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.     

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.     

Predictive and prognostic factors in the complex treatment of patients with colorectal cancer

Colon cancer is the second most prevalent lethal cancer. The main cause for high mortality rate is that the prognosis for progressed metastatic colon cancer is most unfavorable. Recent data suggest that disease outcome can be further improved by the addition of targeted biological agents to the first- or second-line treatment. As a result of molecularly targeted anti-EGFR therapies (cetuximab and panitumumab) complementing chemotherapy, liver metastases can reduce in size and become operable in certain patients, which can contribute to the complete recovery of the patient. The main problem, however, is the fact that a positive response only occurs in one third of the patients, even in the case of chemotherapy combined protocol, and the side effects are considerable. For the application of individually tailored treatments, it is an urgent need to develop a system of biomarkers that can predict the effect of treatment and provide information about the optimal selection of both chemotherapy and biological treatment. It should be clarified what the most important requirements of a good and reliable biomarker are. As currently there is no precise predictive molecular diagnostics at our disposal, oncologists have to make one of two choices: they treat a large number of patients with anti-EGFR agents which has negative effects on the quality of life and also reduces the patient's chances of getting appropriate treatment or, if the oncologists refuse to take risks, they omit the use of anti-EGFR treatment in which case those patients for whom this would have been the appropriate treatment are also denied the chance of short-term survival or recovery. Clinical data (response rate, time to progression (TTP) and overall survival (OS)) of 130 colorectal cancer patients have been retrospectively analyzed. Patients have received different chemotherapy protocols in combination with anti-VEGF antibody or with anti-EGFR antibody therapies. EGFR expression was evaluated with immunohistochemistry, KRAS, BRAF and PIK3CA mutations were evaluated by direct sequencing and high resolution melting analysis in the archived formalin-fixed, paraffin-embedded tissue samples. The study found similar efficacy of first-line therapeutic protocols. Protocols combining chemotherapy with biological therapies achieved better overall survival but this difference was not significant (OS: 35.9 versus 36.7 months). The frequency of KRAS mutations was 44% (n=100). None of the KRAS mutant tumors responded to the anti-EGFR monotherapy. TTP in the case of cetuximab monotherapy was twice longer (208 months) than in the KRAS mutant tumors (104 months). One BRAF mutant tumor was also identified (4%) This tumor was also resistant to cetuximab monotherapy. The KRAS and BRAF mutations excluded each other. Except one case, the KRAS status was identical in both the primary tumor and the metastasis. In contrast, PIK3CA mutations were heterogeneous in different tumor samples. In 5 out of 6 cases the mutation status of PIK3CA was different in the primary tumor and the metastasis. New biological therapies provide an additional clinical benefit only for a subset of patients. We need biomarkers to identify these patients. KRAS and most probably BRAF testing can double the efficacy of the anti-EGFR therapies, but we need additional molecular diagnostic tests. PIK3CA is an important candidate but we might need to take biopsy directly from the metastasis or we have to evaluate the circulating tumor cells to judge the molecular status of distant metastasis.     

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 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.     

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.     

Epigenetic biomarkers in colorectal cancer: premises and prospects

Context: Colorectal cancer is one of the most common cancers worldwide. Epigenetic alterations play an important role in the pathogenesis of the colorectal cancer.

Objective: This review has focused on the most recent investigations, which has suggested potential epigenetic biomarkers in colorectal cancer.

Methods: Evidences were achieved by searching online medical databases including Google scholar, Pubmed, Scopus and Science Direct.

Results: Extensive studies have indicated that aberrant epigenetic modifications could serve as potential biomarkers for diagnosis, prognosis and prediction of colorectal cancer.

Conclusion: Advances in aberrant epigenetic modifications can open new avenues for exploration of reliable and robust biomarkers to improve the management of CRC patients.     

MicroRNAs as potential investigative and predictive biomarkers in colorectal cancer

Colorectal cancer (CRC) is a noticeable reason of cancer-associated deaths with a high incidence and mortality rate. Countless effort have been put into the improving clinical management of CRC patients including more effective tools and a wide variety of biomarkers for diagnostic, prognostic or predictive purposes. In recent years, dysregulated miRNAs have been emerged as highly sensitive and specific markers to manage CRC in an effective way. They can play key roles in carcinogenesis as potential oncogenes, tumor suppressors or regulators of cancer network. Therefore, miRNAs may serve as molecular tools that can be quantified and used in diagnostic and prognostic approaches. Growing evidence also suggests that forced expression of tumor suppressor miRNAs or inhibiting the oncogene ones, can be used as a novel treatment strategy. In this review, we focus on the clinical applications of miRNAs as promising biomarkers of early cancer detection, prognosis and treatment.     

Non-coding RNAs as emerging regulators and biomarkers in colorectal cancer

Molecular and Cellular Biochemistry - CRC is the third most common cancer occurring worldwide and the second leading cause of cancer deaths. In the year 2020, 1,931,590 new cases of CRC and 935,173...     

Faecal microbial biomarkers in early diagnosis of colorectal cancer

Colorectal cancer (CRC) is ranked as the second most common cause of cancer deaths and the third most common cancer globally. It has been described as a ‘silent disease’ which is often easily treatable if detected early—before progression to carcinoma. Colonoscopy, which is the gold standard for diagnosis is not only expensive but is also an invasive diagnostic procedure, thus, effective and non-invasive diagnostic methods are urgently needed. Unfortunately, the current methods are not sensitive and specific enough in detecting adenomas and early colorectal neoplasia, hampering treatment and consequently, survival rates. Studies have shown that imbalances in such a relationship which renders the gut microbiota in a dysbiotic state are implicated in the development of adenomas ultimately resulting in CRC. The differences found in the makeup and diversity of the gut microbiota of healthy individuals relative to CRC patients have in recent times gained attention as potential biomarkers in early non-invasive diagnosis of CRC, with promising sensitivity, specificity and even cost-effectiveness. This review summarizes recent studies in the application of these microbiota biomarkers in early CRC diagnosis, limitations encountered in the area of the faecal microbiota studies as biomarkers for CRC, and future research exploits that address these limitations.     

Serum ferritin in colorectal cancer patients and its prognostic evaluation

The aim of this study was to investigate the relationship between preoperative serum ferritin levels, clinico-pathological parameters and survival analysis of patients with colorectal cancer. Ninety-four patients (57 males) with a mean age of 65 years (39-87 years) underwent 63 curative and 31 palliative operations. Follow-up was at least 5 years. Patients were categorized with normal (30-215 ng/mL in men and 11-148 ng/mL in women), low, or high serum ferritin levels. Prognostic evaluation was undertaken with stratified survival analysis and Cox's regression model. Twenty-nine of the patients (30.9%) had raised ferritin levels and 14 (14.9%) had low values. Comparisons of the survival curves showed significant differences in stage C disease; specifically, patients with either low or high ferritin levels had a shorter survival than patients with normal levels. Patients who underwent palliative surgery and had high ferritin serum values also had a shorter survival. In multivariate analysis, the variables with a negative effect on survival were stage, serum ferritin levels and age. Our data suggest that patients with advanced colorectal cancer having normal preoperative serum ferritin levels may have a better prognosis, although the prognostic value related to this association requires further investigation.     

Progress in the identification of plasma biomarkers of colorectal cancer

Proteomic analysis of human tissue and plasma samples has been a useful tool in recent years for the identification of potential biomarkers to aid in the early diagnosis of colorectal cancer. However, biomarkers relating to the crucial transition between adenomatous lesions and invasive colorectal malignancy have not previously been described. The work of Choi et al. (Proteomics 2013, 13, 2361–2374) attempts to address this issue. Using plasma samples from age‐matched patients with colorectal adenomas or invasive disease this group identified a range of plasma proteins and cytokines that were differentially expressed. This information not only provides insights into the biology of the adenoma to carcinoma progression sequence but it also represents a step towards the goal of achieving diagnostically accurate and clinically acceptable biomarkers in early colorectal cancer.     

Proteomic analysis of colorectal cancer: discovering novel biomarkers

Colorectal cancer is one of the most common cancers in the Western world. When detected at an early stage, the majority of cancers can be cured with current treatment modalities. However, most cancers present at an intermediate stage. The discovery of sensitive and specific biomarkers has the potential to improve preclinical diagnosis of primary and recurrent colorectal cancer, and holds the promise of prognostic and therapeutic application. Current biomarkers such as carcinoembryonic antigen lack sensitivity and specificity for general population screening. This review aims to highlight the role of current proteomic technologies in the discovery and validation of potential biomarkers with a view to translation to the clinic.     

Identification of biomarkers for colorectal cancer through proteomics-based approaches

The early detection of colorectal cancer is one of the great challenges in the battle against this disease. However, owing to its heterogeneous character, single markers are not likely to provide sufficient diagnostic power to be used in colorectal cancer population screens. This review provides an overview of recent studies aimed at the discovery of new diagnostic protein markers through proteomics-based approaches. It indicates that studies that start with the proteomic analysis of tumor tissue or tumor cell lines (near the source) have a high potential to yield novel and colorectal cancer-specific biomarkers. In the next step, the diagnostic accuracy of these candidate markers can be assessed by a targeted ELISA assay using serum from colorectal cancer patients and healthy controls. Instead, direct proteomic analysis of serum yields predominantly secondary markers composed of fragments of abundant serum proteins that may be associated with tumor-associated protease activity, and alternatively, immunoproteomic analysis of the serum antibody repertoire provides a valuable tool to identify the molecular imprint of colorectal cancer-associated antigens directly from patient serum samples. The latter approach also allows a relatively easy translation into targeted assays. Eventually, multimarker assays should be developed to reach a diagnostic accuracy that meets the stringent criteria for colorectal cancer screening at the population level.     

Noninvasive molecular biomarkers for the detection of colorectal cancer

Colorectal cancer (CRC) is the third most common malignancy in the world. Because CRC develops slowly from removable precancerous lesions, detection of the disease at an early stage during regular health examinations can reduce both the incidence and mortality of the disease. Although sigmoidoscopy offers significant improvements in the detection rate of CRC, its diagnostic value is limited by its high costs and inconvenience. Therefore, there is a compelling need for the identification of noninvasive biomarkers that can enable earlier detection of CRC. Accordingly, many validation studies have been conducted to evaluate genetic, epigenetic or protein markers that can be detected in the stool or in serum. Currently, the fecal-occult blood test is the most widely used method of screening for CRC. However, advances in genomics and proteomics combined with developments in other relevant fields will lead to the discovery of novel non invasive biomarkers whose usefulness will be tested in larger validation studies. Here, noninvasive molecular biomarkers that are currently used in clinical settings and have the potential for use as CRC biomarkers are discussed.     

Proteomic analysis of colorectal cancer: discovering novel biomarkers

Colorectal cancer is one of the most common cancers in the Western world. When detected at an early stage, the majority of cancers can be cured with current treatment modalities. However, most cancers present at an intermediate stage. The discovery of sensitive and specific biomarkers has the potential to improve preclinical diagnosis of primary and recurrent colorectal cancer, and holds the promise of prognostic and therapeutic application. Current biomarkers such as carcinoembryonic antigen lack sensitivity and specificity for general population screening. This review aims to highlight the role of current proteomic technologies in the discovery and validation of potential biomarkers with a view to translation to the clinic.     

Immunohistochemical investigation of prognostic biomarkers in resected colorectal liver metastases: a systematic review and meta-analysis

Background

Many studies have investigated the prognostic role of biomarkers in colorectal liver metastases (CRLM). However, no biomarker has been established in routine clinical practice. The aim of this study was to scrutinize the current literature for biomarkers evaluated by immunohistochemistry as prognostic markers in patients with resected CRLM.

Methods

A systematic review was performed according to the PRISMA guidelines. Articles were identified in the PubMed database with selected search terms and by cross-references search. The REMARK quality criteria were applied. Markers were included if they reported the prognostic impact of immunohistochemical markers in a multivariable setting in relation to overall survival (OS). A meta-analysis was conducted when more than one original article provided survival data of a marker.

Results

In total, 26 biomarkers were identified as independent significant markers for OS in resected CRLM. These biomarkers were found to be involved in multiple oncogenic signalling pathways that control cell growth, apoptosis, angiogenesis and evasion of immune detection. Among these biomarker candidates were Ki-67, EGFR, p53, hTERT, CD34, TSP-1, KISS1, Aurora kinase A and CDX2. CD34 and TSP-1 were reported as significantly associated with survival by more than one study and where therefore pooled in a meta-analysis.

Conclusion

A number of independent prognostic biomarkers for resected CRLM were identified. However, most markers were evaluated in a retrospective setting with small patient cohorts, without external validation. Large, prospective, multicentre studies with standardised methods are needed before biomarkers can translated into the clinic.