Fatigue is a common symptom of cancer patients, which can impair quality of life even years after treatment. Little is known about genetic determinants of fatigue, especially in prostate cancer (PCa). This study aims to identify SNPs associated with long-term fatigue in a prospective cohort of PCa patients. A genome-wide association study was conducted in non-metastatic PCa patients treated with radiotherapy in 7 European countries and the USA. A total of 1,381 men recorded fatigue using the EORTC QLQ-C30 and 877 men additionally completed the Multidimensional Fatigue Inventory (MFI) up to two years post-radiotherapy. Clinically important fatigue is defined for the EORTC QLQ-C30 based on the proposed threshold as scores ≥39 and for the MFI as scores ≥75th percentile in the general German male population aged ≥60 years. Regression models adjusted for demographic, disease- and treatment-specific characteristics examine SNPs associated with clinically important fatigue. Differential gene expressions are explored using expression quantitative trait analysis. rs142212041 located in the ACTR3/CBWD2 gene region is significantly associated (P = 3×10-8) with long-term physical fatigue in 643 men without physical fatigue pre-radiotherapy. Several potential risk loci (P < 5×10-6) are identified for distinct fatigue phenotypes. Gene expression differences are observed for ACTR3 and CBWD2, although not significant after correction for multiple testing. The results emphasise the multidimensionality of fatigue and suggest a plausible biological mechanism in fatigue pathophysiology, previously discussed for myalgic encephalomyelitis/chronic fatigue syndrome, which might be a potential intervention target.
Nature communications. 2026 Apr 22*** epublish ***
Philipp Heumann, Miguel E Aguado-Barrera, Harkeran K Jandu, David Azria, Erik Briers, Renée Bultijnck, Jenny Chang-Claude, Ananya Choudhury, Alison M Dunning, Laura Fachal, Olivia Fuentes-Ríos, Antonio Gómez-Caamaño, Sara Gutiérrez-Enríquez, Rudolf Kaaks, Sarah L Kerns, Maarten Lambrecht, Juan Camilo Rosas Romero, Barry S Rosenstein, Dirk De Ruysscher, Martina E Schmidt, Elena Sperk, Hilary Stobart, R Paul Symonds, Liv Veldeman, Marlon R Veldwijk, Tim Ward, Adam Webb, Catharine M L West, Tiziana Rancati, Tim Rattay, Ana Vega, REQUITE Consortium , Christopher J Talbot, Petra Seibold
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Instituto de Investigación Sanitaria De Santiago de Compostela, Santiago de Compostela, Spain., University of Leicester, Leicester, United Kingdom., Fédération Universitaire d'Oncologie Radiothérapie d'Occitanie Méditerranée, ICM, Univ Montpellier INSERM U1194 IRCM, Montpellier, France., Ghent University, Department of Human Structure and Repair, Ghent, Belgium., University of Manchester, Christie Hospital NHS Foundation Trust, Manchester, United Kingdom., University of Cambridge, Cambridge, United Kingdom., Wellcome Sanger Institute, Hinxton, United Kingdom., Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Santiago de Compostela, Spain., Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., Medical College of Wisconsin, Milwaukee, USA., University Hospital Leuven, Leuven, Belgium., Icahn School of Medicine at Mount Sinai, New York, USA., MAASTRO Clinic, Maastricht, Netherlands., Division of Physical Activity, Cancer Prevention and Survivorship, German Cancer Research Center (DKFZ), Heidelberg, Germany., Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Ghent University Hospital, Ghent, Belgium., Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. .