DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients

Simple Summary Head and neck cancer (HNC) is characterized by radio- and chemoresistance contributing to treatment failure and poor prognosis. There is evidence that a common inherited variation related to DNA damage signaling and repair may modulate individual DNA repair capacity and the results of anticancer treatment. This study evaluated the impact of a panel of single-nucleotide polymorphisms in key genes involved in DNA double-strand break response and repair on three clinical endpoints in HNC patients undergoing radiotherapy and cisplatin-based chemoradiotherapy. We identified variants independently associated with therapy outcome and disease progression. Our findings suggest that these germline variants may be potential biomarkers to be used together with conventional clinical factors for better risk stratification in HNC patients receiving DNA-damaging therapy, which may provide a basis for future treatment modifications.Abstract 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 were MRE11 rs2155209, XRCC5 rs828907, RAD51 rs1801321, rs12593359, LIG4 rs1805388, CHEK1 rs558351, TP53 rs1042522, ATM rs1801516, XRCC6 rs2267437 and NBN rs2735383. Only CHEK1 rs558351 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.