Obesity-associated changes in molecular biology of primary breast cancer

Ha Linh Nguyen; Tatjana Geukens; Marion Maetens; Samuel Aparicio; Ayse Bassez; Ake Borg; Jane Brock; Annegien Broeks; Carlos Caldas; Fatima Cardoso; Maxim De Schepper; Mauro Delorenzi; Caroline A. Drukker; Annuska M. Glas; Andrew R. Green; Edoardo Isnaldi; Jórunn Eyfjörð; Hazem Khout; Stian Knappskog; Savitri Krishnamurthy; Sunil R. Lakhani; Anita Langerod; John W.M. Martens; Amy E. McCart Reed; Leigh Murphy; Stefan Naulaerts; Serena Nik-Zainal; Ines Nevelsteen; Patrick Neven; Martine Piccart; Coralie Poncet; Kevin Punie; Colin Purdie; Emad A. Rakha; Andrea Richardson; Emiel Rutgers; Anne Vincent-Salomon; Peter T. Simpson; Marjanka K. Schmidt; Christos Sotiriou; Paul N. Span; Kiat Tee Benita Tan; Alastair Thompson; Stefania Tommasi; Karen Van Baelen; Marc Van de Vijver; Steven Van Laere; Laura van’t Veer; Giuseppe Viale; Alain Viari; Hanne Vos; Anke T. Witteveen; Hans Wildiers; Giuseppe Floris; Abhishek D. Garg; Ann Smeets; Diether Lambrechts; Elia Biganzoli; François Richard; Christine Desmedt

doi:10.1038/s41467-023-39996-z

Obesity-associated changes in molecular biology of primary breast cancer

Ha Linh Nguyen
, Tatjana Geukens
, Marion Maetens
, Samuel Aparicio
, Ayse Bassez
, Ake Borg
, Jane Brock
, Annegien Broeks
, Carlos Caldas
, Fatima Cardoso
, Maxim De Schepper
, Mauro Delorenzi
, Caroline A. Drukker
, Annuska M. Glas
, Andrew R. Green
, Edoardo Isnaldi
, Jórunn Eyfjörð
, Hazem Khout
, Stian Knappskog
, Savitri Krishnamurthy

Sunil R. Lakhani, Anita Langerod, John W.M. Martens, Amy E. McCart Reed, Leigh Murphy, Stefan Naulaerts, Serena Nik-Zainal, Ines Nevelsteen, Patrick Neven, Martine Piccart, Coralie Poncet, Kevin Punie, Colin Purdie, Emad A. Rakha, Andrea Richardson, Emiel Rutgers, Anne Vincent-Salomon, Peter T. Simpson, Marjanka K. Schmidt, Christos Sotiriou, Paul N. Span, Kiat Tee Benita Tan, Alastair Thompson, Stefania Tommasi, Karen Van Baelen, Marc Van de Vijver, Steven Van Laere, Laura van’t Veer, Giuseppe Viale, Alain Viari, Hanne Vos, Anke T. Witteveen, Hans Wildiers, Giuseppe Floris, Abhishek D. Garg, Ann Smeets, Diether Lambrechts, Elia Biganzoli, François Richard, Christine Desmedt (Lead / Corresponding author)

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

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Abstract

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients’ body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

Original language	English
Article number	4418
Number of pages	17
Journal	Nature Communications
Volume	14
Early online date	21 Jul 2023
DOIs	https://doi.org/10.1038/s41467-023-39996-z
Publication status	Published - 2023

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Breast cancer
Cancer genomics
Tumour heterogeneity

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-39996-zLicence: CC BY

Final Published VersionFinal published version, 5.1 MBLicence: CC BY

Cite this

Nguyen, H. L., Geukens, T., Maetens, M., Aparicio, S., Bassez, A., Borg, A., Brock, J., Broeks, A., Caldas, C., Cardoso, F., De Schepper, M., Delorenzi, M., Drukker, C. A., Glas, A. M., Green, A. R., Isnaldi, E., Eyfjörð, J., Khout, H., Knappskog, S., ... Desmedt, C. (2023). Obesity-associated changes in molecular biology of primary breast cancer. Nature Communications, 14, Article 4418. https://doi.org/10.1038/s41467-023-39996-z

@article{e4fa877d521b43d5a37e197675159580,

title = "Obesity-associated changes in molecular biology of primary breast cancer",

abstract = "Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients{\textquoteright} body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.",

keywords = "Breast cancer, Cancer genomics, Tumour heterogeneity",

author = "Nguyen, \{Ha Linh\} and Tatjana Geukens and Marion Maetens and Samuel Aparicio and Ayse Bassez and Ake Borg and Jane Brock and Annegien Broeks and Carlos Caldas and Fatima Cardoso and \{De Schepper\}, Maxim and Mauro Delorenzi and Drukker, \{Caroline A.\} and Glas, \{Annuska M.\} and Green, \{Andrew R.\} and Edoardo Isnaldi and J{\'o}runn Eyfj{\"o}r{\dh} and Hazem Khout and Stian Knappskog and Savitri Krishnamurthy and Lakhani, \{Sunil R.\} and Anita Langerod and Martens, \{John W.M.\} and \{McCart Reed\}, \{Amy E.\} and Leigh Murphy and Stefan Naulaerts and Serena Nik-Zainal and Ines Nevelsteen and Patrick Neven and Martine Piccart and Coralie Poncet and Kevin Punie and Colin Purdie and Rakha, \{Emad A.\} and Andrea Richardson and Emiel Rutgers and Anne Vincent-Salomon and Simpson, \{Peter T.\} and Schmidt, \{Marjanka K.\} and Christos Sotiriou and Span, \{Paul N.\} and Tan, \{Kiat Tee Benita\} and Alastair Thompson and Stefania Tommasi and \{Van Baelen\}, Karen and \{Van de Vijver\}, Marc and \{Van Laere\}, Steven and \{van{\textquoteright}t Veer\}, Laura and Giuseppe Viale and Alain Viari and Hanne Vos and Witteveen, \{Anke T.\} and Hans Wildiers and Giuseppe Floris and Garg, \{Abhishek D.\} and Ann Smeets and Diether Lambrechts and Elia Biganzoli and Fran{\c c}ois Richard and Christine Desmedt",

note = "{\textcopyright} 2023, The Author(s). The study was financially supported by the Luxembourg Cancer Foundation (grant FC/2018/07), the Consolidator Grant approved by the European Research Council (ERC, FAT-BC 101003153), and the Internal Funds KU Leuven (3M180676). K.V.B. and M.D.S. are funded by the KU Leuven Fund Nadine de Beauffort. F.R. and T.G. are funded by FWO through a research fellowship. G.F. is the recipient of a post-doctoral mandate from the Klinsche Onderzoek en OpleidingsRaad (KOOR) of the University Hospitals Leuven. The METABRIC project was funded by Cancer Research UK, the British Columbia Cancer Foundation, and Canadian Breast Cancer Foundation BC/Yukon. The project also received support from the University of Cambridge, Hutchinson Whampoa, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, the Centre for Translational Genomics (CTAG) Vancouver, and the BCCA Breast Cancer Outcomes Unit. The ICGC-BRCA project has been funded through the ICGC Breast Cancer Working Group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community{\textquoteright}s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006; the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z) and the HER2+ project funded by Institut National du Cancer (INCa) in France (Grants N° 226-2009, 02-2011, 41-2012, 144-2008, 06-2012). The ICGC Asian Breast Cancer Project was funded through a grant from the Korean Health Technology R\&D Project, Ministry of Health \& Welfare, Republic of Korea (A111218-SC01). The MINDACT trial has received grants from the European Commission Framework Programme VI (FP6-LSHC-CT-2004-503426), the Breast Cancer Research Foundation, Novartis, F. Hoffman La Roche, Sanofi-Aventis, the National Cancer Institute (NCI), the EBCC-Breast Cancer Working Group (BCWG grant for the MINDACT biobank), the Jacqueline Seroussi Memorial Foundation (2006 JSMF award), Prix Mois du Cancer du Sein (2004 award), Susan G. Komen for the Cure (SG05-0922-02), Fondation Belge Contre le Cancer (SCIE 2005-27), Dutch Cancer Society (KWF), Association Le Cancer du Sein, Parlons-en!, Deutsche Krebshilfe, the Grant Simpson Trust and Cancer Research UK. This trial was also supported by the EORTC Cancer Research Fund. Whole genome analysis was provided in kind by Agendia. The BioKey study was supported by an MSD grant to A.S., by Fonds Nadine De Beauffort to A.S., by a {\textquoteleft}Kom op Tegen Kanker{\textquoteright} to A.S. and H.W., by the Stichting Tegen Kanker and the Flemish Fund for Scientific Research (FWO; project G0B6120N) Belgium, by Agilent Technologies (Thought Leader award) to D.L. This VIB Grand Challenges project also received support from the Flemish Government under Management Agreement 2017–2021 (VR 2016 2312 doc.1521/4), from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under grant agreement no. 847912 (RESCUER) and from KU Leuven grant (C14/18/092) Symbiosys3. We are grateful to all women who participated and donated tissue in all studies used in this project and their families; all the investigators, surgeons, pathologists, and research nurses; and finally our close collaborators for their help in the data collection process and the collaboration on the scientific work.",

year = "2023",

doi = "10.1038/s41467-023-39996-z",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Nguyen, HL, Geukens, T, Maetens, M, Aparicio, S, Bassez, A, Borg, A, Brock, J, Broeks, A, Caldas, C, Cardoso, F, De Schepper, M, Delorenzi, M, Drukker, CA, Glas, AM, Green, AR, Isnaldi, E, Eyfjörð, J, Khout, H, Knappskog, S, Krishnamurthy, S, Lakhani, SR, Langerod, A, Martens, JWM, McCart Reed, AE, Murphy, L, Naulaerts, S, Nik-Zainal, S, Nevelsteen, I, Neven, P, Piccart, M, Poncet, C, Punie, K, Purdie, C, Rakha, EA, Richardson, A, Rutgers, E, Vincent-Salomon, A, Simpson, PT, Schmidt, MK, Sotiriou, C, Span, PN, Tan, KTB, Thompson, A, Tommasi, S, Van Baelen, K, Van de Vijver, M, Van Laere, S, van’t Veer, L, Viale, G, Viari, A, Vos, H, Witteveen, AT, Wildiers, H, Floris, G, Garg, AD, Smeets, A, Lambrechts, D, Biganzoli, E, Richard, F & Desmedt, C 2023, 'Obesity-associated changes in molecular biology of primary breast cancer', Nature Communications, vol. 14, 4418. https://doi.org/10.1038/s41467-023-39996-z

TY - JOUR

T1 - Obesity-associated changes in molecular biology of primary breast cancer

AU - Nguyen, Ha Linh

AU - Geukens, Tatjana

AU - Maetens, Marion

AU - Aparicio, Samuel

AU - Bassez, Ayse

AU - Borg, Ake

AU - Brock, Jane

AU - Broeks, Annegien

AU - Caldas, Carlos

AU - Cardoso, Fatima

AU - De Schepper, Maxim

AU - Delorenzi, Mauro

AU - Drukker, Caroline A.

AU - Glas, Annuska M.

AU - Green, Andrew R.

AU - Isnaldi, Edoardo

AU - Eyfjörð, Jórunn

AU - Khout, Hazem

AU - Knappskog, Stian

AU - Krishnamurthy, Savitri

AU - Lakhani, Sunil R.

AU - Langerod, Anita

AU - Martens, John W.M.

AU - McCart Reed, Amy E.

AU - Murphy, Leigh

AU - Naulaerts, Stefan

AU - Nik-Zainal, Serena

AU - Nevelsteen, Ines

AU - Neven, Patrick

AU - Piccart, Martine

AU - Poncet, Coralie

AU - Punie, Kevin

AU - Purdie, Colin

AU - Rakha, Emad A.

AU - Richardson, Andrea

AU - Rutgers, Emiel

AU - Vincent-Salomon, Anne

AU - Simpson, Peter T.

AU - Schmidt, Marjanka K.

AU - Sotiriou, Christos

AU - Span, Paul N.

AU - Tan, Kiat Tee Benita

AU - Thompson, Alastair

AU - Tommasi, Stefania

AU - Van Baelen, Karen

AU - Van de Vijver, Marc

AU - Van Laere, Steven

AU - van’t Veer, Laura

AU - Viale, Giuseppe

AU - Viari, Alain

AU - Vos, Hanne

AU - Witteveen, Anke T.

AU - Wildiers, Hans

AU - Floris, Giuseppe

AU - Garg, Abhishek D.

AU - Smeets, Ann

AU - Lambrechts, Diether

AU - Biganzoli, Elia

AU - Richard, François

AU - Desmedt, Christine

N1 - © 2023, The Author(s). The study was financially supported by the Luxembourg Cancer Foundation (grant FC/2018/07), the Consolidator Grant approved by the European Research Council (ERC, FAT-BC 101003153), and the Internal Funds KU Leuven (3M180676). K.V.B. and M.D.S. are funded by the KU Leuven Fund Nadine de Beauffort. F.R. and T.G. are funded by FWO through a research fellowship. G.F. is the recipient of a post-doctoral mandate from the Klinsche Onderzoek en OpleidingsRaad (KOOR) of the University Hospitals Leuven. The METABRIC project was funded by Cancer Research UK, the British Columbia Cancer Foundation, and Canadian Breast Cancer Foundation BC/Yukon. The project also received support from the University of Cambridge, Hutchinson Whampoa, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, the Centre for Translational Genomics (CTAG) Vancouver, and the BCCA Breast Cancer Outcomes Unit. The ICGC-BRCA project has been funded through the ICGC Breast Cancer Working Group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006; the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z) and the HER2+ project funded by Institut National du Cancer (INCa) in France (Grants N° 226-2009, 02-2011, 41-2012, 144-2008, 06-2012). The ICGC Asian Breast Cancer Project was funded through a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111218-SC01). The MINDACT trial has received grants from the European Commission Framework Programme VI (FP6-LSHC-CT-2004-503426), the Breast Cancer Research Foundation, Novartis, F. Hoffman La Roche, Sanofi-Aventis, the National Cancer Institute (NCI), the EBCC-Breast Cancer Working Group (BCWG grant for the MINDACT biobank), the Jacqueline Seroussi Memorial Foundation (2006 JSMF award), Prix Mois du Cancer du Sein (2004 award), Susan G. Komen for the Cure (SG05-0922-02), Fondation Belge Contre le Cancer (SCIE 2005-27), Dutch Cancer Society (KWF), Association Le Cancer du Sein, Parlons-en!, Deutsche Krebshilfe, the Grant Simpson Trust and Cancer Research UK. This trial was also supported by the EORTC Cancer Research Fund. Whole genome analysis was provided in kind by Agendia. The BioKey study was supported by an MSD grant to A.S., by Fonds Nadine De Beauffort to A.S., by a ‘Kom op Tegen Kanker’ to A.S. and H.W., by the Stichting Tegen Kanker and the Flemish Fund for Scientific Research (FWO; project G0B6120N) Belgium, by Agilent Technologies (Thought Leader award) to D.L. This VIB Grand Challenges project also received support from the Flemish Government under Management Agreement 2017–2021 (VR 2016 2312 doc.1521/4), from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 847912 (RESCUER) and from KU Leuven grant (C14/18/092) Symbiosys3. We are grateful to all women who participated and donated tissue in all studies used in this project and their families; all the investigators, surgeons, pathologists, and research nurses; and finally our close collaborators for their help in the data collection process and the collaboration on the scientific work.

PY - 2023

Y1 - 2023

N2 - Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients’ body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

AB - Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients’ body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

KW - Breast cancer

KW - Cancer genomics

KW - Tumour heterogeneity

UR - https://www.scopus.com/pages/publications/85165361124

U2 - 10.1038/s41467-023-39996-z

DO - 10.1038/s41467-023-39996-z

M3 - Article

C2 - 37479706

AN - SCOPUS:85165361124

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 4418

ER -

Obesity-associated changes in molecular biology of primary breast cancer

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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