION
BREAST
COHORT
INFERTILITY
MORTALITY
OBESITY
PATHWAYS
PROGESTIN

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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., Aittomaki, K., Andrulis, I. L., Arnold, N., Arun, B. K., Ausems, M. G. E. M., Azzollini, J., Barrowdale, D., Barwell, J., Benitez, J., ... Huo, D. (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

@article{34a89501a6d547d2903cd3e4f8e71297,

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/m(2) increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P-interaction <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.",

keywords = "ANTHROPOMETRIC MEASURES, APOPTOSIS, ASSOCIATION, BREAST, COHORT, INFERTILITY, MORTALITY, OBESITY, PATHWAYS, PROGESTIN",

author = "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 Aittomaki 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 Bialkowska and Valerie Bonadona and Julika Borde and Ake Borg and Bradbury, {Angela R.} and Joan Brunet and Buys, {Saundra S.} and Trinidad Caldes and Caligo, {Maria A.} and Ian Campbell and Jonathan Carter and Jocelyne Chiquette and Chung, {Wendy K.} and Claes, {Kathleen B. M.} and Collee, {J. Margriet} and Marie-Agnes Collonge-Rame 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 Lidia Feliubado and Lenka Foretova and Eitan Friedman and {Gomez Garcia}, Encarna and {KConFab Investigators} and {HEBON Investigators} and {GEMO Study Collaborators} and {EMBRACE Collaborators} and CIMBA and Dezheng Huo",

note = "Funding Information: Competing interests: G.P. received honoraria and grant from Pfizer, Roche, Novartis, Accord, AstraZeneca, Amgen, Accord and Lilly. R.S. served on advisory board for Tesaro, Clovis, Astra Zeneca, Ethicon and Genmab, and speaker{\textquoteright}s bureau for Tesaro and Genentech. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019, Cancer Research UK.",

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",

}

Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Gomez Garcia, E, KConFab Investigators, HEBON Investigators, GEMO Study Collaborators, EMBRACE Collaborators, CIMBA & Huo, D 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

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 - 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 - Aittomaki, 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 - Bialkowska, Katarzyna

AU - Bonadona, Valerie

AU - Borde, Julika

AU - Borg, Ake

AU - Bradbury, Angela R.

AU - Brunet, Joan

AU - Buys, Saundra S.

AU - Caldes, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Carter, Jonathan

AU - Chiquette, Jocelyne

AU - Chung, Wendy K.

AU - Claes, Kathleen B. M.

AU - Collee, J. Margriet

AU - Collonge-Rame, Marie-Agnes

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 - Feliubado, Lidia

AU - Foretova, Lenka

AU - Friedman, Eitan

AU - Gomez Garcia, Encarna

AU - KConFab Investigators

AU - HEBON Investigators

AU - GEMO Study Collaborators

AU - EMBRACE Collaborators

AU - CIMBA

AU - Huo, Dezheng

N1 - Funding Information: Competing interests: G.P. received honoraria and grant from Pfizer, Roche, Novartis, Accord, AstraZeneca, Amgen, Accord and Lilly. R.S. served on advisory board for Tesaro, Clovis, Astra Zeneca, Ethicon and Genmab, and speaker’s bureau for Tesaro and Genentech. The other authors declare no competing interests. Publisher Copyright: © 2019, Cancer Research UK.

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/m(2) increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P-interaction <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/m(2) increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P-interaction <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.

KW - ANTHROPOMETRIC MEASURES

KW - APOPTOSIS

KW - ASSOCIATION

KW - BREAST

KW - COHORT

KW - INFERTILITY

KW - MORTALITY

KW - OBESITY

KW - PATHWAYS

KW - PROGESTIN

U2 - 10.1038/s41416-019-0492-8

DO - 10.1038/s41416-019-0492-8

M3 - Article

C2 - 31213659

SN - 0007-0920

VL - 121

SP - 180

EP - 192

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 2

ER -