Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

GEMO Study Collaborators; Frank Qian; Shengfeng Wang; Jonathan Mitchell; Lesley McGuffog; Daniel Barrowdale; Goska Leslie; Jan C Oosterwijk; Wendy K Chung; D Gareth Evans; Christoph Engel; Karin Kast; Cora M Aalfs; Muriel A Adank; Julian Adlard; Bjarni A Agnarsson; Kristiina Aittomäki; Elisa Alducci; Irene L Andrulis; Banu K Arun; Margreet G E M Ausems; Jacopo Azzollini; Emmanuelle Barouk-Simonet; Julian Barwell; Muriel Belotti; Javier Benitez; Andreas Berger; Ake Borg; Angela R Bradbury; Joan Brunet; Saundra S Buys; Trinidad Caldes; Maria A Caligo; Ian Campbell; Sandrine M Caputo; Jocelyne Chiquette; Kathleen B M Claes; J Margriet Collée; Fergus J Couch; Isabelle Coupier; Mary B Daly; Rosemarie Davidson; Orland Diez; Susan M Domchek; Alan Donaldson; Cecilia M Dorfling; Ros Eeles; Lidia Feliubadaló; Lenka Foretova; Jeffrey Fowler; Eitan Friedman

doi:10.1093/jnci/djy132

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

GEMO Study Collaborators, Frank Qian, Shengfeng Wang, Jonathan Mitchell, Lesley McGuffog, Daniel Barrowdale, Goska Leslie, Jan C Oosterwijk, Wendy K Chung, D Gareth Evans, Christoph Engel, Karin Kast, Cora M Aalfs, Muriel A Adank, Julian Adlard, Bjarni A Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L Andrulis, Banu K ArunMargreet G E M Ausems, Jacopo Azzollini, Emmanuelle Barouk-Simonet, Julian Barwell, Muriel Belotti, Javier Benitez, Andreas Berger, Ake Borg, Angela R Bradbury, Joan Brunet, Saundra S Buys, Trinidad Caldes, Maria A Caligo, Ian Campbell, Sandrine M Caputo, Jocelyne Chiquette, Kathleen B M Claes, J Margriet Collée, Fergus J Couch, Isabelle Coupier, Mary B Daly, Rosemarie Davidson, Orland Diez, Susan M Domchek, Alan Donaldson, Cecilia M Dorfling, Ros Eeles, Lidia Feliubadaló, Lenka Foretova, Jeffrey Fowler, Eitan Friedman

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

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Abstract

BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.

METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.

RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.

CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

Original language	English
Pages (from-to)	350-364
Number of pages	15
Journal	Journal of the National Cancer Institute
Volume	111
Issue number	4
DOIs	https://doi.org/10.1093/jnci/djy132
State	Published - Mar 1 2019

Keywords

Adult
BRCA1 Protein/genetics
BRCA2 Protein/genetics
Body Height
Body Mass Index
Breast Neoplasms/etiology
Female
Genetic Predisposition to Disease
Humans
Mendelian Randomization Analysis
Mutation
Polymorphism, Single Nucleotide
Prognosis
Risk Factors

UN SDGs

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

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10.1093/jnci/djy132

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GEMO Study Collaborators, Qian, F., Wang, S., Mitchell, J., McGuffog, L., Barrowdale, D., Leslie, G., Oosterwijk, J. C., Chung, W. K., Evans, D. G., Engel, C., Kast, K., Aalfs, C. M., Adank, M. A., Adlard, J., Agnarsson, B. A., Aittomäki, K., Alducci, E., Andrulis, I. L., ... Friedman, E. (2019). Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study. Journal of the National Cancer Institute, 111(4), 350-364. https://doi.org/10.1093/jnci/djy132

@article{ffc3287423cc40d3a670391c5db3929e,

title = "Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study",

abstract = "BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.",

keywords = "Adult, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Body Height, Body Mass Index, Breast Neoplasms/etiology, Female, Genetic Predisposition to Disease, Humans, Mendelian Randomization Analysis, Mutation, Polymorphism, Single Nucleotide, Prognosis, Risk Factors",

author = "{GEMO Study Collaborators} and Frank Qian and Shengfeng Wang and Jonathan Mitchell and Lesley McGuffog and Daniel Barrowdale and Goska Leslie and Oosterwijk, {Jan C} and Chung, {Wendy K} and Evans, {D Gareth} and Christoph Engel and Karin Kast and Aalfs, {Cora M} and Adank, {Muriel A} and Julian Adlard and Agnarsson, {Bjarni A} and Kristiina Aittom{\"a}ki and Elisa Alducci and Andrulis, {Irene L} and Arun, {Banu K} and Ausems, {Margreet G E M} and Jacopo Azzollini and Emmanuelle Barouk-Simonet and Julian Barwell and Muriel Belotti and Javier Benitez and Andreas Berger 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 Caputo, {Sandrine M} and Jocelyne Chiquette and Claes, {Kathleen B M} and {Margriet Coll{\'e}e}, J and Couch, {Fergus J} and Isabelle Coupier and Daly, {Mary B} and Rosemarie Davidson and Orland Diez and Domchek, {Susan M} and Alan Donaldson and Dorfling, {Cecilia M} and Ros Eeles and Lidia Feliubadal{\'o} and Lenka Foretova and Jeffrey Fowler and Eitan Friedman",

year = "2019",

month = mar,

day = "1",

doi = "10.1093/jnci/djy132",

language = "English",

volume = "111",

pages = "350--364",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "4",

}

GEMO Study Collaborators, Qian, F, Wang, S, Mitchell, J, McGuffog, L, Barrowdale, D, Leslie, G, Oosterwijk, JC, Chung, WK, Evans, DG, Engel, C, Kast, K, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Aittomäki, K, Alducci, E, Andrulis, IL, Arun, BK, Ausems, MGEM, Azzollini, J, Barouk-Simonet, E, Barwell, J, Belotti, M, Benitez, J, Berger, A, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Claes, KBM, Margriet Collée, J, Couch, FJ, Coupier, I, Daly, MB, Davidson, R, Diez, O, Domchek, SM, Donaldson, A, Dorfling, CM, Eeles, R, Feliubadaló, L, Foretova, L, Fowler, J & Friedman, E 2019, 'Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study', Journal of the National Cancer Institute, vol. 111, no. 4, pp. 350-364. https://doi.org/10.1093/jnci/djy132

TY - JOUR

T1 - Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers

T2 - A Mendelian Randomization Study

AU - GEMO Study Collaborators

AU - Qian, Frank

AU - Wang, Shengfeng

AU - Mitchell, Jonathan

AU - McGuffog, Lesley

AU - Barrowdale, Daniel

AU - Leslie, Goska

AU - Oosterwijk, Jan C

AU - Chung, Wendy K

AU - Evans, D Gareth

AU - Engel, Christoph

AU - Kast, Karin

AU - Aalfs, Cora M

AU - Adank, Muriel A

AU - Adlard, Julian

AU - Agnarsson, Bjarni A

AU - Aittomäki, Kristiina

AU - Alducci, Elisa

AU - Andrulis, Irene L

AU - Arun, Banu K

AU - Ausems, Margreet G E M

AU - Azzollini, Jacopo

AU - Barouk-Simonet, Emmanuelle

AU - Barwell, Julian

AU - Belotti, Muriel

AU - Benitez, Javier

AU - Berger, Andreas

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 - Caputo, Sandrine M

AU - Chiquette, Jocelyne

AU - Claes, Kathleen B M

AU - Margriet Collée, J

AU - Couch, Fergus J

AU - Coupier, Isabelle

AU - Daly, Mary B

AU - Davidson, Rosemarie

AU - Diez, Orland

AU - Domchek, Susan M

AU - Donaldson, Alan

AU - Dorfling, Cecilia M

AU - Eeles, Ros

AU - Feliubadaló, Lidia

AU - Foretova, Lenka

AU - Fowler, Jeffrey

AU - Friedman, Eitan

PY - 2019/3/1

Y1 - 2019/3/1

N2 - BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

AB - BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

KW - Adult

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Body Height

KW - Body Mass Index

KW - Breast Neoplasms/etiology

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Mendelian Randomization Analysis

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - Risk Factors

UR - http://www.scopus.com/inward/record.url?scp=85064286333&partnerID=8YFLogxK

U2 - 10.1093/jnci/djy132

DO - 10.1093/jnci/djy132

M3 - Article

C2 - 30312457

SN - 0027-8874

VL - 111

SP - 350

EP - 364

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 4

ER -

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

Abstract

Keywords

UN SDGs

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