Common Susceptibility Loci for Male Breast Cancer

Sarah Maguire; Eleni Perraki; Katarzyna Tomczyk; Michael E. Jones; Olivia Fletcher; Matthew Pugh; Timothy Winter; Kyle Thompson; Rosie Cooke; Alison Trainer; Paul James; Stig Bojesen; Henrik Flyger; Heli Nevanlinna; Johanna Mattson; Eitan Friedman; Yael Laitman; Domenico Palli; Giovanna Masala; Ines Zanna; Laura Ottini; Valentina Silvestri; Antoinette Hollestelle; Maartje J. Hooning; Srdjan Novaković; Mateja Krajc; Manuela Gago-Dominguez; Jose Esteban Castelao; Hakan Olsson; Ingrid Hedenfalk; Emmanouil Saloustros; Vasilios Georgoulias; Douglas F. Easton; Paul Pharoah; Alison M. Dunning; D. Timothy Bishop; Susan L. Neuhausen; Linda Steele; Alan Ashworth; Montserrat Garcia Closas; Richard Houlston; Anthony Swerdlow; Nick Orr; KConFab Consortium

doi:10.1093/jnci/djaa101

Common Susceptibility Loci for Male Breast Cancer

Sarah Maguire, Eleni Perraki, Katarzyna Tomczyk, Michael E. Jones, Olivia Fletcher, Matthew Pugh, Timothy Winter, Kyle Thompson, Rosie Cooke, Alison Trainer, Paul James, Stig Bojesen, Henrik Flyger, Heli Nevanlinna, Johanna Mattson, Eitan Friedman, Yael Laitman, Domenico Palli, Giovanna Masala, Ines ZannaLaura Ottini, Valentina Silvestri, Antoinette Hollestelle, Maartje J. Hooning, Srdjan Novaković, Mateja Krajc, Manuela Gago-Dominguez, Jose Esteban Castelao, Hakan Olsson, Ingrid Hedenfalk, Emmanouil Saloustros, Vasilios Georgoulias, Douglas F. Easton, Paul Pharoah, Alison M. Dunning, D. Timothy Bishop, Susan L. Neuhausen, Linda Steele, Alan Ashworth, Montserrat Garcia Closas, Richard Houlston, Anthony Swerdlow, Nick Orr, KConFab Consortium

14 Citations (Scopus)

Abstract

BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.

METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.

RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30).

CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Original language	English
Journal	Journal of the National Cancer Institute
Volume	113
Issue number	4
Pages (from-to)	453-461
Number of pages	9
ISSN	1052-6773
DOIs	https://doi.org/10.1093/jnci/djaa101
Publication status	Published - 6 Apr 2021

Keywords

Breast Neoplasms, Male/chemistry
Case-Control Studies
Confidence Intervals
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Linear Models
Linkage Disequilibrium
Male
Odds Ratio
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Receptors, Estrogen

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10.1093/jnci/djaa101

Cite this

Maguire, S., Perraki, E., Tomczyk, K., Jones, M. E., Fletcher, O., Pugh, M., Winter, T., Thompson, K., Cooke, R., Trainer, A., James, P., Bojesen, S., Flyger, H., Nevanlinna, H., Mattson, J., Friedman, E., Laitman, Y., Palli, D., Masala, G., ... KConFab Consortium (2021). Common Susceptibility Loci for Male Breast Cancer. Journal of the National Cancer Institute, 113(4), 453-461. https://doi.org/10.1093/jnci/djaa101

Maguire, S, Perraki, E, Tomczyk, K, Jones, ME, Fletcher, O, Pugh, M, Winter, T, Thompson, K, Cooke, R, Trainer, A, James, P, Bojesen, S , Flyger, H, Nevanlinna, H, Mattson, J, Friedman, E, Laitman, Y, Palli, D, Masala, G, Zanna, I, Ottini, L, Silvestri, V, Hollestelle, A, Hooning, MJ, Novaković, S, Krajc, M, Gago-Dominguez, M, Castelao, JE, Olsson, H, Hedenfalk, I, Saloustros, E, Georgoulias, V, Easton, DF, Pharoah, P, Dunning, AM, Bishop, DT, Neuhausen, SL, Steele, L, Ashworth, A, Garcia Closas, M, Houlston, R, Swerdlow, A, Orr, N & KConFab Consortium 2021, 'Common Susceptibility Loci for Male Breast Cancer', Journal of the National Cancer Institute, vol. 113, no. 4, pp. 453-461. https://doi.org/10.1093/jnci/djaa101

@article{4b492370fd2c4cc7b08d4207503ab26d,

title = "Common Susceptibility Loci for Male Breast Cancer",

abstract = "BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30).CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.",

keywords = "Breast Neoplasms, Male/chemistry, Case-Control Studies, Confidence Intervals, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linear Models, Linkage Disequilibrium, Male, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Estrogen",

author = "Sarah Maguire and Eleni Perraki and Katarzyna Tomczyk and Jones, {Michael E.} and Olivia Fletcher and Matthew Pugh and Timothy Winter and Kyle Thompson and Rosie Cooke and Alison Trainer and Paul James and Stig Bojesen and Henrik Flyger and Heli Nevanlinna and Johanna Mattson and Eitan Friedman and Yael Laitman and Domenico Palli and Giovanna Masala and Ines Zanna and Laura Ottini and Valentina Silvestri and Antoinette Hollestelle and Hooning, {Maartje J.} and Srdjan Novakovi{\'c} and Mateja Krajc and Manuela Gago-Dominguez and Castelao, {Jose Esteban} and Hakan Olsson and Ingrid Hedenfalk and Emmanouil Saloustros and Vasilios Georgoulias and Easton, {Douglas F.} and Paul Pharoah and Dunning, {Alison M.} and Bishop, {D. Timothy} and Neuhausen, {Susan L.} and Linda Steele and Alan Ashworth and {Garcia Closas}, Montserrat and Richard Houlston and Anthony Swerdlow and Nick Orr and {KConFab Consortium}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2020. Published by Oxford University Press. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine",

year = "2021",

month = apr,

day = "6",

doi = "10.1093/jnci/djaa101",

language = "English",

volume = "113",

pages = "453--461",

journal = "Journal of the National Cancer Institute",

issn = "1052-6773",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - Common Susceptibility Loci for Male Breast Cancer

AU - Maguire, Sarah

AU - Perraki, Eleni

AU - Tomczyk, Katarzyna

AU - Jones, Michael E.

AU - Fletcher, Olivia

AU - Pugh, Matthew

AU - Winter, Timothy

AU - Thompson, Kyle

AU - Cooke, Rosie

AU - Trainer, Alison

AU - James, Paul

AU - Bojesen, Stig

AU - Flyger, Henrik

AU - Nevanlinna, Heli

AU - Mattson, Johanna

AU - Friedman, Eitan

AU - Laitman, Yael

AU - Palli, Domenico

AU - Masala, Giovanna

AU - Zanna, Ines

AU - Ottini, Laura

AU - Silvestri, Valentina

AU - Hollestelle, Antoinette

AU - Hooning, Maartje J.

AU - Novaković, Srdjan

AU - Krajc, Mateja

AU - Gago-Dominguez, Manuela

AU - Castelao, Jose Esteban

AU - Olsson, Hakan

AU - Hedenfalk, Ingrid

AU - Saloustros, Emmanouil

AU - Georgoulias, Vasilios

AU - Easton, Douglas F.

AU - Pharoah, Paul

AU - Dunning, Alison M.

AU - Bishop, D. Timothy

AU - Neuhausen, Susan L.

AU - Steele, Linda

AU - Ashworth, Alan

AU - Garcia Closas, Montserrat

AU - Houlston, Richard

AU - Swerdlow, Anthony

AU - Orr, Nick

AU - KConFab Consortium

PY - 2021/4/6

Y1 - 2021/4/6

N2 - BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30).CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

AB - BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30).CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

KW - Breast Neoplasms, Male/chemistry

KW - Case-Control Studies

KW - Confidence Intervals

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Linear Models

KW - Linkage Disequilibrium

KW - Male

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Receptors, Estrogen

UR - http://www.scopus.com/inward/record.url?scp=85102459182&partnerID=8YFLogxK

U2 - 10.1093/jnci/djaa101

DO - 10.1093/jnci/djaa101

M3 - Journal article

C2 - 32785646

AN - SCOPUS:85102459182

SN - 1052-6773

VL - 113

SP - 453

EP - 461

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 4

ER -

Common Susceptibility Loci for Male Breast Cancer

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Keywords

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