Department of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Radiat Oncol. 2024 Oct 30;19(1):150. doi: 10.1186/s13014-024-02541-3.
Head and neck squamous cell carcinoma (HNSCC) negative for Human Papillomavirus (HPV) has remained a difficult to treat entity, whereas tumors positive for HPV are characterized by radiosensitivity and favorable patient outcome. On the cellular level, radiosensitivity is largely governed by the tumor cells` ability to repair radiation-induced DNA double-strand breaks (DSBs), but no biomarker is established that could guide clinical decision making. Therefore, we tested the impact of the expression levels of ATM, the central kinase of the DNA damage response as well as DNA-PKcs and Ku80, two major factors in the main DSB repair pathway non-homologous end joining (NHEJ).
A tissue microarray of a single center HNSCC cohort was stained for ATM, DNA-PKcs and Ku80 and the expression scored based on staining intensity and the percentages of tumor cells stained. Scores were correlated with clinicopathological parameters and survival.
Samples from 427 HNSCC patients yielded interpretable stainings and were scored following an established algorithm. The majority of tumors showed strong expression of both NHEJ factors, whereas the expression of ATM varied more. The expression scores of ATM and DNA-PKcs were not associated with patient survival. For HPV-negative HNSCC, the minority of tumors without strong Ku80 expression trended towards superior survival when treatment included radiotherapy. Focusing stronger on staining intensity to define the subgroup with lowest and therefore potentially insufficient expression levels in the HPV-negative subgroup, we observed significantly better overall survival for patients treated with radiotherapy but not with surgery alone.
Our data suggest that HPV-negative HNSCC with particularly low Ku80 expression represent a highly radiosensitive subpopulation. Confirmation in independent cohorts is required.
人乳头瘤病毒（HPV）阴性的头颈部鳞状细胞癌（HNSCC）仍然是一种难以治疗的疾病，而 HPV 阳性的肿瘤则以放射敏感性和患者预后良好为特征。在细胞水平上，放射敏感性在很大程度上取决于肿瘤细胞修复辐射诱导的 DNA 双链断裂（DSB）的能力，但没有建立可以指导临床决策的生物标志物。因此，我们测试了 ATM 的表达水平对放射敏感性的影响，ATM 是 DNA 损伤反应的核心激酶，以及 DNA-PKcs 和 Ku80，这两种非同源末端连接（NHEJ）主要 DSB 修复途径中的主要因素。
对一个单中心 HNSCC 队列的组织微阵列进行 ATM、DNA-PKcs 和 Ku80 的染色，并根据染色强度和染色的肿瘤细胞百分比对评分进行评分。评分与临床病理参数和生存相关。
来自 427 例 HNSCC 患者的样本可进行可解释的染色，并按照既定算法进行评分。大多数肿瘤显示出两种 NHEJ 因子的强表达，而 ATM 的表达则更为多样化。ATM 和 DNA-PKcs 的表达评分与患者的生存无关。对于 HPV 阴性的 HNSCC，没有强烈 Ku80 表达的少数肿瘤在治疗包括放疗时趋向于更好的生存。通过更关注染色强度来定义 HPV 阴性亚组中表达水平最低且可能不足的亚组，我们观察到接受放疗但单独接受手术治疗的患者的总生存率显著提高。
我们的数据表明，HPV 阴性的 HNSCC 中特别低的 Ku80 表达代表了一个高度放射敏感的亚群。需要在独立的队列中进行确认。
