胸膜间皮瘤（PM）是一种罕见的疾病，预后不佳。系统治疗选择包括化疗和免疫疗法，但缺乏用于个体化治疗的生物标志物。唯一经FDA批准的诊断生物标志物是可溶性间皮瘤素相关蛋白（SMRP）。Krebs von den Lungen-6（KL-6）是一种人类黏液蛋白1（MUC1）糖蛋白，已显示出在其他恶性肿瘤中作为生物标志物具有诊断和预后价值。本研究调查了KL-6是否可以作为PM的诊断和/或预后生物标志物。采用全自动化化学发光酶免疫测定（CLEIA）检测KL-6和SMRP的胸腔积液样本，研究了87例连续PM患者和25例非恶性胸膜疾病患者。此外，还测定了相应患者的血清中的KL-6和SMRP水平以及独立验证队列（n = 122）中的水平。PM原代细胞系的MUC1 mRNA和蛋白表达以及细胞系上清液中的KL-6水平在体外进行了研究。PM患者胸腔积液中的KL-6水平明显高于非恶性对照组（AUC 0.78，p < 0.0001）。在PM患者中，上皮样或双相组织学的患者KL-6水平最高。胸腔积液中的KL-6水平与SMRP呈强正相关（p < 0.0001）。血清中的KL-6水平同样与PM的诊断相关，但程度较低（AUC 0.71，p = 0.008）。胸腔积液中KL-6水平较高（≥303 IU/mL）的PM患者与KL-6水平较低的患者相比，整体生存期显著更长（HR 0.51，p = 0.004）。相应地，原代细胞系中高肿瘤细胞MUC1 mRNA表达与相应患者的生存期显著延长相关（HR 0.35，p = 0.004）。这些发现在独立验证队列中得到了证实。这是首个证明KL-6作为潜在新型基于液体的PM诊断和预后生物标志物的研究。版权所有 © 2023Elsevier B.V. 保留所有权利。

Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM.Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro.PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort.This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM.Copyright © 2023 Elsevier B.V. All rights reserved.