Purpose: Genetic variations in DNA damage repair (DDR) genes may influence radiation therapy (RT)–induced acute normal tissue toxicity in patients with breast cancer. Identifying an individual or multiple single-nucleotide polymorphisms (SNPs) associated with RT–induced early adverse skin reactions (EASR) is critical for precision medicine in radiation oncology. Methods and Materials: At the completion of RT, EASR was assessed using the Oncology Nursing Society scale (0-6) in 416 patients with breast cancer, and Oncology Nursing Society score ≥4 was considered RT-induced EASR. PLINK set-based tests and subsequent individual SNP association analyses were conducted to identify genes and SNPs associated with EASR among the 53 DDR genes and 1968 SNPs. A weighted polygenic risk score (PRS) model was constructed to ascertain the association between the joint effect of risk alleles and EASR. Results: The study population consisted of 264 Hispanic whites, 86 blacks or African Americans, 55 non-Hispanic whites, and 11 others. A total of 115 patients (27.6%) developed EASR. Five genes (ATM, CHEK1, ERCC2, RAD51C, and TGFB1) were significantly associated with RT-induced EASR. Nine SNPs within these 5 genes were further identified: ATM rs61915066, CHEK1 rs11220184, RAD51C rs302877, rs405684, TBFB1 rs4803455, rs2241714, and ERCC2 rs60152947, rs10404465, rs1799786. In a multivariable-adjusted PRS model, patients in a higher quartile of PRS were more likely to develop EASR compared with patients in the lowest quartile (ORq2 vs.q1 = 1.94, 95% CI, 0.86-4.39; ORq3 vs.q1 = 3.46, 95% CI, 1.57-7.63; ORq4 vs.q1 = 8.64, 95% CI, 3.92-19.02; and Ptrend < .0001). Conclusions: We newly identified the associations between 9 SNPs in ATM, CHEK1, RAD51C, TGFB1, and ERCC2 and RT-induced EASR. PRS modeling showed its potential in identifying populations at risk. Multiple SNPs in DDR genes may jointly contribute to interindividual variation in RT-induced EASR. Validation in an independent external cohort is required to determine the clinical significance of these predictive biomarkers.
|Original language||English (US)|
|Journal||International Journal of Radiation Oncology Biology Physics|
|State||Accepted/In press - Jan 1 2020|
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging
- Cancer Research