Radiotherapy and cisplatin-based chemotherapy belong to the main treatment modalities for head and neck squamous cell carcinoma (HNSCC) and induce cancer cell death by generating DNA damage, including the most severe double-strand breaks (DSBs). Alterations in DSB response and repair genes may affect individual DNA repair capacity and treatment sensitivity, contributing to the therapy resistance and poor prognosis often observed in HNSCC. In this study, we investigated the association of a panel of single-nucleotide polymorphisms (SNPs) in 20 DSB signaling and repair genes with therapy results and prognosis in 505 HNSCC patients treated non-surgically with DNA damage-inducing therapies. In the multivariate analysis, there were a total of 14 variants associated with overall, locoregional recurrence-free or metastasis-free survival. Moreover, we identified 10 of these SNPs as independent predictors of therapy failure and unfavorable prognosis in the whole group or in two treatment subgroups. These wereMRE11rs2155209,XRCC5rs828907,RAD51rs1801321, rs12593359,LIG4rs1805388,CHEK1rs558351,TP53rs1042522,ATMrs1801516,XRCC6rs2267437 andNBNrs2735383. OnlyCHEK1rs558351 remained statistically significant after correcting for multiple testing. These results suggest that specific germline variants related to DSB response and repair may be potential genetic modifiers of therapy effects and disease progression in HNSCC treated with radiotherapy and cisplatin-based chemoradiation.
放疗和以顺铂为基础的化疗是头颈部鳞状细胞癌的主要治疗手段，通过诱导DNA损伤（包括最严重的DNA双链断裂）来引发癌细胞死亡。DSB反应与修复基因的改变可能影响个体DNA修复能力及治疗敏感性，这常与HNSCC患者出现的治疗抵抗和不良预后相关。本研究在505例接受非手术DNA损伤诱导治疗的HNSCC患者中，探讨了20个DSB信号与修复基因中的单核苷酸多态性与治疗效果及预后的关联。多变量分析显示，共有14个变异位点与总生存期、局部无复发生存期或无转移生存期相关。其中，我们在全组或两个治疗亚组中确定了10个SNPs作为治疗失败和不良预后的独立预测因子，包括MRE11 rs2155209、XRCC5 rs828907、RAD51 rs1801321、rs12593359、LIG4 rs1805388、CHEK1 rs558351、TP53 rs1042522、ATM rs1801516、XRCC6 rs2267437和NBN rs2735383。经多重检验校正后，仅CHEK1 rs558351仍保持统计学显著性。这些结果表明，与DSB反应和修复相关的特定种系变异，可能是接受放疗及以顺铂为基础的放化疗的HNSCC患者治疗效果和疾病进展的潜在遗传修饰因子。
肿瘤(癌症)患者之家