Genetic Polymorphisms Influencing Cardiotoxicity in Osteosarcoma: Insights into Chemotherapy Response and Toxicity

Introduction Osteosarcoma (OS) known as the most common primary malignant tumor arising from bone which occurs most often in children and adolescence. ()The first-line treatment of OS is the combination of surgical and chemotherapy treatment with MAP regimen concluding high-dosage methotrexate, anthracycline (most frequency doxorubicin) and platinum (cisplatin). The predominant side effect of doxorubicin is cardiotoxicity (CTX), which manifests as heart failure (HF) and cardiomyopathy. As a result, identifying patients at high risk for CTX and detecting it early is critical for providing timely cardioprotective medication. We posited that pharmacogenomic profiling of osteosarcoma patients could enhance the adjustment of existing treatment regimens to improve outcomes and reduce the incidence of late effects. Method Several databases were systematically searched (۲۰۲۰-august ۲۰۲۳). Genetic association studies were included if they have reported the association between gene polymorphisms and adverse reactions to MAP regimen. Result The studies investigated genetic polymorphisms linked to cardiotoxicity in osteosarcoma patients undergoing chemotherapy, particularly focusing on doxorubicin-induced cardiac dysfunction. Several genes appeared across multiple studies, providing valuable insights into their role in modulating toxicity. In Windsor et al. (۲۰۱۱), polymorphisms in MTHFD۱ (c.۱۹۵۸G>A) and MTHFR (c.۱۲۹۸A>C) were linked to increased risks of anemia and recurrent chemotherapy toxicity. In the same way, ABCC۲ (۳۵۶۳T>A) variants increased the risk of leucopenia by ۵.۲ times. This shows how important drug efflux is in reducing toxicity. Sapkota et al. (۲۰۲۲) identified ABCC۲ as a key player in cardiotoxicity. The ABCC۲ (rs۳۷۴۰۰۶۶) variant was associated with lower ejection fraction, confirming the findings from Windsor’s study. Both studies highlight ABCC۲’s critical function in drug transport and efflux, with its polymorphisms consistently linked to increased toxicity risk. The KCNK۱۷ (rs۲۸۱۵۰۶۳-A) allele was also found to be significantly associated with a ۲.۹۷-fold increase in cardiac dysfunction risk, while SLC۲۲A۷ (rs۴۱۴۹۱۷۸-G) showed a protective role. Sági et al. (۲۰۱۸) also supported the significance of ABCC۲ and SLC۲۲A۶ in cardiotoxicity, as variants like ABCC۲ (rs۳۷۴۰۰۶۶) and SLC۲۲A۶ (rs۶۵۹۱۷۲۲) were tied to reduced heart function post-therapy. The NQO۱ (rs۱۰۴۳۴۷۰) variant in their study further confirmed its detrimental effect on heart performance. Fonoudi et al. (۲۰۲۴) used CRISPR/Cas۹ to demonstrate ABCC۲’s importance, where knockout models showed increased doxorubicin toxicity, aligning with findings from previous studies. CAT and CBR۱, crucial in oxidative stress handling, also emerged as key players in modulating cardiotoxicity. Lastly, Heemelaar et al. (۲۰۲۳) highlighted demographic factors, linking younger age and higher cumulative doses of doxorubicin with increased heart failure risk, though no genetic data were presented. Conclusion In conclusion, ABCC۲ consistently plays a crucial role in chemotherapy-induced cardiotoxicity across multiple studies. Personalized treatment approaches targeting this gene could significantly reduce long-term cardiac complications in osteosarcoma patients, improving overall outcomes.

کلیدواژه ها:

osteosarcoma ، cardiotoxicity ، pharmacogenetic ، genes ، side effect