Biomarkers for gastric cancer: prognostic,predictive or targets of therapy?

Gastric cancer is an aggressive disease often diagnosed at an advanced stage. Despite improvements in surgical and adjuvant treatment approaches, gastric cancer remains a global public health problem with a 5-year overall survival of less than 25 %. This is a heterogeneous disease, both in terms of biology and genetics, and many prognostic biomarkers have been pointed out in the literature; nevertheless, their application remains debatable. In this review, we opted to give relevance to those biomarkers that have been the subject of studies with significant statistical power, which have been replicated and have been/are in targeted therapy clinical trials and, which as a consequence, have their prognostic and/or predictive value established. Some gastric cancer biomarkers that may help in defining the course of treatment are also discussed. Accepted practical guidelines, wet-lab protocols for the detection of these biomarkers, as well as ongoing and completed clinical trials have been compiled. In summary, clinical approaches based on the combination of correct staging with targeted and conventional systemic therapies may improve gastric cancer patients’ outcome, but are only in their infancy. Some major challenges in identifying reliable prognostic/predictive biomarkers are individual genetic variation and tumour heterogeneity that often influence response to therapy and drug resistance. Prognostic and predictive biomarkers may nevertheless be extremely valuable to correctly stratify gastric cancer patients for treatment and, ultimately, improve survival.     

MicroRNA profiling of clear cell renal cell carcinoma by whole‐genome small RNA deep sequencing of paired frozen and formalin‐fixed,paraffin‐embedded tissue specimens

Renal cell carcinoma (RCC) is one of the leading causes of cancer mortality. Characterization of microRNA (miRNA) expression of RCC will help disclose new pathogenic pathways in tumourigenesis and progression and may lead to the development of molecular biomarkers and target‐specific therapies for diagnosis, prognostication and treatment. With limitations in test specificity and the ability to detect novel miRNA and other small non‐coding RNAs (smRNAs), microarray and RT–PCR techniques are being replaced by the evolving deep‐sequencing technologies, at least in the discovery phase. Until now, cancer miRNA profiling of human benign and tumour specimen sets, using smRNA deep‐sequencing (smRNA‐seq), has not been reported. Specifically, due to concern over possible poor RNA quality/integrity, formalin‐fixed paraffin‐embedded (FFPE) samples have not been used for such studies. Here, we performed whole‐genome smRNA‐seq analysis using a benign and RCC specimen set and have successfully profiled the miRNA expression. Studies performed on paired frozen and FFPE specimens showed very similar results. Moreover, a comparison study of microarray, deep‐sequencing and RT–PCR methodologies also showed a high correlation among the three technologies. To our knowledge, this is the first study to demonstrate that FFPE specimens can be used reliably for miRNA deep‐sequencing analysis, making future large‐scale clinical cohort/trial‐based studies possible. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Targeted therapies in gynaecological cancers

The treatment of cancer has changed dramatically over the last decade, driven by increased understanding of the cancer genome, immune landscape, molecular alterations and aberrant pathways that drive cancer progression. Advances in molecular biology have led to the development of targeted agents, including monoclonal antibodies, small molecules and check-point inhibitors. Unlike chemotherapy, which inhibits DNA replication and mitosis, these agents target cancer signalling pathways, stroma, immune microenvironment and vasculature in tumour tissues. In gynaecological cancer, drugs targeting defective DNA repair, such as PARP inhibitors, have been approved for advanced ovarian cancer, and drugs targeting angiogenesis have been used in the treatment of advanced or recurrent ovarian and cervical cancers. Immune check-point inhibitors such as anti-PD-1/PD-L1 antibodies have proved successful for mismatch repair-deficient endometrial cancers and HPV-targeted therapies are under development for HPV-related malignancies. In this era of precision medicine, improved understanding of cancer biology and genomics needs to be utilised to develop predictive biomarkers for these targeted therapies to maximise patient benefit.     

Molecular genetics and genomics progress in urothelial bladder cancer

The clinical management of solid tumor patients has recently undergone a paradigm shift as the result of the accelerated advances in cancer genetics and genomics. Molecular diagnostics is now an integral part of routine clinical management in lung, colon, and breast cancer patients. In a disappointing contrast, molecular biomarkers remain largely excluded from current management algorithms of urologic malignancies. The need for new treatment alternatives and validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management is pressing. Identifying robust predictive biomarkers that can stratify response to newly introduced targeted therapeutics is another crucially needed development. The following is a brief discussion of some promising candidate biomarkers that may soon become a part of clinical management of bladder cancers.     

Brain cancer stem cells display preferential sensitivity to Akt inhibition

Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer superior efficacy and less toxicity than conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biology may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched nonstem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased the survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anticancer stem cell therapies.     

Expression and clinical significance of the nin one binding protein and p38 MAPK in prostate carcinoma

Background: Prostate carcinoma is a major cause of morbidity and mortality. The MAPK Signaling Pathway plays an important role in multiple tumors, including prostate carcinoma. MAPK signaling is mediated by ERK1/2, JNK and p38 MAPK, which are important in the control of cell proliferation, differentiation and apoptosis. However, relatively little is known about the regulatory mechanism of p38 MAPK in prostate cancers. NOB1 is among the most novel topic in MAPK studies currently. Recent studies found its vital role in tumor metastasis in glioblastoma proliferation, however, its expression profile and its prognostic value in prostate carcinoma have not been investigated. Methods: To determine the relationship between NOB1 and p38 MAPK expressions, a population-based study was conducted for immunohistochemical staining analysis of tumor tissues, in matched malignant and nonmalignant prostatectomy samples from 132 PCa patients. Moreover, Western blot analysis and NOB1 interference studies of prostate cancer cell lines. To evaluate the diagnostic and prognostic between NOB1 and p38 MAPK in prostate cancer (PCa) tissue after radical prostatectomy, the hypothesis that prostate cancers with NOB1 expression have distinct clinical, prognostic and molecular attributes was tested. Results: Among 132 prostate cancers, NOB1 expression was detected in 117 (88.7%) tumors by immunohistochemistry. NOB1 and p38 MAPK expression had significant positive correlation with carcinogenesis, tumor progression and patient survival. Immunohistochemically, NOB1 expression in prostate cancer was independently associated with p38 MAPK activation (P=0.0002). Furthermore, p38 MAPK expression was completely suppressed by NOB1 interference in the prostate cancer cell lines DU-145 and PC-3. Conclusions: NOB1 expression status was closely correlated with important histopathologic characteristics and the recurrence and metastasis of prostate carcinomas. These data support a potential link between NOB1 and p38 MAPK, and suggest that NOB1 may identify a subset of prostate cancer patients with a poor prognosis. This study proved that NOB1 in PCa tissue can be used, in combination with traditional clinicopathological factors, as promising diagnostic and prognostic tools.     

The roles and applications of autoantibodies in progression,diagnosis, treatment and prognosis of human malignant tumours

The existence of autoantibodies towards an individual's own proteins or nucleic acids has been established for more than 100 years, and for a long period, these autoantibodies have been believed to be closely associated with autoimmune diseases. However, in recent years, researchers have become more interested in the role and application of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Over the past few decades, numerous epidemiological studies have shown that the risk of certain cancers is significantly altered (increased or decreased) in patients with autoimmune diseases, which suggests that autoantibodies may play either promoting or suppressing roles in cancer progression. The idea that autoantibodies are directly involved in tumour progression gains special support by the findings that some antibodies secreted by a variety of cancer cells can promote their proliferation and metastasis. Because the cancer cells generate cell antigenic changes (neoantigens), which trigger the immune system to produce autoantibodies, serum autoantibodies against tumour-associated antigens have been established as a novel type of cancer biomarkers and have been extensively studied in different types of cancer. The autoantibodies as biomarkers in cancer diagnosis are not only more sensitive and specific than antigens, but also could appear before clinical evidences of the tumours, thus disclosing them. The observations that cancer risk is lower in patients with some autoimmune diseases suggest that certain autoantibodies may be protective from certain cancers. Moreover, the presence of autoantibodies in healthy individuals implies that it could be safe to employ autoantibodies to treat cancer. Of note, an autoantibodies derived from lupus murine model received much attention due to their selective cytotoxicity for malignant tumour cell without harming normal ones. These studies showed the therapeutic value of autoantibodies in cancer. In this review, we revisited the pathological or protective role of autoantibodies in cancer progression, summarize the application of autoantibodies in cancer diagnosis and prognosis, and discuss the value of autoantibodies in cancer therapy. The studies established to date suggest that autoantibodies not only regulate cancer progression but also promise to be valuable instruments in oncological diagnosis and therapy.     

A critical appraisal of prognostic and predictive factors for common lung cancers

The outlook for patients with lung cancer remains poor despite advances in the understanding of the pathology and biology of this disease. To optimize treatment protocols prognostic data are essential. The current era with molecular research on mRNA expression analysis and proteomics will lead to a plethora of new molecular markers, which are likely to be correlated, at least in part, with each other and with disease activity, progression and survival. However, although the number of prognostic factors analysed in published systematic reviews on lung cancer is large, the scope of these factors in individual studies is often narrow. In daily practice prognostic factors other than general TNM staging are not implemented. To assess the efficacy of new prognostic factors for the management of individual patients with non-small cell lung cancer, studies with clinically relevant modelling are required. In this review arguments are provided to use a model combining radiological and histopathological growth rate, histopathological diagnosis and molecular characteristics as markers for metastatic capacity, tumour volume doubling time and expected response to targeted therapy. This may reveal time-related predictive information useful for treatment guidance of the individual patient.     

An insight into the roles of piRNAs and PIWI proteins in the diagnosis and pathogenesis of oral,esophageal, and gastric cancer

P-Element induced wimpy testis (PIWI)-interacting RNA (piRNA) is a member of the non-coding RNAs family. Four PIWI proteins are found to be expressed in humans. The number of studies focusing on the roles of piRNAs and PIWI proteins in the field of cancer is increasing. Oral, esophageal, and gastric cancers are considered as important causes of death. PIWI proteins and piRNAs are suggested to be involved in the pathogenesis of these diseases. Thus, studying these molecules may be beneficial for finding new therapeutics. Since it is shown that currently used biomarkers for these cancers have low sensitivity and specificity, there is a necessity for identifying novel non-invasive biomarkers which are highly sensitive and specific. This paper will provide an insight into current knowledge about the functions of PIWI proteins and piRNAs in the oral, esophageal, and gastric cancer. We discuss how PIWI proteins and piRNAs can be involved in the pathogenesis of these cancers. Moreover, we review the studies concerning with the roles of PIWI proteins and piRNAs as biomarkers which are used for diagnostic and prognostic purposes.     

Modulating apoptosis as a target for effective therapy

Alterations in cell proliferation and cell death are essential determinants in the pathogenesis and progression of several diseases such as cancer, neurodegenerative disorders or autoimmune diseases among others. Complex networks of regulatory factors determine whether cells proliferate or die. Recent progress in understanding the molecular changes offer the possibility of specifically targeting molecules and pathways to achieve more effective and rational therapies. Drugs that target molecules involved in apoptosis are used as treatment against several diseases. Candidates such as TNF death receptor family, caspase inhibitors, antagonists of the p53-MDM2 interaction, NF-kappaB and PI3K pathways and Bcl-2 family members have been targeted as cancer cell killing agents. Moreover, apoptosis of tumor cells can also be achieved by targeting the inhibitor of apoptosis proteins, IAPs, in addition to the classical antiproliferative approach. Disruption of STAT activation and interferon beta therapy have been used as a treatment to prevent the progression of some autoimmune diseases. In models of Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, blocking of Par-4 expression or function, as well as caspase activation, prevents neuronal cell death. Finally, it has been shown that gene therapy may be an encouraging approach for treatment of neurodegenerative disorders.     

Identifizierung und Validierung klinisch relevanter molekularer Veränderungen im Prostatakarzinom

Significant cellular alterations required for the development and progression of cancers are detectable at the molecular level and represent potential targets for gene-specific therapies. Modern chip techniques allow the parallel analysis of virtually all known human genes and proteins in a single experiment. Using modern high-throughput techniques, numerous potential new biomarkers for the diagnosis and prediction of prostate cancer have been identified. However, so far none of these markers has improved clinical practice. One of the most important challenges in the coming years is the extensive clinical validation of molecular data using clinically relevant end points. For this venture the pivotal prerequisite is the availability of large, comprehensively annotated and standardized high-quality bioresources.     

Human asthma phenotypes: from the clinic, to cytokines, and back again

A large body of experimental evidence supports the hypothesis that T-helper 2 (Th2) cytokines orchestrate allergic airway inflammation in animal models. However, human asthma is heterogeneous with respect to clinical features, cellular sources of inflammation, and response to common therapies. This disease heterogeneity has been investigated using sputum cytology as well as unbiased clustering approaches using cellular and clinical data. Important differences in cytokine-driven inflammation may underlie this heterogeneity, and studies in human subjects with asthma have begun to elucidate these molecular differences. This molecular heterogeneity may be assessed by existing biomarkers (induced sputum evaluation or exhaled nitric oxide testing) or may require novel biomarkers. Effective testing and application of emerging therapies that target Th2 cytokines will depend on accurate and easily obtained biomarkers of this molecular heterogeneity in asthma. Furthermore, whether other non-Th2 cytokine pathways underlie airway inflammation in specific subsets of patients with asthma is an unresolved question and an important goal of future research using both mouse models and human studies.     

Molecular assays in breast cancer pathology

Recent advances in understanding the molecular pathology of breast cancer offer significant potential to identify patients who may benefit from adjuvant therapies. To date, few of these advances are utilised in a routine setting. We review molecular assays that are currently in use or are in the advanced stages of development, which may be used as predictive or prognostic biomarkers in breast cancer.The only widely used breast cancer molecular assay is in situ hybridisation (ISH) for human epidermal growth factor receptor 2 (HER2) gene amplification and we highlight key issues with the interpretation of this assay, with particular attention to the difficulties of the equivocal category. New molecular assays such as ISH for the topoisomerase II alpha (TOP2A) gene and for the aberrations in the copy number of the centromeric region of chromosome 17 are readily performed in a standard histopathology laboratory, but to date there are insufficient data to support their routine use. We also review the current data on two commercially available multigene expression assays, Oncotype DX and MammaPrint and discuss their potential use. Overall, while new molecular assays have significant potential to improve patient selection for therapy, well-performed histopathology with reliable interpretation of standard hormone and HER2 assays provides the most important predictive and prognostic information in early breast cancer.     

ER,PR and HER2 testing in breast cancer

The application of targeted therapies has played important roles in the improvement of breast cancer survival rate during the past two decades. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are well established biomarkers for breast cancer prognosis and for guiding treatment. Emerging data furthers our understanding of the biomarkers and their validity as predictive and prognostic indicators. Breast cancer biomarker testing guidelines have been recently updated. There are still several key challenges in the evaluations of these markers, including pre-analytic standards, tissue selection for testing and re-testing, result interpretations, and tumour heterogeneity. In addition to ER, PR and HER2, newer markers and multigene testings may provide additional information in guiding targeted therapy for breast cancer.     

Renal cell carcinoma staging: pitfalls,challenges, and updates

Renal cell carcinoma (RCC) is unusual among cancers in that it often grows as a spherical, well‐circumscribed mass. Increasing tumour size influences the pathological pT stage category within pT1 and pT2, with cutoffs of 40, 70 and 100 mm; however, with increasing size also comes a sharp increase in the likelihood of renal sinus or renal vein tributary invasion, such that clear cell RCC rarely reaches 70 mm without invading one of these. To clarify some previous challenges in assigning tumour stage, the American Joint Committee on Cancer 2016 tumor–node–metastasis classification has removed the requirements than vein invasion be recognised grossly and that vein walls contain muscle for the diagnosis of vein invasion. Renal pelvis invasion has also been added as an additional route to pT3a. Multinodularity or finger‐like extensions from a renal mass should be viewed with great suspicion for the possibility of vein or renal sinus invasion, and, as tumour size increases to over 40–50 mm, thorough sampling of the renal sinus interface should always be undertaken. With increasing interest in adjuvant therapy in renal cancer, the pathologist's role in RCC staging will continue to be an important prognostic parameter and a tool for selection of patients for enrolment in clinical trials.     

Renal epithelial neoplasms: diagnostic applications of gene expression profiling

Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults. RCC is a significant challenge for pathologic diagnosis and clinical management. The primary approach to diagnosis is by light microscopy, using the World Health Organization (WHO) classification system, which defines histopathologic tumor subtypes with distinct clinical behavior and underlying genetic mutations. However, light microscopic diagnosis of RCC subtypes can be difficult due to variable histology, morphologic features shared by tumor subtypes, and a growing frequency of small tumor biopsies with limited morphologic information. In addition to these diagnostic problems, the clinical behavior of RCC is highly variable, and therapeutic response rates are poor. Few clinical assays are available to predict outcome in RCC or correlate behavior with histology. Therefore, novel RCC classification systems based on gene expression should be useful for diagnosis, prognosis, and treatment. Recent microarray studies have shown that renal tumors are characterized by distinct gene expression profiles, which can be used to discover novel diagnostic and prognostic biomarkers. Here, we review clinical features of kidney cancer, the WHO classification system, and the growing role of molecular classification for diagnosis, prognosis, and therapy of this disease.     

Diagnostic and prognostic molecular markers in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, representing also the main cause of death among cirrhotic patients. In contrast to most other solid tumors, the underlying cirrhotic liver disease in HCC patients greatly impairs tumor related prognosis, conferring this neoplasm a unique situation, in which accurate prognostic prediction is a relevant and unmet need. Although clinical staging systems have improved significantly and now comprise tumor characteristics, liver function and patient performance status, the integration of molecular data into these algorithms is still hypothetical. Molecular profiling of HCC has led to a better understanding of the physiopathology of this neoplasm and has allowed developing novel therapeutic approaches (e.g. molecular targeted therapies) for a tumor previously considered as therapy-refractory. Integrative analysis of different reported genomic datasets has revealed common subclasses between different studies, highlighting their biological relevance in HCC. Gene signatures derived from tumors and from the adjacent tissue have been able to differentiate subclasses with different outcomes and have been proposed as potential predictive markers in the clinical setting. Genomic characterization of surrounding non-tumor tissue might be of particular interest to identify patients at high risk of developing HCC and therefore to select those patients that would benefit of potential chemopreventive strategies. Epigenetic analyses (methylation and miRNA profiling) are adding up to the knowlegde derived from gene expression data and should not be forgotten in the molecular diagnosis of HCC. Integrative analyses of genetic and epigenetic information of the tumor and the surrounding tissue should be used to identify novel biomarkers and therapeutic targets in HCC, to improve existing treatment algorithms and to eventually design a more personalized medicine in this devastating disease.     

Integrating complex genomic datasets and tumour cell sensitivity profiles to address a 'simple' question: which patients should get this drug?

It is becoming increasingly apparent that cancer drug therapies can only reach their full potential through appropriate patient selection. Matching drugs and cancer patients has proven to be a complex challenge, due in large part to the substantial molecular heterogeneity inherent to human cancers. This is not only a major hurdle to the improvement of the use of current treatments but also for the development of novel therapies and the ability to steer them to the relevant clinical indications. In this commentary we discuss recent studies from Kuo et al., published this month in BMC Medicine, in which they used a panel of cancer cell lines as a model for capturing patient heterogeneity at the genomic and proteomic level in order to identify potential biomarkers for predicting the clinical activity of a novel candidate chemotherapeutic across a patient population. The findings highlight the ability of a 'systems approach' to develop a better understanding of the properties of novel candidate therapeutics and to guide clinical testing and application.