Common susceptibility loci for male breast cancer

Sarah Maguire; Eleni Perrakis; Katarzyna Tomczyk; Michael Jones; Olivia Fletcher; Matthew Pugh; Timothy Winter; Kyle Thompson; Rosie Cooke; Alison H Trainer; James Paul; Stig E 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; Håkan 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 García-Closas; Richard Houlston; Anthony J Swerdlow; Nick Orr

doi:10.1093/jnci/djaa101

Common susceptibility loci for male breast cancer

Sarah Maguire, Eleni Perrakis, Katarzyna Tomczyk, Michael Jones, Olivia Fletcher, Matthew Pugh, Timothy Winter, Kyle Thompson, Rosie Cooke, Alison H Trainer, James Paul, Stig E 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, Håkan 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 García-Closas, Richard Houlston, Anthony J Swerdlow, Nick Orr^*

^*Corresponding author for this work

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

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Abstract

Background

The aetiology 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 (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.

Methods

We performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD 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 (PRS) and MBC. All statistical tests were two-sided.

Results

The GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold 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 x 10-30).

Conclusions

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

Original language	English
Article number	dja101
Journal	Journal of the National Cancer Institute
Volume	2020
Early online date	12 Aug 2020
DOIs	https://doi.org/10.1093/jnci/djaa101
Publication status	Early online date - 12 Aug 2020

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10.1093/jnci/djaa101Licence: CC BY

Common susceptibility loci for male breast cancer
© The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Supplementary data
Accepted author manuscript, 3.3 MBLicence: CC BY

Nick Orr
- nick.orrqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Reader
- Patrick G Johnston Centre for Cancer Research
Person: Academic

Cite this

Maguire, S., Perrakis, E., Tomczyk, K., Jones, M., Fletcher, O., Pugh, M., Winter, T., Thompson, K., Cooke, R., Trainer, A. H., Paul, J., Bojesen, S. E., Flyger, H., Nevanlinna, H., Mattson, J., Friedman, E., Laitman, Y., Palli, D., Masala, G., ... Orr, N. (2020). Common susceptibility loci for male breast cancer. Journal of the National Cancer Institute, 2020, [dja101]. https://doi.org/10.1093/jnci/djaa101

Maguire, Sarah ; Perrakis, Eleni ; Tomczyk, Katarzyna ; Jones, Michael ; Fletcher, Olivia ; Pugh, Matthew ; Winter, Timothy ; Thompson, Kyle ; Cooke, Rosie ; Trainer, Alison H ; Paul, James ; Bojesen, Stig E ; Flyger, Henrik ; Nevanlinna, Heli ; Mattson, Johanna ; Friedman, Eitan ; Laitman, Yael ; Palli, Domenico ; Masala, Giovanna ; Zanna, Ines ; Ottini, Laura ; Silvestri, Valentina ; Hollestelle, Antoinette ; Hooning, Maartje J ; Novaković, Srdjan ; Krajc, Mateja ; Gago-Dominguez, Manuela ; Castelao, Jose Esteban ; Olsson, Håkan ; Hedenfalk, Ingrid ; Saloustros, Emmanouil ; Georgoulias, Vasilios ; Easton, Douglas F ; Pharoah, Paul ; Dunning, Alison M ; Timothy Bishop, D ; Neuhausen, Susan L ; Steele, Linda ; Ashworth, Alan ; García-Closas, Montserrat ; Houlston, Richard ; Swerdlow, Anthony J ; Orr, Nick. / Common susceptibility loci for male breast cancer. In: Journal of the National Cancer Institute. 2020 ; Vol. 2020.

@article{549ad52111484008b7671a9f0ecf4a66,

title = "Common susceptibility loci for male breast cancer",

abstract = "BackgroundThe aetiology 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 (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD 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 (PRS) and MBC. All statistical tests were two-sided.ResultsThe GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold 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 x 10-30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.",

author = "Sarah Maguire and Eleni Perrakis and Katarzyna Tomczyk and Michael Jones and Olivia Fletcher and Matthew Pugh and Timothy Winter and Kyle Thompson and Rosie Cooke and Trainer, {Alison H} and James Paul and Bojesen, {Stig E} 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 H{\aa}kan Olsson and Ingrid Hedenfalk and Emmanouil Saloustros and Vasilios Georgoulias and Easton, {Douglas F} and Paul Pharoah and Dunning, {Alison M} and {Timothy Bishop}, D and Neuhausen, {Susan L} and Linda Steele and Alan Ashworth and Montserrat Garc{\'i}a-Closas and Richard Houlston and Swerdlow, {Anthony J} and Nick Orr",

year = "2020",

month = aug,

day = "12",

doi = "10.1093/jnci/djaa101",

language = "English",

volume = "2020",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

}

Maguire, S, Perrakis, E, Tomczyk, K, Jones, M, Fletcher, O, Pugh, M, Winter, T , Thompson, K, Cooke, R, Trainer, AH, Paul, J, Bojesen, SE, 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, Timothy Bishop, D, Neuhausen, SL, Steele, L, Ashworth, A, García-Closas, M, Houlston, R, Swerdlow, AJ & Orr, N 2020, 'Common susceptibility loci for male breast cancer', Journal of the National Cancer Institute, vol. 2020, dja101. https://doi.org/10.1093/jnci/djaa101

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

In: Journal of the National Cancer Institute, Vol. 2020, dja101, 12.08.2020.

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

TY - JOUR

T1 - Common susceptibility loci for male breast cancer

AU - Maguire, Sarah

AU - Perrakis, Eleni

AU - Tomczyk, Katarzyna

AU - Jones, Michael

AU - Fletcher, Olivia

AU - Pugh, Matthew

AU - Winter, Timothy

AU - Thompson, Kyle

AU - Cooke, Rosie

AU - Trainer, Alison H

AU - Paul, James

AU - Bojesen, Stig E

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, Håkan

AU - Hedenfalk, Ingrid

AU - Saloustros, Emmanouil

AU - Georgoulias, Vasilios

AU - Easton, Douglas F

AU - Pharoah, Paul

AU - Dunning, Alison M

AU - Timothy Bishop, D

AU - Neuhausen, Susan L

AU - Steele, Linda

AU - Ashworth, Alan

AU - García-Closas, Montserrat

AU - Houlston, Richard

AU - Swerdlow, Anthony J

AU - Orr, Nick

PY - 2020/8/12

Y1 - 2020/8/12

N2 - BackgroundThe aetiology 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 (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD 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 (PRS) and MBC. All statistical tests were two-sided.ResultsThe GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold 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 x 10-30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.

AB - BackgroundThe aetiology 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 (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD 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 (PRS) and MBC. All statistical tests were two-sided.ResultsThe GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold 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 x 10-30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.

U2 - 10.1093/jnci/djaa101

DO - 10.1093/jnci/djaa101

M3 - Article

VL - 2020

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

M1 - dja101

ER -

Common susceptibility loci for male breast cancer

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