Phenotypic risk factors linked to acute radiation-induced toxicities: a phenome-wide Mendelian randomization study of 12,042 cancer patients.

Abstract

Objective: This study aims to systematically evaluate phenome-wide clinical factors contributing to radiation-induced toxicities (RITs) and provide evidence to identify acute RITs-associated risk factors for personalized radiation treatment stratification.

Methods: Leveraging genome-wide association study data from 12,042 patients with prostate, head and neck, breast, or lung cancer, we conducted MR-PheWAS (phenome-wide association study integrated with Mendelian randomization) to evaluate the impact of 22,872 phenotypic traits on the susceptibility to acute RITs.

Results: MR-PheWAS pinpointed diverse acute RITs-associated phenotypic traits, including previously noted and novel ones. Proteins related to infection and immunity, like C-reactive protein and Interleukin-4 receptor alpha, were found to augment the risk of acute RITs, whereas growth differentiation factor 15, fibroblast growth factor-2 and Interleukin-16 seemingly reduce it. Notably, systolic/diastolic blood pressure, and lipoprotein or cholesterol levels could elevate the risk, but fatty acids, lipids and body mass index-adjusted leptin levels offered protection. Real-world validation in 1,078 breast cancer patients who underwent radiotherapy in our department showed that red blood cell count (lowering risk), serum urea and uric acid levels (increasing risk) before radiotherapy were linked to acute RITs. Moreover, we estimated the direct causal link between the associated traits and acute RITs through multivariate MR analyses, and unveiled that systemic lupus erythematosus, and high-density lipoprotein cholesterol levels remained significantly associated with acute RITs.

Conclusion: This study identified the phenome-wide risk factors linked to acute RITs, and future research was needed to clarify their underlying mechanisms for effective prevention of acute RITs.