Molecular and Circulating Biomarkers of Gastric Cancer

Gastric cancer (GC)—a common tumor that affects humans worldwide—is highly malignant with a poor prognosis. GC is frequently not diagnosed until a relatively advanced stage. Early detection and efficient monitoring of tumor dynamics are prerequisites for reducing disease burden and mortality. Minimally invasive methods are needed to establish a diagnosis or monitoring the response to treatment of gastric cancer. Blood-based biomarker assays for the detection of early-stage GC could be of great relevance both for the risk group or for population-wide based screening programs, The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of gastric cancer. Here we review the available literature on plasma classical tumor markers, circulating free microRNAs (cfmiRNAs), circulating cell-free DNA (cfDNA), circulating tumor cells (CTCs), autoantibodies against tumor associated antigens (TAAs), and circulating extracellular vesicles (EVs) for diagnosis and monitoring of gastric cancer. This review summarizes the present status and approaches for these biomarkers, which could be potentially used for early diagnosis and accurate prediction of therapeutic approaches. We also discuss the future perspective and challenges in the search for new biomarkers of gastric cancer.     

A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.     

MicroRNAs as Biomarkers for Diagnosis,Prognosis and Theranostics in Prostate Cancer

Prostate cancer (PC) includes several phenotypes, from indolent to highly aggressive cancer. Actual diagnostic and prognostic tools have several limitations, and there is a need for new biomarkers to stratify patients and assign them optimal therapies by taking into account potential genetic and epigenetic differences. MicroRNAs (miRNAs) are small sequences of non-coding RNA regulating specific genes involved in the onset and development of PC. Stable miRNAs have been found in biofluids, such as serum and plasma; thus, the measurement of PC-associated miRNAs is emerging as a non-invasive tool for PC detection and monitoring. In this study, we conduct an in-depth literature review focusing on miRNAs that may contribute to the diagnosis and prognosis of PC. The role of miRNAs as a potential theranostic tool in PC is discussed. Using a meta-analysis approach, we found a group of 29 miRNAs with diagnostic properties and a group of seven miRNAs with prognostic properties, which were found already expressed in both biofluids and PC tissues. We tested the two miRNA groups on The Cancer Genome Atlas dataset of PC tissue samples with a machine-learning approach. Our results suggest that these 29 miRNAs should be considered as potential panel of biomarkers for the diagnosis of PC, both as in vivo non-invasive test and ex vivo confirmation test.     

MicroRNAs as Innovative Biomarkers for Inflammatory Bowel Disease and Prediction of Colorectal Cancer

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). These are autoimmune diseases of the gastrointestinal tract with a chronic relapsing and remitting course. Due to complex interactions between multiple factors in the etiology of IBD, the discovery of new predictors of disease course and response to therapy, and the development of effective therapies is a significant challenge. The dysregulation of microRNAs (miRNAs), a class of conserved endogenous, small non-coding RNA molecules with a length of 18–25 nucleotides, that regulate gene expression by an RNA interference process, is implicated in the complex pathogenetic context of IBD. Both tissue-derived, circulating, and fecal microRNAs have been explored as promising biomarkers in the diagnosis and the prognosis of disease severity of IBD. In this review, we summarize the expressed miRNA profile in blood, mucosal tissue, and stool and highlight the role of miRNAs as biomarkers with potential diagnostic and therapeutic applications in ulcerative colitis and Crohn’s disease. Moreover, we discuss the new perspectives in developing a new screening model for the detection of colorectal cancer (CRC) based on fecal miRNAs.     

Circulating Exosomal miRNAs as Biomarkers for the Diagnosis and Prognosis of Colorectal Cancer

Colorectal cancer (CRC) is one of the most common malignant tumors in the gastrointestinal tract. It is a multifactorial disease that involves environmental factors, genetic factors, and lifestyle factors. Due to the absence of specific and sensitive biomarkers, CRC patients are usually diagnosed at an advanced stage and consequently suffer from a low 5-year overall survival rate. Despite improvements in surgical resection and adjuvant chemotherapy, the prognosis of patients with CRC remains unfavorable due to local and distant metastases. Several studies have shown that small noncoding RNAs, such as microRNAs packed in exosomes, are potential biomarkers in various types of cancers, including CRC, and that they can be detected in a stable form in both serum and plasma. In this review, we report the potential of circulating exosomal miRNAs to act as biomarkers for the diagnosis and prognosis of CRC.     

Circulating MicroRNAs as Biomarkers of Acute Stroke

MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. Due to the complexity of the pathology, identifying stroke specific microRNAs has been a challenge. This study shows that microRNA profiles reflect not only the temporal progression of stroke but also the specific etiologies. A panel of 32 microRNAs, which could differentiate stroke etiologies during acute phase was identified and verified using a customized TaqMan Low Density Array (TLDA). Furthermore we also found 5 microRNAs, miR-125b-2*, -27a*, -422a, -488 and -627 to be consistently altered in acute stroke irrespective of age or severity or confounding metabolic complications. Differential expression of these 5 microRNAs was also observed in rat stroke models. Hence, their specificity to the stroke pathology emphasizes the possibility of developing these microRNAs into accurate and useful tools for diagnosis of stroke.     

Cytokines and MicroRNAs as Candidate Biomarkers for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with varied course and symptoms. Its etiology is very complex and not clearly understood. There is growing evidence of the important role of cytokines in SLE pathogenesis, as well as their utility as biomarkers and targets in new therapies. Other potential new SLE biomarkers are microRNAs. Recently, over one hundred different microRNAs have been demonstrated to have a significant impact on the immune system. Various alterations in these microRNAs, associated with disease pathogenesis, have been described. They influence the signaling pathways and functions of immune response cells. Here, we aim to review the emerging new data on SLE etiology and pathogenesis.     

Proteomics of Muscle Microdialysates Identifies Potential Circulating Biomarkers in Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is caused by a complex epigenetic mechanism finally leading to the misexpression of DUX4 in skeletal muscle. Detecting DUX4 and quantifying disease progression in FSHD is extremely challenging, thus increasing the need for surrogate biomarkers. We applied a shotgun proteomic approach with two different setups to analyze the protein repertoire of interstitial fluids obtained from 20 muscles in different disease stages classified by magnetic resonance imaging (MRI) and serum samples from 10 FSHD patients. A total of 1156 proteins were identified in the microdialysates by data independent acquisition, 130 of which only found in muscles in active disease stage. Proteomic profiles were able to distinguish FSHD patients from controls. Two innate immunity mediators (S100-A8 and A9) and Dermcidin were upregulated in muscles with active disease and selectively present in the sera of FSHD patients. Structural muscle and plasminogen pathway proteins were downregulated. Together with the upstream inhibition of myogenic factors, this suggests defective muscle regeneration and increased fibrosis in early/active FSHD. Our MRI targeted exploratory approach confirmed that inflammatory response has a prominent role, together with impaired muscle regeneration, before clear muscle wasting occurs. We also identified three proteins as tissue and possibly circulating biomarkers in FSHD.     

MicroRNAs and ‘Sponging’ Competitive Endogenous RNAs Dysregulated in Colorectal Cancer: Potential as Noninvasive Biomarkers and Therapeutic Targets

The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells contained within this complex organ system has been shown to be highly regulated by the effect of microRNAs (miRNA). Multiple efforts have uncovered that these miRNAs are often tightly influential in either the suppression or overexpression of inflammatory, apoptotic, and differentiation-related genes and proteins in a variety of cell types in colorectal cancer (CRC). The early detection of CRC and other GI cancers can be difficult, attributable to the invasive nature of prophylactic colonoscopies. Additionally, the levels of miRNAs associated with CRC in biofluids can be contradictory and, therefore, must be considered in the context of other inhibiting competitive endogenous RNAs (ceRNA) such as lncRNAs and circRNAs. There is now a high demand for disease treatments and noninvasive screenings such as testing for bloodborne or fecal miRNAs and their inhibitors/targets. The breadth of this review encompasses current literature on well-established CRC-related miRNAs and the possibilities for their use as biomarkers in the diagnoses of this potentially fatal GI cancer.     

Biomarkers for Cancer Cachexia: A Mini Review

Cancer cachexia is a common condition in many cancer patients, particularly those with advanced disease. Cancer cachexia patients are generally less tolerant to chemotherapies and radiotherapies, largely limiting their treatment options. While the search for treatments of this condition are ongoing, standards for the efficacy of treatments have yet to be developed. Current diagnostic criteria for cancer cachexia are primarily based on loss of body mass and muscle function. However, these criteria are rather limiting, and in time, when weight loss is noticeable, it may be too late for treatment. Consequently, biomarkers for cancer cachexia would be valuable adjuncts to current diagnostic criteria, and for assessing potential treatments. Using high throughput methods such as “omics approaches”, a plethora of potential biomarkers have been identified. This article reviews and summarizes current studies of biomarkers for cancer cachexia.     

Molecular and Circulating Biomarkers in Patients with Glioblastoma

Glioblastoma is the most aggressive malignant tumor of the central nervous system with a low survival rate. The difficulty of obtaining this tumor material represents a major limitation, making the real-time monitoring of tumor progression difficult, especially in the events of recurrence or resistance to treatment. The identification of characteristic biomarkers is indispensable for an accurate diagnosis, the rigorous follow-up of patients, and the development of new personalized treatments. Liquid biopsy, as a minimally invasive procedure, holds promise in this regard. The purpose of this paper is to summarize the current literature regarding the identification of molecular and circulating glioblastoma biomarkers and the importance of their integration as a valuable tool to improve patient care.     

Exosomal MicroRNAs as Potential Biomarkers of Hepatic Injury and Kidney Disease in Glycogen Storage Disease Type Ia Patients

Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.     

HIV-Associated Cancer Biomarkers: A Requirement for Early Diagnosis

Globally, HIV/AIDS and cancer are increasingly public health problems and continue to exist as comorbidities. The sub-Saharan African region has the largest number of HIV infections. Malignancies previously associated with HIV/AIDS, also known as the AIDS-defining cancers (ADCs) have been documented to decrease, while the non-AIDS defining cancer (NADCs) are on the rise. On the other hand, cancer is a highly heterogeneous disease and precision oncology as the most effective cancer therapy is gaining attraction. Among HIV-infected individuals, the increased risk for developing cancer is due to the immune system of the patient being suppressed, frequent coinfection with oncogenic viruses and an increase in risky behavior such as poor lifestyle. The core of personalised medicine for cancer depends on the discovery and the development of biomarkers. Biomarkers are specific and highly sensitive markers that reveal information that aid in leading to the diagnosis, prognosis and therapy of the disease. This review focuses mainly on the risk assessment, diagnostic, prognostic and therapeutic role of various cancer biomarkers in HIV-positive patients. A careful selection of sensitive and specific HIV-associated cancer biomarkers is required to identify patients at most risk of tumour development, thus improving the diagnosis and prognosis of the disease.     

MicroRNAs in Salivary Exosome as Potential Biomarkers of Aging

The aim of this study was to examine whether salivary exosomal miRNAs could be identified as aging biomarkers. Fifteen young healthy volunteers (median age, 21.0 years) and 13 old individuals (median age, 66.0 years) were recruited. Unstimulated whole saliva was collected, salivary exosomes were isolated, and total RNA was extracted. In a microarray, 242 miRNAs were commonly detected in these two mixed samples. Based on the cut-off values of 2- or 0.5-fold changes (FC) and regulatory power for aging process, six candidate miRNAs (miR-24-3p, miR-371a-5p, miR-3175, miR-3162-5p, miR-671-5p, and miR-4667-5p) were selected. After comparing each total RNA obtained by the 15 young and 13 old individuals to validate the FC values using quantitative real-time PCR, miR-24-3p was identified as a novel candidate aging biomarker. This pilot study suggested that salivary exosomal miRNAs could be identified as candidate aging biomarkers. To confirm whether miR-24-3p in salivary exosomes are suitable biomarkers of aging, further validation research is required.     

Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%–>50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control–case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.     

Biomarkers for colorectal cancer

Colorectal cancer (CRC) is the third most common epithelial malignancy in the world. Since CRC develops slowly from removable precancerous lesions, detection of the lesion at an early stage by regular health examinations can reduce the incidence and mortality of this malignancy. Colonoscopy significantly improves the detection rate of CRC, but the examination is expensive and inconvenient. Therefore, we need novel biomarkers that are non-invasive to enable us to detect CRC quite early. A number of validation studies have been conducted to evaluate genetic, epigenetic or protein markers for identification in the stool and/or serum. Currently, the fecal occult blood test is the most widely used method of screening for CRC. However, advances in genomics and proteomics will lead to the discovery of novel non-invasive biomarkers.