Special issue “The advance of solid tumor research in China”: Multi-omics analysis based on 1311 clear cell renal cell carcinoma samples identifies a glycolysis signature associated with prognosis and treatment response

In clear cell renal cell carcinoma (ccRCC), glycolysis is enhanced mainly because of the increased expression of key enzymes in glycolysis. Hence, the discovery of new molecular biomarkers for glycolysis may help guide and establish a precise system of diagnosis and treatment for ccRCC. Expression profiles of 1079 tumor samples of ccRCC patients (including 311 patients treated with everolimus or nivolumab) were downloaded from public databases. Proteomic profiles of 232 ccRCC samples were obtained from Fudan University Shanghai Cancer Center (FUSCC). Biological changes, tumor microenvironment and prognostic differences were explored between samples with various glycolysis characteristics. There were significant differences in CD8⁺ effector T cells, epithelial-to-mesenchymal transition and pan-fibroblast TGFb between the Low and High glyScore groups. The tumor mutation burden of the Low glyScore group was lower than that of the High glyScore group. And higher glyScore was significantly associated with worse overall survival (OS) in 768 ccRCC patients (P < .0001). External validation in FUSCC cohort also indicated that glyScore was of strong ability for predicting OS (P < .05). GlyScore may serve as a biomarker for predicting everolimus response in ccRCC patients due to its significant associations with progression-free survival (PFS). And glyScore may also predict overall survival in patients treated with nivolumab. We calculated the glyScore in ccRCC and the defined glyScore was of strong ability for predicting OS. In addition, glyScore may also serve as a biomarker for predicting PFS in patients treated with everolimus and could predict OS in patients treated with nivolumab.     

特发性肺纤维化急性加重期证候与血清生物标志物的相关性研究＊

目的 通过分析特发性肺纤维化急性加重期（AE-IPF）患者证候与血清生物标志物的关系，为中医辨证治疗提供参考。方法 采用观察性研究设计，收集2019年3月至2019年11月三个中心的AE-IPF患者76例，其中痰热壅肺证26例、痰浊阻肺证50例，并纳入健康志愿者10例作为对照。采用ELISA测定患者血清CCL18、HMGB1、KL-6、MMP-7、SP-A和SP-D水平，分析与中医证候的相关性。结果 AE-IPF患者血清CCL18、HMGB1、KL-6、MMP-7、SP-A和SP-D水平均显著高于健康对照组。血清CCL18、HMGB1、KL-6、MMP-7和SP-D水平在痰热壅肺证和痰浊阻肺证患者间无显著性差异（P＞0.05），而血清SP-A水平存在显著性差异（P＜0.05）。结论 血清SP-A与AE-IPF证候存在一定的相关性，血清SP-A的浓度升高，与痰热壅肺证关系越密切，反之，血清SP-A浓度降低，则与痰浊阻肺证关系越密切。AE-IPF痰热壅肺证患者的预后可能较痰浊阻肺证患者更差。     

Neutrophil-to-Lymphocyte Ratio Predicts Cancer Outcome in Locally Advanced Clear Renal Cell Carcinoma

BackgroundTo evaluate the association of neutrophil-to-lymphocyte ratio (NLR) with recurrence-free survival (RFS) and overall survival (OS) in patients with locally advanced nonmetastatic clear cell renal cell carcinoma (ccRCC) undergoing radical nephrectomy.Material and MethodsWe retrospectively identified 880 nephrectomies performed between January 2009 and December 2016 in a single center, reviewed data from 478 radical nephrectomies for kidney tumors and identified 187 patients with locally advanced nonmetastatic ccRCC (pT3-T4 N0M0). NLR was obtained preoperatively and calculated by dividing absolute neutrophil count by absolute lymphocyte count. OS and RFS were evaluated by the Kaplan–Meier method. Cox proportional-hazards regression models were used to evaluate predictors of RFS and OS.ResultsAmong 187 patients with ccRCC (mean age 63.4 ± 11.5 years; 118 [63.1%] male), the median follow-up was 48.7 months. On univariate analysis, in patients with Fuhrman nuclear grade of differentiation 3-4, the median time to recurrence was significantly shorter with NLR ≥ 4 than < 4 (24 vs. 55 months, P = .045). On multivariable analysis adjusted for NLR ≥ 4, among all variables analyzed (NLR, microvascular invasion, sarcomatoid differentiation, tumor size and body mass index), only nuclear grade of differentiation was an independent predictor of recurrence (hazard ratio 2.18; 95% confidence interval 1.07-4.92, P = .03). The 3-year OS had no statistically significant difference between patients with NLR ≥ 4 or < 4.ConclusionFor patients with locally advanced, nonmetastatic ccRCC, RFS was reduced with high nuclear grade of differentiation and high preoperative NLR. These findings suggest an association between higher NLR and worse outcomes in locally advanced ccRCC.     

Top advances of the year: Hepatobiliary cancers

This commentary reviews top advances in hepatobiliary cancer research in 2021–2022, focusing on leveraging immunotherapeutics in combination with other therapies earlier in the disease course and targeted to patient's individualized biomarkers that may predict response or resistance to checkpoint inhibitors.     

长链非编码RNA AFAP1-AS1在实体肿瘤中的作用与分子机制

长链非编码RNA（LncRNA）是一种长度超过200个核苷酸的内源RNA。大量研究表明，LncRNA可参与多种生物过程，如转录激活和干扰、细胞分化、增殖、迁移、侵袭和凋亡。近年来许多研究表明LncRNA在人类癌症中作为致癌基因或肿瘤抑制基因发挥着重要作用。大量新研究表明LncRNA肌动蛋白丝相关蛋白1反义RNA1（AFAP1-AS1）参与了多种恶性肿瘤的发生发展。已证实AFAP1-AS1的失调表达与肿瘤发生和肿瘤进展相关；AFAP1-AS1可能成为肿瘤诊断和肿瘤治疗靶点的新型潜在分子生物标志物。在本篇综述中，我们总结了现阶段关于AFAP1-AS1在人类肿瘤发生和发展过程中的生物学功能和分子机制的研究问题。     

Relationship between tRNA-derived fragments and human cancers

tRNA-derived fragments, a class of small noncoding RNAs (sncRNAs), have been identified in numerous studies in recent years. tRNA-derived fragments are classified into two main groups, including tRNA halves (tiRNAs) and tRNA-derived small RNA fragments (tRFs), according to different cleavage positions of the precursor or mature tRNAs. Instead of random tRNA degradation debris, a growing body of evidence has shown that tRNA-derived fragments are precise products of specific tRNA modifications and play important roles in biological activities, such as regulating protein translation, affecting gene expression, and altering immune signaling. Recently, the relations between tRNA-derived fragments and the occurrence of human diseases, especially cancers, have generated wide interest. It has been demonstrated that tRNA-derived fragments are involved in cancer cell proliferation, metastasis, progression and survival. In this review, we will describe the biogenesis of tRNA-derived fragments, the distinct expression and function of tRNA-derived fragments in the development of cancers, and their emerging roles as diagnostic and prognostic biomarkers and precise targets of future treatments.     

Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer

Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially‐methylated genes between responders and non–responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression‐free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC.     

基于TCGA数据库分析ASPM在肺腺癌中的表达及临床意义

目的：探讨异常纺锤体样小头畸形相关基因（ASPM）在肺腺癌中的表达水平，及其与患者临床病理指标和预后的关系。方法：从癌症基因组图谱（TCGA）数据库下载肺腺癌组织和癌旁组织mRNA表达水平和临床病例资料，比较ASPM mRNA在癌组织和癌旁组织中的表达差异，统计学分析ASPM表达水平与肺腺癌患者临床病理指标及预后关系。通过R语言ballgown和ggplot包筛选高低表达ASPM组间差异基因并绘制火山图；利用DAVID工具对差异基因进行GO分析，采用GSEA预测ASPM可能调控的信号通路；STRING和Cytoscape分析关键基因及差异表达基因间的相互作用。结果：ASPM mRNA在肺腺癌中表达水平显著高于癌旁组织（P < 0.05）；ASPM表达水平与生存期相关，高表达ASPM肺腺癌患者预后较差（P < 0.05），是肺腺癌患者预后的独立危险因素，R语言ballgown包筛选出ASPM高低表达组间的差异表达基因共183个，差异表达基因富集到生物过程（BP）、细胞组分（CC）、分子功能（MF）在3个类别共19个亚类和18条KEGG通路；Cytoscape软件发现4个枢纽蛋白。结论：ASPM mRNA在肺腺癌患者中呈高表达且高表达组预后差，可作为判断肺腺癌预后的标志物。