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.

中文翻译：

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DNA损伤修复基因的多态性与放射治疗在乳腺癌人群中引起的早期不良皮肤反应之间的关联：一种多基因风险评分方法。

目的DNA损伤修复（DDR）基因的遗传变异可能会影响放射治疗（RT）诱导的乳腺癌患者的急性正常组织毒性。鉴定与RT引起的早期不良皮肤反应（EASR）相关的单个或多个单核苷酸多态性（SNP）对于放射肿瘤学中的精密医学至关重要。方法和材料在RT结束时，使用肿瘤护理学会量表（0-6）对416例乳腺癌患者进行EASR评估，并且肿瘤护理学会评分≥4被认为是RT诱导的EASR。进行了基于PLINK集的测试以及随后的各个SNP关联分析，以识别53个DDR基因和1968个SNP中与EASR相关的基因和SNP。建立了加权多基因风险评分（PRS）模型，以确定风险等位基因与EASR的联合作用之间的关联。结果研究人群包括264名西班牙裔白人，86名黑人或非裔美国人，55名非西班牙裔白人和11名其他人。共有115名患者（27.6％）患上了EASR。五个基因（ATM，CHEK1，ERCC2，RAD51C和TGFB1）与RT诱导的EASR显着相关。进一步鉴定了这5个基因中的9个SNP：ATM rs61915066，CHEK1 rs11220184，RAD51C rs302877，rs405684，TBFB1 rs4803455，rs2241714和ERCC2 rs60152947，rs10404465，rs1799786。在多变量调整的PRS模型中，与最低四分位数的患者相比，较高四分位数的PRS患者更有可能发展EASR（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；和Ptrend <.0001）。结论我们新发现了ATM，CHEK1，RAD51C，TGFB1和ERCC2中的9个SNP与RT诱导的EASR之间的关联。PRS建模显示了其在识别高危人群中的潜力。DDR基因中的多个SNP可能共同导致RT诱导的EASR个体间变异。需要进行独立外部队列验证以确定这些预测性生物标志物的临床意义。