Genetic determinants of fatigue up to 2 years after radiotherapy in prostate cancer patients
摘要
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.