Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC
Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC
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DOI：
10.1158/0008-5472.can-18-3388
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发表时间：
2019-11-01
期刊：
影响因子：
11.2
通讯作者：
Vens, Conchita
中科院分区：
文献类型：
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作者：
Essers, Paul B. M.;van der Heijden, Martijn;Vens, Conchita
头颈部鳞状细胞癌（HNSCC）的特点是频繁表现为DNA交联修复缺陷。我们建立了新的基于表达的DNA修复缺陷标记物，以确定此类修复缺陷的临床影响。使用对DNA交联剂丝裂霉素C和奥拉帕尼的超敏反应作为一组25个HNSCC细胞系中功能性DNA修复缺陷的代理，我们应用机器学习来定义预测修复缺陷的基因表达模型。在两个独立的数据集中，建立的表达谱预测了对DNA损伤剂的超敏反应，并与交联修复基因的突变以及DNA损伤反应和修复基因的下调相关。在两个回顾性队列中评估了修复缺陷预测特征的预后价值，共180例晚期HPV阴性HNSCC患者接受了基于顺铂的放化疗。DNA修复缺陷，如预测的配置文件，与不良的结果，在两个患者队列。在含氧量正常的肿瘤样本中，预后不良的相关性特别强，并与远处转移的风险增加有关。在体外，只有交联修复缺陷型HNSCC细胞系具有高度迁移性和侵袭性。这种表型也可以通过抑制具有修复能力的rad 51而在细胞中诱导，并且通过DNA-PK抑制而降低。总之，DNA交联修复预测表达谱揭示了HNSCC.Significance预后不良的关联：本研究采用创新的基于机器学习的方法来推导模型，预测DNA修复缺陷对HNSCC治疗结果的影响。
Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents, mitomycin C and olaparib, as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA-damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 patients with advanced HPV-negative HNSCC, who were treated with cisplatin-based chemoradiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair-defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC.Significance: This study uses innovative machine learning-based approaches to derive models that predict the effect of DNA repair defects on treatment outcome in HNSCC.