BACKGROUND Germ cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines. METHODS Two hundred seven GCT patients' specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients' specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines. RESULTS GCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio = 0.38, 95% confidence interval: 0.12-1.23, p = 0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines. CONCLUSIONS XPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.

中文翻译：

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XPA水平升高可能是生殖细胞肿瘤对顺铂耐药的基础。

背景技术生殖细胞肿瘤（GCT）代表高度可治愈的恶性肿瘤，因为它们对基于顺铂（CDDP）的化疗反应良好。然而，一小部分GCT患者复发或对治疗无反应。由于这可能是由于修复CDDP引起的DNA损伤的能力增强所致，因此鉴定预测对CDDP反应不充分或异常的DNA修复生物标记物，以及因此对GCT患者的不良预后提出了挑战。这项研究的目的是检查GCT患者和细胞系中关键核苷酸切除修复（NER）因子XPA，ERCC1和XPF的表达水平。方法收集了277例GCT患者的标本，这些标本具有足够的随访临床病理资料，以及成对结合的对CDDP耐药和敏感的GCT细胞系。免疫组织化学检测GCT患者标本中ERCC1，XPF和XPA的蛋白表达水平，Western blot和qRT-PCR检测GCT细胞株中蛋白和mRNA表达水平。结果XPA低表达的GCT患者总生存率明显高于高表达的患者（危险比= 0.38，95％置信区间：0.12-1.23，p = 0.0228）。此外，在非精原细胞学亚型，IGCCCG预后不良组，S期增加以及肺，肝和非肺脏内脏转移的存在下，XPAA表达增加。重要的是，在GCT细胞系中也发现了在GCT患者中发现的CDDP反应不足或异常与XPA表达之间的相关性。结论XPA表达是用于GCT分层的另一种独立的预后生物标志物，可以改善难治性或复发性高风险患者的治疗决策。此外，它可能代表GCT中的新型治疗靶标。