Obesity-associated changes in molecular biology of primary breast cancer.
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.
Acknowledgements: 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.
European Commission Horizon 2020 (H2020) Societal Challenges (847912)