Autoantibodies in cancer: prognostic biomarkers and immune activation

The development of proteomic technologies that display a wide variety of antigenic structures has led to the identification of autoantibodies to cancer-derived tumor antigens. These autoantibodies have been detected in sera from patients with multiple cancer types, and are being evaluated as biomarkers for early cancer detection. It is not known whether these antibodies also contribute to active immune surveillance or even tumorigenicity of developing tumors. Here, we review which tumor antigen-specific antibodies are prognostic biomarkers of cancer outcome, and emerging proteomic methods for the isolation and cloning of these antibodies for potential molecular diagnostics and therapeutics.     

Predictive and prognostic biomarkers in colorectal cancer

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in the United States.Three quarters of patients diagnosed with colorectal cancer will have early s...     

Grade-specific diagnostic and prognostic biomarkers in breast cancer

An integrative approach is presented to identify grade-specific biomarkers for breast cancer. Grade-specific molecular interaction networks were constructed with differentially expressed genes (DEGs) of cancer grade 1, 2, and 3. We observed that the molecular network of grade3 is predominantly associated with cancer-specific processes. Among the top ten connected DEGs in the grade3, the increase in the expression of UBE2C and CCNB2 genes was statistically significant across different grades. Along with UBE2C and CCNB2 genes, the CDK1, KIF2C, NDC80, and CCNB2 genes are also profoundly expressed in different grades and reduce the patient's survival. Gene set enrichment analysis of these six genes reconfirms their role in metastatic phenotype. Moreover, the coexpression network shows a strong association of these six genes promotes cancer specific biological processes and possibly drives cancer from lower to a higher grade. Collectively the identified genes can act as potential biomarkers for breast cancer diagnosis and prognosis.     

Autoantibodies against tumor-associated antigens in sputum as biomarkers for lung cancer

Tumor antigens (TAs) can initiate host immune responses and produce TA-associated autoantibody (TAAbs), potential cancer biomarkers. Sputum is directly generated from the upper and lower airways, and thus can be used as a surrogate sample for the diagnosis of lung cancer based on molecular analysis. To develop sputum TAAb biomarkers for the early detection of lung cancer, the leading cause of cancer death, we probed a protein microarray containing more than 9,000 antigens with sputum supernatants of a discovery set of 30 lung cancer patients and 30 cancer-free smokers. Twenty-eight TAs with higher reactivity in sputum of lung cancer cases vs. controls were identified. The diagnostic significance of TAAbs against the TAs was determined by enzyme-linked immunosorbent assays (ELISAs) in sputum of the discovery set and additional 166 lung cancer patients and 213 cancer-free smokers (validation set). Three sputum TAAbs against DDX6, ENO1, and 14–3-3ζ were developed as a biomarker panel with 81% sensitivity and 83% specificity for diagnosis of lung cancer, regardless of stages, locations, and histological types of lung tumors. This study provides the first evidence that sputum TAAbs could be used as biomarkers for the early detection of lung cancer.     

microRNAs: New prognostic,diagnostic, and therapeutic biomarkers in cervical cancer

Cervical cancer is as a kind of cancer beginning from the cervix. Given that cervical cancer could be observed in women who infected with papillomavirus, regular oral contraceptives, and multiple pregnancies. Early detection of cervical cancer is one of the most important aspects of the therapy of this malignancy. Despite several efforts, finding and developing new biomarkers for cervical cancer diagnosis are required. Among various prognostic, diagnostic, and therapeutic biomarkers, miRNA have been emerged as powerful biomarkers for detection, treatment, and monitoring of response to therapy in cervical cancer. Here, we summarized various miRNAs as an employable platform for prognostic, diagnostic, and therapeutic biomarkers in the treatment of cervical cancer.     

Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: A review

Colorectal cancer is a leading cause of cancer related mortality in the Western world. In recent years, combination 5-fluorouracil based adjuvant chemotherapy as first line treatment of this disease has led to improved disease free and overall survival. However drug resistance, both innate and acquired, remains an obstacle in the effective treatment of this disease. Apoptotic pathways are frequently altered in both tumor progression and drug resistance; therefore proteins associated with this pathway may have potential as prognostic biomarkers for this disease. Identification of clinical biomarkers that are able to identify patients who are more likely to respond to specific chemotherapy will lead to more personalized, effective, and less toxic therapy. This review focuses on the current status of apoptosis related proteins as biomarkers for colorectal cancer and discusses the possible application of systems approaches in this context.     

生物信息学分析筛选结直肠癌靶基因及评估预后价值

为寻找与结直肠癌发展和预后相关的潜在关键基因及信号通路.从美国国立信息中心NCBI的GEO数据库获得结直肠癌基因表达数据集GSE106582,通过PCA对样本进行分组,利用GEO2R进行综合分析,筛选结直肠癌与癌旁对照组的差异表达基因;通过DAVID在线工具对差异表达基因进行GO本体分析和KEGG通路富集分析,初步分析...     

DNA methylation-based diagnostic,prognostic, and predictive biomarkers in colorectal cancer

DNA methylation is an epigenetic mechanism regulating gene expression. Changes in DNA methylation were suggested to be useful biomarkers for diagnosis, and for the determination of prognosis and treatment response. Here, we provide an overview of methylation-based biomarkers in colorectal cancer.First, we start with the two methylation-based diagnostic biomarkers already approved for colorectal cancer, SEPT9 and the combination of NDRG4 and BMP3. Then, we provide a list-based overview of new biomarker candidates depending on the sample source including plasma, stool, urine, and surgically removed tumor tissues. The most often identified markers like SDC2, VIM, APC, MGMT, SFRP1, SFRP2, and NDRG4 have distinct functions previously linked to tumor progression.Although numerous studies have identified tumor-specific methylation changes, most of these alterations were observed in a single study only. The lack of validation in independent samples means low reproducibility and is a major limitation. The genome-wide determination of methylation status (methylome) can provide data to solve these issues. In the third section of the review, methylome studies focusing on different aspects related to CRC, including precancerous lesions, CRC-specific changes, molecular subtypes, aging, and chemotherapy response are summarized. Notably, techniques simultaneously analyzing a large set of regions can also uncover epigenetic regulation of genes which have not yet been associated with tumorigenesis previously.A remaining constraint of studies published to date is the low patient number utilized in these preventing the identification of clinically valuable biomarker candidates. Either future large-scale studies or the integration of already available methylome-level data will be necessary to uncover biomarkers sufficiently robust for clinical application.     

The sentinel within: exploiting the immune system for cancer biomarkers

The release of proteins from tumors triggers an immune response in cancer patients. These tumor antigens arise from several mechanisms including tumor-specific alterations in protein expression, mutation, folding, degradation, or intracellular localization. Responses to most tumor antigens are rarely observed in healthy individuals, making the response itself a biomarker that betrays the presence of underlying cancer. Antibody immune responses show promise as clinical biomarkers because antibodies have long half-lives in serum, are easy to measure, and are stable in blood samples. However, our understanding of the specificity and the impact of the immune response in early stages of cancer is limited. The immune response to cancer, whether endogenous or driven by vaccines, involves highly specific T lymphocytes (which target tumor-derived peptides bound to self-MHC proteins) and B lymphocytes (which generate antibodies to tumor-derived proteins). T cell target antigens have been identified either by expression cloning from tumor cDNA libraries, or by prediction based on patterns of antigen expression ("reverse immunology"). B cell targets have been similarly identified using the antibodies in patient sera to screen cDNA libraries derived from tumor cell lines. This review focuses on the application of recent advances in proteomics for the identification of tumor antigens. These advances are opening the door for targeted vaccine development, and for using immune response signatures as biomarkers for cancer diagnosis and monitoring.     

Autoantibodies as potential biomarkers for nasopharyngeal carcinoma

Autoantibody signatures, as new biomarkers, may improve the early detection of nasopharyngeal carcinoma (NPC). We constructed a T7 phage cDNA library from mixed NPC tissues, and we isolated 31 tumor-associated proteins using biopan enrichment techniques with sera from NPC patients and from healthy population. DNA sequence analysis showed that among 31 phage-displayed proteins, 22 have sequence identity with known or putative tumor-associated proteins. The results of immunochemical reactivity of patients' sera with phage-expressed proteins showed enrichment in the number of immunogenic phage clones in the biopanning process and also confirmed that antibodies were present in the sera of patients but not in the sera of healthy donors. The autoantibody against phage-expressed protein MAGE, HSP70, Fibronectin, and CD44 measured by ELISA had greater predictive value than that against EBNA-1, respectively. The antibody levels against MAGE in sera positively correlated with the clinical stages of NPC, and the antibody levels against other three proteins partly correlated with the clinical stages of NPC. Our studies suggested that the autoantibodies against tumor-associated antigens in the sera of NPC patients could be used as a screening test for NPC. Studies of the corresponding proteins may have significances in tumor biology, novel drug development, and immunotherapy.     

基于单细胞转录组的多级别胶质瘤异质性及免疫微环境分析揭示了潜在的预后生物标志物

脑胶质瘤(glioma)是中枢神经系统最常见的内在肿瘤,具有发病率高、预后较差等特点。本研究旨在鉴定多形性胶质母细胞瘤(glioblastoma multiforme,GBM)和低级别胶质瘤(lower-grade gliomas, LGG)之间的差异表达基因(differentially expressed genes, DEGs),以探讨不同级别胶质瘤的预后影响因素。从NCBI基因表达综合数据库中收集了胶质瘤的单细胞转录组测序数据,其中包括来自3个数据集的共29 097个细胞样本。对于不同分级的人脑胶质瘤进行分析,经过滤得到21 071个细胞,通过基因本体分析、京都基因与基因组百科全书途径分析,从差异表达基因中筛选出70个基因,我们通过查阅文献,聚焦到delta样典型Notch配体3 (delta like canonical Notch ligand 3,DLL3)这个基因。基于TCGA的基因表达谱交互分析(gene expression profiling interactive analysis, GEPIA)数据库用于探索LGG和GBM中DLL3基因的表达差异,采用基因表达...     

Tissue and serum proteomic profiling for diagnostic and prognostic bladder cancer biomarkers

A panel of biomarkers for the early detection of bladder cancer has not yet been identified. Many different molecules, including DNA, RNA or proteins have been reported but none have provided adequate sensitivity for a single-tier screening test or a test to replace cystoscopy. Therefore, multimarker panels are discussed at present to give a more-precise answer to the biomarker quest. Mass spectrometry or 2D gel-electrophoresis have evolved greatly within recent years and are capable of analyzing multiple proteins or peptides in parallel with high sensitivity and specificity. However, transmission of screening results from one laboratory to another is still the main pitfall of those methods; a fact that emphasizes the need for consistent and standardized procedures as suggested by the Human Proteome Organization (HUPO). In this article, recent results in screening approaches and other proteomic techniques used for biomarker evaluation in bladder cancer are discussed with a focus on serum and tissue biomarkers.     

Tissue and serum proteomic profiling for diagnostic and prognostic bladder cancer biomarkers

A panel of biomarkers for the early detection of bladder cancer has not yet been identified. Many different molecules, including DNA, RNA or proteins have been reported but none have provided adequate sensitivity for a single-tier screening test or a test to replace cystoscopy. Therefore, multimarker panels are discussed at present to give a more-precise answer to the biomarker quest. Mass spectrometry or 2D gel-electrophoresis have evolved greatly within recent years and are capable of analyzing multiple proteins or peptides in parallel with high sensitivity and specificity. However, transmission of screening results from one laboratory to another is still the main pitfall of those methods; a fact that emphasizes the need for consistent and standardized procedures as suggested by the Human Proteome Organization (HUPO). In this article, recent results in screening approaches and other proteomic techniques used for biomarker evaluation in bladder cancer are discussed with a focus on serum and tissue biomarkers.     

Assessment of pre-diagnosis biomarkers of immune activation and inflammation: insights on the etiology of lymphoma

The DNA-modifying processes that are involved in B lymphocyte activation, somatic hypermutation (SHM), and IgH class switch recombination (CSR) have the potential to lead to genetic errors that lead to the genesis of B cell cancers, such as lymphoma. Given the potential contribution of these immune mechanisms to the development of cancer, assessment of the expression of cytokines, and other immune stimulatory molecules that drive B cell activation, prior to lymphoma diagnosis, may provide insights into the etiology of these cancers. Here, we review studies that have examined prediagnosis protein biomarkers for non-Hodgkin lymphoma (NHL), both AIDS-related NHL, as well as NHL seen in immunocompetent populations. Overall, these studies provide support for the notion that B cell hyper-activation is elevated preceding the appearance of AIDS-NHL, particularly those forms of AIDS-NHL that are not driven by EBV infection and that presumably arise from errors in IgH CSR and SHM. In more limited studies, it appears that dysregulation of cytokine production also precedes the diagnosis of NHL in HIV-negative persons. The availability of prediagnosis serum/plasma from cohort studies provides unique opportunities for proteomic approaches to identify novel prediagnosis etiologic biomarkers for NHL.     

LncRNAs as potential diagnostic and prognostic biomarkers in gastric cancer: A novel approach to personalized medicine

Gastric cancer is the third leading cause of cancer death with 5-year survival rate of about 30–35%. Since early detection is associated with decreased mortality, identification of novel biomarkers for early diagnosis and proper management of patients with the best response to therapy is urgently needed. Long noncoding RNAs (lncRNAs) due to their high specificity, easy accessibility in a noninvasive manner, as well as their aberrant expression under different pathological and physiological conditions, have received a great attention as potential diagnostic, prognostic, or predictive biomarkers. They may also serve as targets for treating gastric cancer. In this review, we highlighted the role of lncRNAs as tumor suppressors or oncogenes that make them potential biomarkers for the diagnosis and prognosis of gastric cancer. Relatively, lncRNAs such as H19, HOTAIR, UCA1, PVT1, tissue differentiation-inducing nonprotein coding, and LINC00152 could be potential diagnostic and prognostic markers in patients with gastric cancer. Also, the impact of lncRNAs such as ecCEBPA, MLK7-AS1, TUG1, HOXA11-AS, GAPLINC, LEIGC, multidrug resistance-related and upregulated lncRNA, PVT1 on gastric cancer epigenetic and drug resistance as well as their potential as therapeutic targets for personalized medicine was discussed.     

S100 proteins: Diagnostic and prognostic biomarkers in laboratory medicine

S100 proteins are members of the superfamily of Ca²⁺-binding proteins characterized by the specific Ca²⁺-binding motif, the EF-hand. Proteins of this superfamily are of clinical use as important diagnostic and prognostic biomarkers in adult and pediatric Laboratory Medicine. For example, measurements of troponin are nowadays the ‘gold standard’ in the diagnosis of patients with acute coronary syndrome. Parvalbumins were identified as major fish allergens and blocking antibodies, induced by immunization with a hypoallergenic parvalbumin mutant, were shown to reduce allergic symptoms. Mutations in calmodulin are linked to inherited ventricular tachycardia, and cardiac arrhythmias. S100 proteins, the largest sub-group within the EF-hand protein family, are closely associated with cardiovascular diseases, various types of cancer, inflammation and autoimmune pathologies and brain diseases. The intention of this review is to focus on the clinical use of S100 proteins as biomarkers and potential drug targets helping to improve the diagnosis of these human diseases in children and adults leading to more selective therapeutic interventions.     

NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer

To establish prognostic biomarkers and to identify potential novel therapeutic targets, we performed integrative immunomonitoring of blood and tumor in patients with resectable pancreatic cancer. Flow cytometry (FC) was employed for phenotyping immune cells, multiplex bead assays for plasma cytokine and chemokine determination, and RNA-Seq for the analysis of gene expression in the tumor. Nineteen pancreatic cancer patients were stratified into those with longer or shorter than median recurrence-free survival after surgery (median, 426 days). There were no significant differences between the two groups for clinical parameters including age, sex, surgical procedure, stage, or postoperative adjuvant therapy. However, we found that the percentages of NK cells as assessed by FC in peripheral blood mononuclear cells were higher in patients with late recurrence (P?=?.037). RNA-Seq data indicated no differences in the amount of immune cells or stromal cells between the two groups, although NK cells in the tumor did tend to be higher in patients with late recurrence (P?=?.058). Type I and II IFN signatures were enriched in late-recurring tumors (FDR q-value <0.001), while genes related to KRAS signaling and the epithelial mesenchymal transition (EMT) were enriched in early recurrence. We conclude that tumor-intrinsic properties of metastasis and recurrence influence prognosis, whereas NK cells that might contribute to prevent metastasis are associated with longer recurrence-free survival. Therefore, enhancement of NK cell activity and inhibition of the EMT and KRAS signaling might represent appropriate therapeutic targets following surgical resection of pancreatic cancer.