■肌肉浸润性膀胱癌(MIBC)仍然是一种流行的癌症,治疗选择有限,消除对创新疗法的需要。表皮生长因子受体(EGFR)是肿瘤进展的关键,是MIBC的潜在治疗靶点。此外,EGFR配体AREG和EREG已显示与结直肠癌患者抗EGFR治疗应答和无进展生存期改善相关.
■我们研究了EGFR的预后意义,区域,和MIBC中的EREG。通过qRT-PCR对100名在曼海姆大学医院接受根治性膀胱切除术的MIBC患者的组织样本进行基因表达和拷贝数分析(MA;中位年龄72,四分位距[IQR]64-78岁,25%女性)。结果在2017年TCGAMIBC队列的361例患者中得到验证(中位年龄69,IQR60-77岁,27%女性),在Chungbuk和MDACC队列中。使用Mann-Whitney检验,基因表达与临床病理参数相关,Kruskal-Wallis检验和Spearman相关性。对于总生存期(OS),使用Kaplan-Meier和Cox比例风险模型分析癌症特异性生存期(CSS)和无病生存期(DFS)基因表达.
■EGFR基因表达差异显著,区域,EREG可以在所有队列中检测到。在TCGA队列中,EGFR扩增和KRAS野生型患者的EGFR表达显著升高。在MA队列中,高AREG表达独立地预测了更长的OS(HR=0.35,CI0.19-0.63,p=0.0004)和CSS(HR=0.42,CI0.18-0.95,p=0.0378)。在TCGA队列中,高EGFR,区域,EREG表达与较短的OS(AREG:HR=1.57,CI1.12-2.20,p=0.0090)和DFS(EGFR:HR=1.91,CI1.31-2.8,p=0.0008)相关。EGFR扩增也与DFS降低相关。
■高EGFR和EREG表明MIBC患者的生存率较差。AREG的预后作用应进一步研究,准系列。四个队列之间不同的生存结果应谨慎解释,考虑到分析方法和人口统计学的差异。进一步的体外研究对于阐明本研究中观察到的关联的功能机制是必要的。
UNASSIGNED: Muscle invasive bladder cancer (MIBC) remains a prevalent cancer with limited therapeutic options, obviating the need for innovative therapies. The epidermal growth factor receptor (EGFR) is a linchpin in tumor progression and presents a potential therapeutic target in MIBC. Additionally, the EGFR ligands
AREG and EREG have shown associations with response to anti-EGFR therapy and improved progression-free survival in colorectal carcinoma.
UNASSIGNED: We investigated the prognostic significance of EGFR,
AREG, and EREG in MIBC. Gene expression and copy number analyses were performed via qRT-PCR on tissue samples from 100 patients with MIBC who underwent radical cystectomy at the University Hospital Mannheim (MA; median age 72, interquartile range [IQR] 64-78 years, 25% female). Results were validated in 361 patients from the 2017 TCGA MIBC cohort (median age 69, IQR 60-77 years, 27% female), in the Chungbuk and MDACC cohort. Gene expressions were correlated with clinicopathologic parameters using the Mann-Whitney test, Kruskal-Wallis- test and Spearman correlation. For overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) gene expression was analyzed with Kaplan-Meier and Cox-proportional hazard models.
UNASSIGNED: Significant gene expression differences in EGFR, AREG, and EREG could be detected in all cohorts. In the TCGA cohort, EGFR expression was significantly elevated in patients with EGFR amplification and KRAS wildtype. High
AREG expression independently predicted longer OS (HR = 0.35, CI 0.19 - 0.63, p = 0.0004) and CSS (HR = 0.42, CI 0.18 - 0.95, p = 0.0378) in the MA cohort. In the TCGA cohort, high EGFR,
AREG, and EREG expression correlated with shorter OS (
AREG: HR = 1.57, CI 1.12 - 2.20, p = 0.0090) and DFS (EGFR: HR = 1.91, CI 1.31 - 2.8, p = 0.0008). EGFR amplification was also associated with reduced DFS.
UNASSIGNED: High EGFR and EREG indicate worse survival in patients with MIBC. The prognostic role of
AREG should further be investigated in large, prospective series. Divergent survival outcomes between the four cohorts should be interpreted cautiously, considering differences in analysis methods and demographics. Further in vitro investigations are necessary to elucidate the functional mechanisms underlying the associations observed in this study.