Genetic Variations in TGFβ1, tPA, and ACE and Radiation-Induced Thoracic Toxicities in Patients with Non–Small-Cell Lung Cancer

IntroductionWe hypothesized that radiation-induced thoracic toxicity (RITT) of the lung, esophagus and pericardium share a similar mechanism, and aimed to examine whether genetic variation of transforming growth factor–beta1 (TGFβ1), tissue plasminogen activator (tPA) and angiotensin converting enzyme (ACE), are associated with RITT in patients with non–small-cell lung cancer (NSCLC).MethodsPatients with stage I–III NSCLC were enrolled and received radiotherapy (RT). Blood samples were obtained pre-RT and at 4 to 5 weeks during RT, and plasma TGF-β1 was measured using an enzyme-linked immunosorbent assay. The DNA samples extracted from blood pre-RT were analyzed for the following frequent genetic variations: TGFβ1 509C/T, tPA -7351 C/T, and ACE I/D. RITT score was defined as the sum of radiation-induced toxicity grades in esophagus, lung, and pericardium.ResultsSeventy-six NSCLC patients receiving definitive RT were enrolled. Patients with TGFβ1 509CC had higher mean grade of esophagitis (1.4 ± 0.2 versus 0.8 ± 0.2, p = 0.019) and RITT score (2.6 ± 0.3 versus 1.6 ± 0.3, p = 0.009) than T allele carriers. Although no significant relationship was observed between RITT and the tPA or ACE variants individually, patients with any high-risk alleles (tPA CC or ACE D or TGFβ1 509CC) had significantly higher grade of developing combined RITT (p < 0.001). Patients with TGFβ1 509CC had greater increase of plasma TGF β1 levels at 4 to 5 weeks during RT than T allele carriers did (CC 1.2 ± 0.2 versus T 0.7 ± 0.1, p = 0.047).ConclusionThis exploratory study demonstrated that sensitivity of radiation toxicity may be determined by genomic factors associated with TGFβ1 and genes involved in TGFβ1 pathway