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

GEMO Study Collaborators, HEBON, EMBRACE

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2 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)350-364
Number of pages15
JournalJournal of the National Cancer Institute
Volume111
Issue number4
DOIs
StatePublished - Apr 1 2019

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Random Allocation
Body Mass Index
Breast Neoplasms
Mutation
Confidence Intervals
Proportional Hazards Models
Research Personnel

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers : A Mendelian Randomization Study. / GEMO Study Collaborators; HEBON; EMBRACE.

In: Journal of the National Cancer Institute, Vol. 111, No. 4, 01.04.2019, p. 350-364.

Research output: Contribution to journalArticle

@article{192e9d6f01ea452aa18892ae973b57cb,
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.",
author = "{GEMO Study Collaborators} and HEBON and EMBRACE 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 = "4",
day = "1",
doi = "10.1093/jnci/djy132",
language = "English (US)",
volume = "111",
pages = "350--364",
journal = "Journal of the National Cancer Institute",
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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 - HEBON

AU - EMBRACE

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 - 2019/4/1

Y1 - 2019/4/1

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.

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U2 - 10.1093/jnci/djy132

DO - 10.1093/jnci/djy132

M3 - Article

C2 - 30312457

AN - SCOPUS:85064286333

VL - 111

SP - 350

EP - 364

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 4

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