InterVenn Biosciences, San Francisco, CA.
Department of Urology, Mayo Clinic Florida, Jacksonville, FL.
Urol Oncol. 2022 Apr;40(4):168.e11-168.e19. doi: 10.1016/j.urolonc.2021.12.005. Epub 2022 Feb 9.
Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS).
Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrell's C-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves.
The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate P ≤ 0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio (HR) of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR = 6.47, P = 9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR = 10.69, P = 0.001), clusterin A2G2 motif (HR = 7.38, P = 0.002), complement component C8A A2G2S2 motif (HR = 11.59, P = 0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR = 6.30, P = 0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9 to 10.7, all with P-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (P < 0.0001).
Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.
关于蛋白质翻译后修饰作为透明细胞肾细胞癌 (ccRCC) 无进展生存期 (PFS) 的生物标志物的利用，目前数据有限。我们采用高通量糖蛋白质组学来评估糖蛋白异构体的差异表达，作为 ccRCC 无进展生存期的新型标志物。
从 77 名接受手术治疗的 ccRCC 患者中获得血浆样本。在进行液相色谱串联质谱分析后进行糖蛋白质组学分析。采用年龄调整的 Cox 比例风险模型评估 PFS。采用优化的 Harrell's C 指数对总体进行二分，以构建 Kaplan-Meier 曲线。
平均随访时间为 3.4 年（范围：0.04-9.83 年）。糖蛋白质组学分析鉴定出 39 个糖肽和 14 个非糖基化肽，这些肽与 PFS 相关，具有统计学显著差异（假发现率 P ≤ 0.05）。其中 5 个糖肽的连续危险比（HR）大于 6（范围 6.3-11.6）。这些包括凝血酶原 A2G2S 聚糖基序（HR = 6.47，P = 9.53E-05）、免疫球蛋白 J 链 FA2G2S2 基序（HR = 10.69，P = 0.001）、簇蛋白 A2G2 基序（HR = 7.38，P = 0.002）、补体成分 C8A A2G2S2 基序（HR = 11.59，P = 0.002）和载脂蛋白 M 糖肽，具有非岩藻糖基化和非唾液酸化的杂合型聚糖（HR = 6.30，P = 0.003）。基于这 5 个糖肽的二分类表达的 Kaplan-Meier 曲线得出的危险比为 3.9 至 10.7，所有 P 值均小于 0.03。使用包含 3 个标志物的多变量模型的 Kaplan-Meier 图得出的 HR 为 11.96（P < 0.0001）。
血浆蛋白的差异糖型丰度可能是透明细胞肾细胞癌临床病程和预后的有用生物标志物来源。
