微小RNA在肺癌中的研究进展

微小RNA（miRNA）的生物学功能广泛而重要,参与发育、生长、死亡等整个生命过程。超过50 %的miRNA位于肿瘤相关区域或脆性区域,与肿瘤发生、发展、侵袭转移关系密切的miRNA的发现使人们对基因表达调节有了新认识,也为肺癌等恶性肿瘤侵袭转移机制的研究以及miRNA在诊断治疗中的应用开拓了新视野。文章综述了miRNA在肺癌发病机制中的作用,并探讨其作为肺癌诊断与预后标志物的可能性及作为潜在治疗性靶点的应用前景。     

microRNA在肺癌早期诊断中的研究进展

 microRNA（miRNA）是一种非编码的约22个核苷酸的小RNA分子,具有转录后基因调控的功能。miRNA与肺癌的发生、发展、诊断、治疗及预后关系密切,本文主要针对miRNA在肺癌早期诊断中的潜在应用价值加以阐述。     

晚期恶性肿瘤基因突变状态二代测序临床意义分析

目的 靶向治疗是晚期恶性肿瘤的重要治疗方法,二代测序能够准确、高通量地检测基因突变情况,对恶性肿瘤治疗有重要意义.本研究运用二代基因测序(next-generation sequencing,NGS)技术检测晚期恶性肿瘤的基因突变情况,并初步分析错义突变的临床意义.方法 2011-09-01-2016-09-30收集陕西省人民医院肿瘤内科93例晚期恶性肿瘤患者病理组织石蜡标本,利用离子个体化基因检测仪(Ion Personal Genome Machine,Ion Torrent PGM)平台检测标本16个肿瘤相关基因428个常见的突变位点的突变状态,并查询临床试验(Clinical Trails)与美国食品与药物管理局(Food and Drug Administration,FDA)官网数据资料.结果 共发现119个错义突变,其中TP53发生频率最高为34.5％(41/119);除TP53突变在各瘤种中均占较大比例外,肺癌突变频率最高为表皮生长因子受体(epidermal growth factor receptor,EGFR) 25.7％(9/35),结直肠癌为KRAS 31.6％ (6/19),胃癌为KDR 3/6,卵巢癌为KRAS 2/7,宫颈癌为KDR 3/5.70例(75.3％,70/93)检测发现＞1个的错义突变位点;93.8％(15/16)的被检测基因有正在研发中的小分子抑制剂和(或)单抗类制剂,75.0％(12/16)的被检测基因已有FDA批准用于特定瘤种的靶向药物,68.8％(11/16)的被检测基因有尚未被FDA批准的靶向药物.结论 晚期恶性肿瘤基因错义突变发生率较高,且不同瘤种的突变谱不同,目前基于NGS指导的恶性肿瘤个体化靶向治疗有广阔的应用前景.     

microRNA与肺癌发生发展关系的研究进展

微小核糖核酸(microRNA,miRNA）是一类由大小为19~24个核苷酸(nucleotide,nt)构成的非编码小分子RNA,广泛存在于真核生物中。研究发现,miRNA通过调控相应靶基因的表达等多种途径参与癌症的发生发展等一系列过程,其中部分miRNA的靶基因已经成为治疗癌症的靶向基因。肺癌是世界范围内发病率与病死率均居首位的恶性肿瘤,目前缺乏理想的早期诊断手段及有效的治疗方法。目前大量研究表明,miRNA表达异常与肺癌的发生发展密切相关。本文就miRNA与肺癌发生发展关系的研究新进展作一综述。     

Identifying molecular drivers of gastric cancer through next-generation sequencing

Gastric cancer is the second most common cause of cancer-related death in the world, representing a major global health issue. The high mortality rate is largely due to the lack of effective medical treatment for advanced stages of this disease. Recently next-generation sequencing (NGS) technology has become a revolutionary tool for cancer research, and several NGS studies in gastric cancer have been published. Here we review the insights gained from these studies regarding how use NGS to elucidate the molecular basis of gastric cancer and identify potential therapeutic targets. We also discuss the challenges and future directions of such efforts.     

循环microRNA在肺癌研究中的进展

microRNA（miRNA）在肺癌的发生、发展中发挥着重要的调控作用。循环miRNA的发现,为肺癌诊断、治疗及预后判断提供了一种潜在的非侵入性生物标志。本文结合国内外最新报道对循环miRNA在肺癌诊断、预后判断及铂类化疗敏感性预测等方面的研究进展作一综述。     

Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma

Cancer molecular heterogeneity might explain the variable response of EGFR mutant lung adenocarcinomas to tyrosine kinase inhibitors (TKIs). We assessed the mutational status of 22 cancer genes by next-generation sequencing (NGS) in poor, intermediate or good responders to first-line gefitinib. Clinical outcome was correlated with Additional Coexisting Mutations (ACMs) and the EGFR Proportion of Mutated Alleles (PMA). Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each). TP53 mutations were exclusive of poor/intermediate responders (66.7% versus 0, p=0.009). Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03). TP53 mutation was the strongest negative modifier (median PFS 4.0 versus 14.0 months). Higher EGFR PMA was present in good versus poor/intermediate responders. Median PFS and survival were longer in patients with EGFR PMA ≥0.36 (12.0 versus 4.0 months, p=0.31; not reached versus 18.0 months, p=0.59). Patients with an EGFR PMA ≥0.36 and no ACMs fared significantly better (p=0.03), with a trend towards increased survival (p=0.06). Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.     

Application of next-generation sequencing in clinical oncology to advance personalized treatment of cancer

With the development and improvement of new sequencing technology,next-generation sequencing(NGS) has been applied increasingly in cancer genomics research over the past decade.More recently,NGS has been adopted in clinical oncology to advance personalized treatment of cancer.NGS is used to identify novel and rare cancer mutations,detect familial cancer mutation carriers,and provide molecular rationale for appropriate targeted therapy.Compared to traditional sequencing,NGS holds many advantages,such as the ability to fully sequence all types of mutations for a large number of genes(hundreds to thousands) in a single test at a relatively low cost.However,significant challenges,particularly with respect to the requirement for simpler assays,more flexible throughput,shorter turnaround time,and most importantly,easier data analysis and interpretation,will have to be overcome to translate NGS to the bedside of cancer patients.Overall,continuous dedication to apply NGS in clinical oncology practice will enable us to be one step closer to personalized medicine.     

肺癌术后复发转移相关微小RNA的研究进展

近年来,与肺癌复发转移相关微小RNA （miRNA）的临床研究取得了重要进展.在PubMed上检索与非小细胞肺癌（NSCLC）术后复发转移相关的miRNA临床研究文献,结果发现miRNA 在肺癌中具有差异性表达,部分已揭示与术后复发转移预后相关,可以作为今后的治疗靶点.但目前临床研究中发现的与NSCLC术后复发转移相关的miRNA,绝大部分尚处在筛选阶段,缺少大样本的临床验证,尤其是随机、对照研究.     

Molecular methods for colorectal cancer screening: Progress with next-generation sequencing evolution

Currently, colorectal cancer(CRC) represents the third most common malignancy and the second most deadly cancer worldwide, with a higher incidence in developed countries. Like other solid tumors, CRC is a heterogeneous genomic disease in which various alterations, such as point mutations, genomic rearrangements, gene fusions or chromosomal copy number alterations, can contribute to the disease development. However, because of its orderly natural history, easily accessible onset location and high...     

Prognostic impact of alternative splicing-derived hMENA isoforms in resected,node-negative,non-small-cell lung cancer

Risk assessment and treatment choice remain a challenge in early non-small-cell lung cancer (NSCLC). Alternative splicing is an emerging source for diagnostic, prognostic and therapeutic tools. Here, we investigated the prognostic value of the actin cytoskeleton regulator hMENA and its isoforms, hMENA^11a and hMENAΔv6, in early NSCLC.The epithelial hMENA^11a isoform was expressed in NSCLC lines expressing E-CADHERIN and was alternatively expressed with hMENAΔv6. Enforced expression of hMENAΔv6 or hMENA^11a increased or decreased the invasive ability of A549 cells, respectively. hMENA isoform expression was evaluated in 248 node-negative NSCLC. High pan-hMENA and low hMENA^11a were the only independent predictors of shorter disease-free and cancer-specific survival, and low hMENA^11a was an independent predictor of shorter overall survival, at multivariate analysis. Patients with low pan-hMENA/high hMENA^11a expression fared significantly better (P≤0.0015) than any other subgroup. Such hybrid variable was incorporated with T-size and number of resected lymph nodes into a 3-class-risk stratification model, which strikingly discriminated between different risks of relapse, cancer-related death, and death. The model was externally validated in an independent dataset of 133 patients.Relative expression of hMENA splice isoforms is a powerful prognostic factor in early NSCLC, complementing clinical parameters to accurately predict individual patient risk.     

肺癌患者深部真菌感染主要病原菌的FCM分析

背景与目的深部真菌感染是晚期肺癌患者的重要并发症和致死原因之一，研究和分析肺癌患者深部真菌感染病原菌有助于早期诊断和治疗晚期肺癌患者深部真菌感染。本研究在细胞生物学水平对肺癌患者深部真菌感染的主要病原菌进行研究，以探讨肺癌患者深部真菌感染发生发展过程中病原菌的变化及其与发病的关系。方法采用流式细胞技术(FCM)对肺癌患者深部真菌感染的主要病原菌——白念珠菌和对照组白念珠菌细胞总DNA含量、增殖指数(PI)及细胞周期进行测量。结果肺癌组与对照组稳定生长阶段的白念珠菌细胞大多数处于G0／G1期。两组G0／G1、G2／M期的细胞构成比和细胞总DNA含量均无显著性差异；肺癌组S期细胞构成比和增殖指数均显著高于对照组(P=0．040，P=0．038)。结论肺癌患者深部真菌感染主要病原菌——白念珠菌细胞DNA合成期比例增加，增殖活性增强，发生了致病力的变化。     

高通量测序技术在肺癌研究中的应用

近十年来,肺癌治疗从基于组织学特点选择化学治疗逐渐走向基于特定驱动基因实施个体化分子靶向治疗。高通量测序技术具有通量更高、运行时间更短、花费更少等优点。应用高通量全基因组深度测序技术从基因组水平揭示肺癌发生发展机制,寻找新的驱动基因作为靶向治疗靶点,发现并鉴定导致耐药的新序列变异,可从基因组序列水平阐明肺癌靶向治疗耐药机制。     

基于深度学习多模态风格迁移技术CBCT图像肺癌靶区自动分割方法研究北大核心CSCD

目的针对CBCT图像中肿瘤与周围组织对比度低的缺点, 研究一种适合于CBCT图像中中心型肺癌的自动分割方法。方法收集221例中心型肺癌患者, 其中176例行CT定位, 45例行强化CT定位。将强化CT图像分别设置为肺窗和纵隔窗, 并与首次CBCT验证图像进行弹性配准获得配对数据集;然后将配对数据集传入cycleGAN网络进行风格迁移, 使得CBCT图像可分别转化为肺窗和纵隔窗下的"强化CT";最后经风格迁移后的图像被载入UNET-attention网络对大体肿瘤体积进行深度学习。通过戴斯相似性系数(DSC)、豪斯多夫距离(HD)和受试者工作特征曲线下面积(AUC)对分割结果进行评价。结果经风格迁移后肿瘤与周围组织对比度明显增强, 采用cycleGAN+UNET-attention网络的DSC值为0.78±0.05, HD值为9.22±3.42, AUC值为0.864。结论采用cycleGAN+UNET-attention网络可有效对CBCT图像中中心型肺癌进行自动分割。     

A microRNA gene signature for identification of lung cancer

BackgroundLung cancer is the leading cause of cancer deaths worldwide, compounded by late diagnosis. MicroRNAs (miRNA) are recently discovered short, noncoding genes that play essential roles in tissue differentiation during normal development and tumorigenesis. miRNA profiles across all histologic grades can provide a reliable and standardized method for the identification of lung cancer.MethodsA microRNA lung cancer dataset was analyzed. Differentially expressed microRNAs were obtained post-normalization of data using t-test (p < 0.01). The data for differentially expressed microRNAs were processed using K-nearest neighbors classification method to obtain unique miRNAs expression patterns. The predicted mRNA targets were identified using TargetScan and the molecular functions associated with the predicted targets were retrieved from the Gene Ontology Consortium and represented using GO IDs in a directed acyclic graph.ResultsThe results indicate that lung cancer samples can be classified using a small panel of 19 unique microRNAs (8 down-regulated and 11 up-regulated) with over 85% classification accuracy. Furthermore, using classical enrichment analysis, this study identified 66 molecular function groups which are potentially the functional signaling pathways altered by these differentially expressed microRNAs.ConclusionsWe identified a microRNA gene signature representative of functioning as a diagnostic biomarker for lung cancer. These findings can potentially form the basis for the development of a standardized diagnostic assay that can be used for early diagnosis of lung cancer equally well from resection specimens and cytology samples.     

Meta‐analysis of microRNA expression in lung cancer

The prognostic and diagnostic value of microRNA (miRNA) expression aberrations in lung cancer has been studied intensely in recent years. However, due to the application of different technological platforms and small sample size, the miRNA expression profiling efforts have led to inconsistent results between the studies. We performed a comprehensive meta‐analysis of 20 published miRNA expression studies in lung cancer, including a total of 598 tumor and 528 non‐cancerous control samples. Using a recently published robust rank aggregation method, we identified a statistically significant miRNA meta‐signature of seven upregulated (miR‐21, miR‐210, miR‐182, miR‐31, miR‐200b, miR‐205 and miR‐183) and eight downregulated (miR‐126‐3p, miR‐30a, miR‐30d, miR‐486‐5p, miR‐451a, miR‐126‐5p, miR‐143 and miR‐145) miRNAs. We conducted a gene set enrichment analysis to identify pathways that are most strongly affected by altered expression of these miRNAs. We found that meta‐signature miRNAs cooperatively target functionally related and biologically relevant genes in signaling and developmental pathways. We have shown that such meta‐analysis approach is suitable and effective solution for identification of statistically significant miRNA meta‐signature by combining several miRNA expression studies. This method allows the analysis of data produced by different technological platforms that cannot be otherwise directly compared or in the case when raw data are unavailable.