The influence of genetic variation on late effects in childhood cancer survivors: An updated systematic review

Introduction Variation in the prevalence and severity of late effects in similarly treated childhood cancer survivors suggests a role for genetic susceptibility. We aimed to provide an overview of genetic factors associated with selected late effects after childhood cancer, including metabolic syndrome, gonadal insufficiency, hearing impairment, and musculoskeletal impairment. Methods A systematic literature search in Medline, Embase, Web of Science, and Cochrane was performed in April 2025. Articles describing ≥ 50 survivors diagnosed with cancer ≤ 21 years of age and reporting on genetic variants associated with one of the selected late effects (present after the end of treatment and onwards) were included. Results From the 4609 unique articles, 60 articles were included (n = 12 on metabolic syndrome (or its components), n = 7 on gonadal insufficiency, n = 26 on hearing impairment, n = 12 on musculoskeletal impairment). Eighty-five variants were significantly associated with one of the selected late effects by ≥ 1 study. One out of twenty variants studied in multiple candidate gene investigations remained significant in meta-analysis (rs4646316/ COMT). Five out of six studies including a polygenic risk score showed improved performance when genetic factors were added to clinical models. There was a high heterogeneity in the quality of reporting according to the STREGA tool. Conclusion Substantial uncertainty remains within the evidence of genetic factors for the selected late effects after childhood cancer. International collaborations, methodological and reporting harmonization, and prioritization of replication and functional validation should help future research to be more consistent, create more robust findings, and bridge the gap between research and clinical practice.