Understanding the genetic basis of radiotherapy toxicity

<p dir="ltr">Breast cancer survival rates are increasing, yet a significant number of patients may experience long-term side-effects from treatment. Radiotherapy is an important treatment for breast cancer and significantly reduces recurrence and improves survival. However, radiotherapy side-effects (toxicity) can impact the quality of life of breast cancer survivors. While factors such as patient age, smoking history, concurrent treatments, and comorbidities are known to influence the risk of radiation toxicity, a large proportion of variation between individuals in their reaction to radiotherapy remains unexplained after accounting for these factors. There is a general consensus that genetic factors may play a role in explaining the remaining unexplained interindividual variation in radiotoxicity. The International REQUITE prospective cohort study enrolled 2,059 breast cancer patients, undergoing radiotherapy at 27 centres in eight countries. Using data from REQUITE, a genome-wide association study (GWAS) was conducted to identify genetic variants associated with clinician-reported toxicity, two years following breast radiotherapy. SNPs associated with 2-year toxicity included the rs643644 variant in the PAX7 gene and the rs11345494 SNP in the ATXN7L1 gene with arm lymphoedema. For telangiectasia, the SNP rs12443861 was identified and linked to the ANKS4B and CRYM genes. A meta-analysis combining data from REQUITE cohort with the external RAPPER cohort confirmed the association of variants in the ATXN7L1 gene with arm oedema. Additionally, SNPs associated with the CCDC25 gene reached genome wide significance for telangiectasia. The metaanalysis also identified novel loci linked to breast oedema on chromosome 10 and 22, with peak SNPs rs34713215 and rs118114482, respectively; however, neither of these peak SNPs reached genome-wide significance. A separate GWAS of patient reported outcomes in the same cohort revealed two SNPs that reached genome-wide significance for breast symptoms: rs62260112 near the RAP1BP2 gene and 3:103747944:CT:C. A separate study demonstrated that a polygenic risk score (PRS) for breast cancer susceptibility does not significantly predict radiotherapy toxicity, suggesting that common breast cancer genetic risk variants have limited clinical relevance in modelling radiotherapy toxicity risk. The radiation-induced lymphocyte apoptosis (RILA) assay is a potential biological predictor of radiotherapy toxicity; however, the underlying mechanism remains unclear. To investigate the genetic determinants, a GWAS was conducted. Notable findings highlight potential roles for the BLMH gene in skin inflammation and wound healing, and CDCA4 in cell proliferation and apoptosis. Across the different REQUITE GWAS, overlaps were observed between the previously reported acute toxicity endpoints, ulceration and desquamation, with a cluster of SNPs on chromosome 9 associated with the PTPN3 gene, reaching genome-wide significance. This connection was expected due to the similarity of these endpoints. Additionally, overlaps between breast symptoms and pain were identified, involving SNPs on chromosome 4 and 7. While several plausible genes associated with these SNP clusters were identified, further work is needed to validate these findings and their implications for personalised radiotherapy in breast cancer patients. Lastly, shared genetic factors between idiopathic pulmonary fibrosis (IPF) and REQUITE radiotoxicity were investigated by cross referencing the IPF, DEMISTIFI and REQUITE datasets. Key findings revealed the shared genetic variant rs36022026 associated with the ROBO1 gene, linked with REQUITE arm lymphoedema and IPF survival, as well as rs112610615, associated with REQUITE induration G2 and lung fibrosis. These results contribute to a growing body of evidence supporting the genetic basis of radiation toxicity. These findings have the potential to inform the development of predictive models and personalised treatment plans to minimize adverse effects while optimising therapeutic benefits for breast cancer survivors.</p>