背景:顺铂(CDDP)仍然是治疗肌肉浸润性膀胱癌(MIBC)的关键药物。然而,部分MIBC患者对化疗无反应,这可能是由于CDDP诱导的DNA损伤修复增加所致。这项研究的目的是探讨MIBC患者中参与核苷酸切除修复(NER)和跨损伤DNA合成(TLS)的蛋白质的预后价值。
方法:这是86例MIBC患者的回顾性分析。XPA,XPF,XPG,ERCC1、POLI、在原发性膀胱肿瘤中对POLH和REV3L蛋白进行染色,并在总队列和接受吉西他滨和CDDP作为一线治疗的转移性尿路上皮癌(mUC)亚组中分析其水平。将两个队列按每种蛋白质染色阳性的癌细胞的百分比分为具有高表达和低表达的亚组。以同样的方式,NER(XPA+ERCC1+XPF+XPG)和TLS(POLI+POLH+REV3L)的组合表达,作为整个路径,被分析。
结果:中位随访120.2个月时,死亡率为89.5%。在总队列中,肿瘤患者XPA染色阳性,与具有阴性染色的那些相比,XPG和POLI具有显著更差的总体存活(OS)[风险比(HR)分别=0.60、0.62和0.53]。在多变量分析(MVA)中,XPG和POLI均为独立的预后因素。此外,在整个队列中,NER和TLS通路表达的增加与OS恶化显著相关(HR分别为0.54和0.60).在mUC亚组中,单变量分析中,高POLI表达与OS显著恶化相关(HR=0.56),MVA显示其独立预后价值。
结论:我们的研究表明,XPG和POLI的肿瘤表达之间存在显着相关性,以及NER和TLS作为整个途径,和劣等操作系统。因此,它们可能构成MIBC的预后生物标志物和潜在有希望的治疗靶点.然而,需要进行进一步验证的前瞻性试验,从而克服了本研究的局限性。
BACKGROUND: Cisplatin (CDDP) remains a key agent in the treatment of muscle-infiltrating bladder carcinoma (MIBC). However, a proportion of MIBC patients do not respond to chemotherapy, which may be caused by the increased repair of CDDP-induced DNA damage. The purpose of this study was to explore the prognostic value of proteins involved in nucleotide excision repair (NER) and translesion DNA synthesis (TLS) in MIBC patients.
METHODS: This is a retrospective analysis of 86 MIBC patients. The XPA, XPF, XPG, ERCC1, POLI, POLH and REV3L proteins were stained in primary bladder tumors and their levels were analyzed both in the total cohort and in a subgroup with metastatic urothelial carcinoma (mUC) that received
gemcitabine and CDDP as a first-line therapy. Both cohorts were divided by percentage of cancer cells stained positive for each protein into subgroups with high and low expression. In the same manner, the combined expression of NER (XPA + ERCC1 + XPF + XPG) and TLS (POLI + POLH + REV3L), as the whole pathways, was analyzed.
RESULTS: Mortality was 89.5% at the median follow-up of 120.2 months. In the total cohort, patients with tumors stained positive for XPA, XPG and POLI had significantly worse overall survival (OS) compared to those with negative staining [hazard ratio (HR) = 0.60, 0.62 and 0.53, respectively]. Both XPG and POLI were independent prognostic factors in multivariate analyses (MVA). In addition, an increase in NER and TLS pathway expression was significantly associated with worse OS in the total cohort (HR = 0.54 and 0.60, respectively). In the mUC subgroup, high POLI expression was associated with significant deterioration of OS (HR = 0.56) in univariate analyses, and its independent prognostic value was shown in MVA.
CONCLUSIONS: Our study showed significant correlations between the tumor expression of XPG and POLI, as well as NER and TLS as the whole pathways, and inferior OS. Hence, they could constitute prognostic biomarkers and potentially promising therapeutic targets in MIBC. However, a prospective trial is required for further validation, thereby overcoming the limitations of this study.