Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Clin Cancer Res. 2011 Apr 1;17(7):2035-43. doi: 10.1158/1078-0432.CCR-10-2641. Epub 2011 Feb 24.
Radiotherapy plays an integral role in the treatment of head and neck squamous cell carcinoma (HNSCC). Although proteins involved in DNA repair may predict HNSCC response to radiotherapy, none has been validated in this context. We examined whether differential expression of double-strand DNA break (DSB) repair proteins in HNSCC, the chief mediators of DNA repair following irradiation, predict for treatment outcomes.
Archival HNSCC tumor specimens (n = 89) were assembled onto a tissue microarray and stained with antibodies raised against 38 biomarkers. The biomarker set was enriched for proteins involved in DSB repair, in addition to established mechanistic markers of radioresistance. Staining was correlated with treatment response and survival alongside established clinical and pathologic covariates. Results were validated in an independent intramural cohort (n = 34).
Ku80, a key mediator of DSB repair, correlated most closely with clinical outcomes. Ku80 was overexpressed in half of all tumors, and its expression was independent of all other covariates examined. Ku80 overexpression was an independent predictor for both locoregional failure and mortality following radiotherapy (P < 0.01). The predictive power of Ku80 overexpression was confined largely to HPV-negative HNSCC, where it conferred a nine-fold greater risk of death at two years.
Ku80 overexpression is a common feature of HNSCC, and is a candidate DNA repair-related biomarker for radiation treatment failure and death, particularly in patients with high-risk HPV-negative disease. It is a promising, mechanistically rational biomarker to select individual HPV-negative HNSCC patients for strategies to intensify treatment.
放射疗法在头颈部鳞状细胞癌（HNSCC）的治疗中起着不可或缺的作用。尽管涉及 DNA 修复的蛋白质可能预测 HNSCC 对放射治疗的反应，但在这种情况下尚未得到验证。我们研究了 HNSCC 中双链 DNA 断裂（DSB）修复蛋白的差异表达是否可以预测治疗结果，这些蛋白是照射后 DNA 修复的主要介质。
收集了 89 例 HNSCC 肿瘤标本，并将其组装成组织微阵列，并用针对 38 种生物标志物的抗体进行染色。除了确定的放射抗性机制标志物外，生物标志物集还富集了参与 DSB 修复的蛋白质。将染色与治疗反应和生存以及既定的临床和病理协变量相关联。在一个独立的院内队列（n = 34）中验证了结果。
DSB 修复的关键介质 Ku80 与临床结果最密切相关。在所有肿瘤中，有一半以上的肿瘤过度表达 Ku80，其表达与所有其他检查的协变量无关。Ku80 过表达是放疗后局部区域失败和死亡的独立预测因子（P <0.01）。Ku80 过表达的预测能力主要局限于 HPV 阴性 HNSCC，其中两年内死亡的风险增加了九倍。
Ku80 过表达是 HNSCC 的常见特征，是与放射治疗失败和死亡相关的 DNA 修复相关生物标志物的候选者，尤其是在高危 HPV 阴性疾病的患者中。它是一种很有前途的、具有机制合理性的生物标志物，可以选择 HPV 阴性 HNSCC 患者进行强化治疗的策略。
