Pavón Miguel Angel, Parreño Matilde, León Xavier, Sancho Francesc J, Céspedes Maria Virtudes, Casanova Isolda, Lopez-Pousa Antonio, Mangues Maria Antonia, Quer Miquel, Barnadas Agustí, Mangues Ramón
Grup d'Oncogènesi i Antitumorals, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER) and Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Int J Cancer. 2008 Sep 1;123(5):1068-79. doi: 10.1002/ijc.23635.
5-Fluorouracil and cisplatin-based induction chemotherapy (IC) is commonly used to treat locally advanced head and neck squamous cell carcinoma (HNSCC). The role of nonhomologous end joining (NHEJ) genes (Ku70, Ku80 and DNA-PKcs) in double-strand break (DSB) repair, genomic instability and apoptosis suggest a possible impact on tumor response to radiotherapy, 5-fluorouracil or cisplatin, as these agents are direct or indirect inductors of DSBs. We evaluated the relationship between Ku80, Ku70 or DNA PKcs mRNA expression in pretreatment tumor biopsies, and tumor response to IC or local recurrence, in 50 patients with HNSCC. Additionally, in an independent cohort of 75 patients with HNSCC, we evaluated the relationship between tumor Ku70 protein expression and the same clinical outcomes or patient survival. Tumors in the responder group had significantly higher mRNA levels for Ku70, Ku80 and DNA-PKcs than those in the nonresponder group. Ku70 mRNA was the marker most significantly associated with response to IC. Moreover, high tumor Ku70 mRNA expression was associated with significantly longer local recurrence-free survival (LRFS). Ku70 protein expression was also significantly related to response, and patients with higher percentage of tumor cells expressing Ku70 had longer LRFS. In addition, the percentage of Ku70 positive cells, tumor localization and node involvement were significantly associated with overall survival of patient. Therefore, Ku70 expression is a candidate predictive marker that could distinguish patients who are likely to benefit from chemoradiotherapy or radiotherapy after the induction chemotherapy treatment, suggesting a contribution of the NHEJ system in HNSCC clinical outcome.
基于5-氟尿嘧啶和顺铂的诱导化疗（IC）常用于治疗局部晚期头颈部鳞状细胞癌（HNSCC）。非同源末端连接（NHEJ）基因（Ku70、Ku80和DNA-PKcs）在双链断裂（DSB）修复、基因组不稳定和细胞凋亡中的作用表明，其可能对肿瘤对放疗、5-氟尿嘧啶或顺铂的反应产生影响，因为这些药物是DSB的直接或间接诱导剂。我们评估了50例HNSCC患者治疗前肿瘤活检中Ku80、Ku70或DNA PKcs mRNA表达与肿瘤对IC的反应或局部复发之间的关系。此外，在一个由75例HNSCC患者组成的独立队列中，我们评估了肿瘤Ku70蛋白表达与相同临床结果或患者生存率之间的关系。反应组肿瘤中Ku70、Ku80和DNA-PKcs的mRNA水平显著高于无反应组。Ku70 mRNA是与IC反应最显著相关的标志物。此外，高肿瘤Ku70 mRNA表达与显著更长的无局部复发生存期（LRFS）相关。Ku70蛋白表达也与反应显著相关，肿瘤细胞表达Ku70百分比更高的患者LRFS更长。此外，Ku70阳性细胞百分比、肿瘤定位和淋巴结受累与患者的总生存率显著相关。因此，Ku70表达是一种候选预测标志物，可区分可能从诱导化疗后的放化疗或放疗中获益的患者，提示NHEJ系统对HNSCC临床结果有贡献。
