Over the past decades, childhood cancer survival rates have increased significantly due to an enhanced understanding of cancer biology and subsequent improved stratification, treatment modalities, and supportive care strategies (Gatta et al., 2014). This expanding population of survivors experiences a lifelong increased risk of morbidity and mortality, secondary to their disease and young age at treatment (Erdmann et al., 2021, Bhakta et al., 2017). For instance, childhood cancer survivors (CCS) have been reported to have twice the burden of chronic diseases at the age of 45 years compared to the general population (Bhakta et al., 2017, Suh et al., 2020). The variability in the prevalence and severity of late effects among similarly treated CCS suggests that genetic susceptibility may contribute to their etiology (Gramatges and Bhatia, 2018, Clemens et al., 2018b).

Genetic susceptibility to various chronic diseases has been widely studied in the general population (Klarin et al., 2018, Estrada et al., 2012, Day et al., 2015). However, relevant genetic variants observed in the general population may not replicate in survivors who experience these same conditions due to cancer treatment-related changes, such as altered methylation patterns (Im et al., 2020). Additionally, potential interactions between specific genetic variants and cancer therapies (Daly, 2010, Lee et al., 2016) require treatment-specific analyses in this high-risk population. Thus, rather than assuming direct transferability from general population findings, dedicated studies in CCS are essential.

Understanding genetic susceptibility of late effects after childhood cancer treatment can facilitate early identification and management of survivors at risk. Moreover, it can inform future dose-reduction trials, support the use of alternative treatment options (where possible), and reveal new biological insights into the mechanisms driving interindividual variability of late effects. Some genetic variants exhibit substantial effect sizes, such as TPMT variant alleles, which are associated with early toxicity through their influence on thiopurine metabolism (Relling et al., 2019). However, most late effects are complex diseases and appear to be polygenic in nature, with an aggregated effect of hundreds or thousands of variants with small effect sizes, as observed for traits like body mass index (BMI) (Sapkota et al., 2022, Yengo et al., 2018). Therefore, the increase of candidate gene studies and genome-wide association studies (GWASs) exploring associations between genetic variants (i.e., single-nucleotide polymorphisms, SNPs) and late effects after childhood cancer has been accompanied by a growing interest in incorporating polygenic risk scores (PRSs, also referred to as genetic risk scores) into clinical prediction models, all aiming to further improve personalized risk stratification of treatment and follow-up.

As the latest overview of genetic susceptibility of selected late effects in CCS was published in 2018 (Clemens et al., 2018a), we conducted an updated systematic literature review to summarize the findings and assess the quality of currently available studies on genetic susceptibility factors associated with selected late effects of childhood cancer (i.e., metabolic syndrome (components), gonadal insufficiency, hearing impairment, and musculoskeletal impairment). Our goal was to identify novel directions for translation to clinical practice, as well as knowledge gaps to prioritize for further research.