Identification of prognostic biomarkers for prostate cancer

PURPOSE: This paper describes a process for the identification of genes that can report on the aggressiveness of prostate tumors and thereby add to the information provided by current pathologic analysis. MATERIALS AND METHODS: Expression profiling data from over 100 laser capture microdissection derived samples from nonneoplastic epithelium; Gleason patterns 3, 4, and 5 and node metastasis prostate cancer were used to identify genes at abnormally high levels in only some tumors. These variably overexpressed genes were stratified by their association with aggressive phenotypes and were subsequently filtered to exclude genes with redundant expression patterns. Selected genes were validated in a case-control study in which cases (systemic progression within 5 years) and controls (no systemic progression at 7 years of follow-up) were matched for all clinical and pathologic criteria from time of prostatectomy (n = 175). Both cases and controls, therefore, could have nodal invasion or seminal vesicle involvement at the time of initial treatment. RESULTS: A number of candidate variably overexpressed genes selected for their association with aggressive prostate cancer phenotype were evaluated in the case control study. The most prominent candidates were SSTR1 and genes related to proliferation, including TOP2A. CONCLUSIONS: The process described here identified genes that add information not available from current clinical measures and can improve the prognosis of prostate cancer.     

Identification of candidate prostate cancer biomarkers in prostate needle biopsy specimens using proteomic analysis

Although serum prostate specific antigen (PSA) is a well-established diagnostic tool for prostate cancer (PCa) detection, the definitive diagnosis of PCa is based on the information contained in prostate needle biopsy (PNBX) specimens. To define the proteomic features of PNBX specimens to identify candidate biomarkers for PCa, PNBX specimens from patients with PCa or benign prostatic hyperplasia (BPH) were subjected to comparative proteomic analysis. 2-DE revealed that 52 protein spots exhibited statistically significantly changes among PCa and BPH groups. Interesting spots were identified by MALDI-TOF-MS/MS. The 2 most notable groups of proteins identified included latent androgen receptor coregulators [FLNA(7-15) and FKBP4] and enzymes involved in mitochondrial fatty acid beta-oxidation (DCI and ECHS1). An imbalance in the expression of peroxiredoxin subtypes was noted in PCa specimens. Furthermore, different post-translationally modified isoforms of HSP27 and HSP70.1 were identified. Importantly, changes in FLNA(7-15), FKBP4, and PRDX4 expression were confirmed by immunoblot analyses. Our results suggest that a proteomics-based approach is useful for developing a more complete picture of the protein profile of PNBX specimen. The proteins identified by this approach may be useful molecular targets for PCa diagnostics and therapeutics.     

Identification of prognostic biomarkers for glioblastomas using protein expression profiling

A set of proteins reflecting the prognosis of patients have clinical significance since they could be utilized as predictive biomarkers and/or potential therapeutic targets. With the aim of finding novel diagnostic and prognostic markers for glioblastoma (GBM), a tissue microarray (TMA) library consisting of 62 GBMs and 28 GBM-associated normal spots was constructed. Immunohistochemistry against 78 GBM-associated proteins was performed. Expression levels of each protein for each patient were analyzed using an image analysis program and converted to H-score [summation of the intensity grade of staining (0-3) multiplied by the percentage of positive cells corresponding to each grade]. Based on H-score and hierarchical clustering methods, we divided the GBMs into two groups (n=19 and 37) that had significantly different survival lengths (p<0.05). In the two groups, expression of nine proteins (survivin, cyclin E, DCC, TGF-β, CDC25B, histone H1, p-EGFR, p-VEGFR2/3, p16) was significantly changed (q<0.05). Prognosis-predicting potential of these proteins were validated with another independent library of 82 GBM TMAs and a public GBM DNA microarray dataset. In addition, we determined 32 aberrant or mislocalized subcellular protein expression patterns in GBMs compared with relatively normal brain tissues, which could be useful for diagnostic biomarkers of GBM. We therefore suggest that these proteins can be used as predictive biomarkers and/or potential therapeutic targets for GBM.     

胃癌分子预后标记物研究进展

胃癌是常见的癌症相关死亡原因。早期胃癌的长期总生存率已有显著提高,但是进展期胃癌的预后仍然很差。胃癌TNM分期是主要的预后指标,但是对于具有相同TNM分期且接受相同治疗的患者,其预后仍有不同。因此,需要新的可与TNM分期相结合的分子预后标记物用以指导临床诊断和治疗。本文将对胃癌分子预后标记物的研究进展及其临床意义进行综述。     

整合生物信息学挖掘胃癌潜在关键生物标志物

目的:通过整合生物信息学挖掘胃癌潜在关键生物标志物.方法:本研究从GEO数据库下载数据集联合分析,借助R语言挖掘差异基因集,并功能注释和富集这些基因的相关生物通路;采用String数据库和Cytoscape软件挖掘关键基因,并借由Onconmine数据库验证关键基因.结果:本研究总共确定了98个共有差异基因,包括30个...     

Identification of a molecular signature of prognostic subtypes in diffuse-type gastric cancer

Gastric Cancer - Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for diffuse-type GC have been identified. Here,...     

Proposal for a tumor budding predictive score derived from endoscopic biopsy samples in colorectal cancer

International Journal of Clinical Oncology - In colorectal cancer, tumor budding is highlighted as both a prognostic indicator and a predictor of chemosensitivity. However, tumor budding has a...     

Immunoprofiles of 11 biomarkers using tissue microarrays identify prognostic subgroups in colorectal cancer

BACKGROUND AND AIMS: Genomewide expression profiling has identified a number of genes expressed at higher levels in colorectal cancer (CRC) than in normal tissues. Our objectives in this study were: 1) to test whether genes were also distinct on the protein level; 2) to evaluate these biomarkers in a series of well-characterized CRCs; and 3) to apply hierarchical cluster analysis to the immunohistochemical data. METHODS: Tissue microarrays (TMAs) comprising 351 CRC specimens from 270 patients were constructed to evaluate the genes Adam10, Cyclin D1, Annexin II, NFKB, Casein kinase 2 beta (CK2B), YB-1, P32, Rad51, c-fos, IGFBP4, and Connexin26 (Cx26). In total, 3,797 samples were analyzed. RESULTS: Unsupervised hierarchical clustering discovered subgroups of CRC that differed by tumor stage and survival. Kaplan-Meier analysis showed that reduced Cx26 expression was significantly associated with shorter patient survival and higher tumor grade (G1/G2 vs G3, P = .02), and Adam10 expression with a higher tumor stage (pT1/2 vs pT3/4, P = .04). CONCLUSIONS: Our study highlights the potential of TMAs for a higher-dimensional analysis by evaluating serial sections of the same tissue core (three-dimensional TMA analysis). In addition, it endorses the use of immunohistochemistry supplemented by hierarchical clustering for the identification of tumor subgroups with diagnostic and prognostic signatures.     

p53 immunoreaction in endoscopic biopsy specimens of colorectal cancer, and its prognostic significance.

The expression of p53 protein was immunohistochemically studied in formalin-fixed paraffin-embedded biopsy specimens of 203 colorectal carcinomas by use of a monoclonal antibody specific for the p53 protein. PAb1801. p53 protein expression with its reactivity localised in nuclei was found in 121 (59.6%) of the cancers. There was no correlation of p53 immunoreactivity with histological classification, wall invasion, lymphatic invasion, venous invasion, lymph node metastases, or peritoneal metastases. p53-positive cancers were more frequently associated with liver metastasis than p53-negative ones. Patients with p53-positive tumours had significantly poorer prognoses than those with p53-negative tumours. The 5 year survival rate was 58.1% for patients with p53-positive tumours, and 76.3% for those with p53-negative tumours. In Dukes'' stage C tumours, an especially good correlation was found between p53 immunoreactivity and prognosis. In addition, patients with p53-positive tumours had higher recurrence rates. The results indicate that p53 immunoreactivity may be a useful prognostic marker of colorectal cancers.     

Identification of potential prognostic biomarkers for hepatocellular carcinoma

BackgroundThe incidence of liver cancer is increasing every year. Hepatocellular carcinoma (HCC) accounts for nearly 90% of liver cancer, and the overall 5-year survival rate of become of Hepatocellular carcinoma patients less than 20%. However, the molecular mechanism of HCC progression and prognosis still requires further exploration.MethodsIn this study, we downloaded the gene expression data from the Cancer Genome Atlas (TCGA) Genomic Data and the official website of GEO database. Weighted gene co-expression network analysis (WGCNA) and Pearson’s correlation coefficient were utilized to detect the gene modules. The shared differentially-expressed genes (DEGs) were screened out by a Venn diagram, and the hub genes were identified through protein-protein interaction (PPI) network analyses. GO and KEGG enrichment analyses were constructed for these hub genes. Overall survival (OS) and correlation analysis were conducted to investigate the relationship between the hub genes and clinical features.ResultsWe screened out 27 shared DEGs, and the mainly enriched GO terms were mitotic nuclear division, chromosomal region, and tubulin binding. Furthermore, the top three enriched KEGG pathways were “cell cycle”, “oocyte meiosis”, and “p53 signaling pathway”. According to the Maximal Clique Centrality (MCC) algorithm, the top 10 candidate hub genes were MYC, MCM3, CDC20, CCNB1, BIRC5, UBE2C, TOP2A, RRM2, TK1, and PTTG1, among which BIRC5, CDC20, and UBE2C showed a strong correlation with the OS.ConclusionsThree hub genes (BIRC5, CDC20, and UBE2C) were identified and found to be correlated to the progression and prognosis of HCC. These may become potential targets for HCC therapy.     

肌层浸润性膀胱癌分子预后标记物研究进展

膀胱癌是泌尿系统常见肿瘤, 可分为非肌层浸润性膀胱癌、肌层浸润性膀胱癌和转移性膀胱癌。临床上患者多为非肌层浸润性膀胱癌, 易于复发, 复发后大多数细胞分化良好, 预后佳。但10%~30%患者肿瘤复发时转变为具有侵袭性的浸润性膀胱癌, 预后不良。目前临床上采用的分级分期方法很难准确预测具有复杂生物学行为的浸润性膀胱癌的预后。近年许多肿瘤标记物相继被发现并用于浸润性膀胱癌的诊断和预后判断。这些分子标记物不仅对浸润性膀胱癌患者预后的判断有提示作用, 同时决定着患者是否适合行保留膀胱的放化疗、新辅助化疗和以铂类为基础的辅助化疗等治疗方式。本文对影响浸润性膀胱癌预后的分子标记物进行综述。      

Discrepancies in histologic diagnoses of early gastric cancer between biopsy and endoscopic mucosal resection specimens

Background  

A preoperative histologic diagnosis of neoplasia is a requirement for endoscopic resection (ER). However, discrepancies may occur between histologic diagnoses based on biopsy specimens versus ER specimens. The aim of this study was to assess the rate of discrepancy between histologic diagnoses from biopsy specimens and ER specimens.     

Routine endoscopy using electronic endoscopes for gastric cancer diagnosis: retrospective study of inconsistencies between endoscopic and biopsy diagnoses

To clarify the actual conditions and problems encountered in the diagnosis of gastric cancer during routine endoscopic examinations using electronic endoscopes, a retrospective study of cases that had shown inconsistencies between the endoscopic and biopsy diagnoses was conducted. The subjects were 5,640 patients who had undergone gastric biopsies. They were selected from among 18,248 patients in whom upper gastrointestinal endoscopy had been performed between July 1992 and July 1997 at the National Cancer Center Hospital East. The study was conducted focusing on macroscopic type, size, location, and pathologic findings of the lesions. Cases showing inconsistencies between the endoscopic and biopsy diagnoses comprised 2.7% of all biopsy cases (150 of 5,640). Most of these inconsistently diagnosed lesions were less than 20 mm in diameter. The frequency of inaccurate diagnosis for depressed lesions in the areas of upper and middle thirds of the stomach from the lesser curvature to the posterior wall was significantly higher in the inconsistent group, compared with the accurate diagnoses from the control group. In diagnostic reviews of depressed lesions, 46.0% (46 of 100) were diagnosed accurately, but cases with fewer malignant indices were recognized. These results indicate that diagnostic accuracy must be enhanced through objective biopsy-implementation standards and the use of image processing in using diagnostic methods that employ electronic endoscopes.     

胃癌预后标记物研究

胃癌的发生发展包括生长信号自我满足、生长抑制信号不敏感、逃逸细胞凋亡、无限的自我复制潜力、持续性血管生成、组织浸润和转移等种机制,需要多种分子参与,这些分子可能成为评价预后的重要指标,提高了预测准确度.     

DNA methylation biomarkers for noninvasive detection of triple-negative breast cancer using liquid biopsy

Noninvasive detection of aberrant DNA methylation could provide invaluable biomarkers for earlier detection of triple-negative breast cancer (TNBC) which could help clinicians with easier and more efficient treatment options. We evaluated genome-wide DNA methylation data derived from TNBC and normal breast tissues, peripheral blood of TNBC cases and controls and reference samples of sorted blood and mammary cells. Differentially methylated regions (DMRs) between TNBC and normal breast tissues were stringently selected, verified and externally validated. A machine-learning algorithm was applied to select the top DMRs, which then were evaluated on plasma-derived circulating cell-free DNA (cfDNA) samples of TNBC patients and healthy controls. We identified 23 DMRs accounting for the methylation profile of blood cells and reference mammary cells and then selected six top DMRs for cfDNA analysis. We quantified un-/methylated copies of these DMRs by droplet digital PCR analysis in a plasma test set from TNBC patients and healthy controls and confirmed our findings obtained on tissues. Differential cfDNA methylation was confirmed in an independent validation set of plasma samples. A methylation score combining signatures of the top three DMRs overlapping with the SPAG6, LINC10606 and TBCD/ZNF750 genes had the best capability to discriminate TNBC patients from controls (AUC = 0.78 in the test set and AUC = 0.74 in validation set). Our findings demonstrate the usefulness of cfDNA-based methylation signatures as noninvasive liquid biopsy markers for the diagnosis of TNBC.     

Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis

Ovarian cancer is the first leading cause of mortality in gynecological malignancies. To identify key genes and microRNAs in ovarian cancer, mRNA microarray dataset GSE36668, GSE18520, GSE14407 and microRNA dataset GSE47841 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained using GEO2R. Functional and pathway enrichment analysis were performed for DEGs using DAVID database. Protein–protein interaction (PPI) network was established by STRING and visualized by Cytoscape. Following, overall survival (OS) analysis of hub genes was performed by the Kaplan–Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Moreover, miRecords was applied to predict the targets of the DEMs. A total of 345 DEGs were obtained, which were mainly enriched in the terms related to cell cycle, mitosis, and ovulation cycle process. A PPI network was constructed, consisting of 141 nodes and 296 edges. Sixteen genes had high degrees in the network. High expression of four genes of the 16 genes was associated with worse OS of patients with ovarian cancer, including CCNB1, CENPF, KIF11, and ZWINT. A significant module was detected from the PPI network. The enriched functions and pathways included cell cycle, nuclear division, and oocyte meiosis. Additionally, a total of 36 DEMs were identified. The expression of KIF11 was negatively correlated with that of has-miR-424 and has-miR-381, and it was also the potential target of two microRNAs. In conclusion, these results identified key genes, which could provide potential targets for ovarian cancer diagnosis and treatment.     

乳腺癌预后分子生物标志物的研究进展

乳腺癌是女性较常见的恶性肿瘤,其发病率和死亡率均居恶性肿瘤前列,严重威胁女性的健康。乳腺癌预后生物标志物对预测乳腺肿瘤恶性程度、转移情况和复发情况,以及指导临床治疗方案等具有重要意义。近年来,乳腺癌预后相关分子生物标志物的研究不断取得进展,为有效预测乳腺癌预后状况提供了更多依据。本文将对乳腺癌预后分子生物标志物进行综述。     

甲状腺乳头状癌潜在预后生物标志物的识别北大核心

目的:探讨甲状腺乳头状癌的潜在发病机制、治疗靶点及预后生物标志物。方法:使用加权基因共表达网络分析(weighted gene co-expression network analysis,WGCNA)基于来自Gene Expression Omnibus数据库的数据集GSE27155和GSE58545构建共表达网络,从而识别与甲状腺乳头状癌密切相关的模块和基因。使用来自于Gene Expression Profiling Interactive Analysis的数据来进行验证。结果:本研究发现棕色模块表明与该疾病密切相关,且该模块中的基因被富集到Ras信号通路、MAPK信号通路及Wnt信号通路等(P<0.05)。基于生存分析发现:4个枢纽基因LMOD1、GHR、GPM6A和ZMAT4与患者预后相关。来自GEPIA的数据显示枢纽基因的差异表达具有显著性意义。结论:本次研究证实棕色模块的枢纽基因LMOD1、GHR、GPM6A和ZMAT4可能为甲状腺乳头状癌潜在发病机制提供了新的切入点,对该疾病临床治疗提供新的见解,对于完善个体化治疗提供一定的帮助。     

去势难治性前列腺癌分子预后标志物研究进展

前列腺癌是老年男性常见的恶性肿瘤,内分泌治疗虽可使大多数患者的病情得到控制和改善,但在经过一段时间的缓解后,绝大多数患者会发展为预后极差的去势难治性前列腺癌（CRPC）。对CRPC患者如何实施个体化治疗,以最小的不良反应和最大的获益来延长生存已成为临床工作者亟待解决的难题。目前临床上采用的分级分期方法很难准确预测具有复杂生物学行为的CRPC患者的预后。近年许多肿瘤标志物相继被发现并用于CRPC患者的预后判断,本文对影响CRPC预后的分子标志物做一综述。      

不同手术前活检方案对早期胃癌及上皮内瘤变行ESD效果的影响

目的：探讨采用不同手术前活检方案对早期胃癌及上皮内瘤变患者行内镜黏膜下剥离术（ESD）效果的影响。方法选择早期胃癌或者上皮内瘤变行ESD患者90例,根据术前胃镜的检查方式的不同分为对照组（40例）和观察组（50例）,对照组患者在不同医院采用传统白光成像内镜（C-WLI）进行多块多次活检方案,再进行放大窄带成像内镜（M-NBI）模式检查,观察组在本院先应用C-WLI,进而进行M-NBI模式,比较不同手术前活检方案对早期胃癌及上皮内瘤变行ESD效果的影响,观察患者手术进行中的相关指标。结果 M-NBI的符合率为95.6%,C-WLI的符合率为70.0%,两种不同活检方案比较差异具有统计学意义（P﹤0.05）;对照组和观察组在标本切除范围时间、标记时间以及处理标本时间差异无统计学意义（P﹥0.05）;观察组在手术过程中黏膜下注射时间、黏膜分离时间以及手术创面处理时间短于对照组,同时手术后活检标本数量少于对照组（P﹤0.05）;观察组取出的标本病理检查符合率为96.0%,对照组的符合率为77.5%,差异具有统计学意义（P﹤0.05）;观察组取材标本数量少于对照组（P﹤0.05）。结论采用放大窄带成像内镜活检方法,能够提高取材阳性率,缩短内镜下ESD手术时间,减少取材标本数量,值得临床推广。