Risk of radiation-induced fibrosis is associated with transcriptional response in irradiated subcutaneous fibroblasts from breast cancer patients Free

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Aim: To verify that radiation-induced transcriptional profiles in subcutaneous fibroblasts from breast cancer patients correlate with risk of radiation-induced fibrosis (RIF), a common long-term adverse effect of ionizing radiotherapy. Materials and methods: We have recently identified a genetic signature from irradiated fibroblasts which correlates with risk of RIF (Rødningen et al, submitted). An update of this signature is verified by real-time PCR in an extended and independent version of 27 patients from the cohort of breast cancer patients treated with post-mastectomy radiotherapy between 1978 and 1982. Results: A set of genes involved in cellular processes like extracellular matrix remodelling, cell adhesion, proliferation and ROS scavenging is differentially expressed in irradiated fibroblast (3 x 3.5 Gy / 2 days) from breast cancer patients and can identify a subset of patients with reduced risk of RIF. Dose-response curves for subcutaneous fibrosis generated for the identified two groups of patients demonstrate an enhancement ratio of 1.25 (1.12-1.40) for risk of RIF. Pathway analysis show that the classifier genes are primarily downstream of TGFβ1, TNFα, and p53. Only minor differences in transcriptional profiles are observed in unirradiated fibroblasts, and these do not correlate with risk of RIF. Conclusions: Knowledge about the underlying biological mechanisms of RIF is important in order to improve ionizing radiotherapy. Although the classifier itself may not be utilized as a predictive assay, it provides valuable new insight into the molecular mechanisms of RIF and identifies candidate genes for association studies between germline variations and risk of RIF.