Cancer Biomarkers - Volume 9, issue 1-6

Authors: Srivastava, Sudhir | Grizzle, William E.

Article Type: Editorial

DOI: 10.3233/CBM-2011-0158

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 1-4, 2011

Authors: Grizzle, William E. | Srivastava, Sudhir | Manne, Upender

Article Type: Research Article

Abstract: With the increasing use of individualized medical care (personalized medicine) in treating and managing patients with cancer, the utilization of biomarkers in selecting and tailoring such medical approaches also is increasing and becoming more important. Specifically, many therapies are effective against only a subgroup of a specific type of tumors and exposing patients with different non-responsive subgroups of the same tumor to ineffective therapies, not only exposes these patients needlessly to acute and chronic side effects of the therapy, but also adds to the costs of medical care. For example, the Oncotype Dx test for estrogen receptor positive tumors that …are node negative has been used to identify low risk tumors for which surgery alone is an adequate therapy. Biomarkers may be used to aid in multiple aspects of medical care related to cancer, including early detection, diagnosis, risk assessment, as well as in predicting the aggressiveness of cancers (i.e., prognosis) and predicting the therapeutic efficacy of treatments (i.e., prediction). Biomarkers may be also used as surrogate endpoints to aid in evaluating therapies and preventive approaches. Types of biomarkers vary greatly and include histopathologic appearance, stage of the lesion, quantitative morphologic features, size of the lesion, metastatic pattern and extent of metastasis, as well as imaging and molecular features. The types of measurements of biomarkers also vary; for example, molecular features can be measured at the DNA, mRNA or protein levels as well as at regulatory levels (e.g., microRNA). The usefulness of each biomarker is limited by its sensitivity and specificity in fulfilling its role (e.g., in early detection) and the requirements of sensitivity and specificity to accomplish specific tasks are affected by multiple variables. For example, both very high specificity and sensitivity of a test are required to screen a population with a low prevalence of a specific tumor. The goal of this manuscript is to introduce the reader to how biomarkers may be used and the limitations on the uses of biomarkers in translational research. Show more

Keywords: Sensitivity, specificity, early detection, prognosis, risk assessment, surrogate endpoints, diagnosis, receiver operating characteristic, prediction, biomarkers, prevalence, medical costs, side effects, histopathology, molecular features, imaging, prevention, treatment, personalized medicine, individualized medical care

DOI: 10.3233/CBM-2011-0159

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 7-20, 2011

Authors: Grizzle, William E. | Srivastava, Sudhir | Manne, Upender

Article Type: Research Article

Abstract: Invasive tumors (cancers or malignant lesions) typically develop in the setting in which there is the presence of putative non-invasive lesions and the development of these non-invasive lesions frequently precedes the development of cancers. For some organs, such as the oral cavity, cervix and skin, the respective putative pre-invasive lesions can be observed over time and documented to progress to invasive lesions. However, for less readily observable lesions, such as those of the prostate, the progression of the pre-invasive lesions, e.g., prostatic intraepithelial neoplasia (PIN) and prostatic proliferative inflammatory atrophy (PIA) to prostatic cancer are more difficult to document. Thus, …for most organ systems, specific pre-invasive neoplastic lesions have been proposed based upon the apparent observations of one or more of the following: 1) microinvasive disease developing from a pre-invasive neoplastic lesion, 2) the general association of the pre-invasive lesion with invasive lesions, 3) the subsequent development of invasive lesions following diagnosis of the pre-invasive lesion, 4) correlations of the molecular features of the putative pre-invasive lesion with the matching invasive lesions, and 5) reductions in the rate of cancer following removal of the pre-invasive lesion. When there are mixtures of pre-invasive lesions with actual cancers in the same case, some of the above specific associations are more difficult to make. Several terms have been used to describe pre-invasive lesions, many of which are now less useful as our knowledge of these lesions increases. It is now commonly accepted that these lesions are a features of the spectrum of neoplastic development and most are accepted as ``neoplastic lesions'' with associated molecular features, even though they may be reversible even if they have mutations in suppressor genes (e.g., p53) or are associated with viral etiologies (e.g., cervical intraepithelial neoplasia). The overall term, "pre-invasive neoplasia", seems to best describe these putative pre-invasive lesions. Thus, terms such as incipient neoplasia should be abandoned. The term "intra-epithelial neoplasia" with an associated grade, which has been developed for pre-invasive neoplastic lesions of the cervix, i.e. cervical intraepithelial neoplasia (CIN), seems to be a terminology that adds consistency across epithelial organs. Thus, adoption of these terms for the additional organ sites of pancreas (PanIN) and prostate (PIN) seems accepted. Less descriptive terms such as the degrees of dysplasia of the oral cavity and bronchopulmonary system and actinic keratosis and Bowen's disease of the skin might be better designated as oral intraepithelial neoplasia (OIN), pulmonary intraepithelial neoplasia (PulIN) and dermal intraepithelial neoplasia (DIN). The etiology of pre-invasive neoplasia is the etiology of the matching cancers. Some obvious initiating factors include exposure to the whole range of ionizing and non-ionizing radiation, tobacco abuse and a broad range of other carcinogens (e.g., benzene). A frequent initiation factor is the setting of long standing continuing damage, inflammation and repair (LOCDIR) which leads to early molecular features associated with neoplasia after about one year. An excellent example of this is ulcerative colitis (UC) in which dysregulation of microsatellite repair enzymes have been documented one year following diagnosis of UC. While the nomenclature, description, diagnosis and etiology of pre-invasive neoplasia has advanced, approaches to therapy of such lesions have not progressed adequately even though it has been identified that, for example, removal of polyps periodically from the colorectum, DCIS from the breast, and high grade CIN from the cervix, results in a reduction in the development of cancers of the colorectum, breast, and cervix, respectively. With the development of more molecularly targeted therapy with fewer side effects, preventive therapies may be more successfully targeted to pre-invasive neoplastic lesions. Show more

Keywords: Intraepithelial neoplasia, pre-invasive neoplasia, prostatic intraepithelial neoplasia, pancreatic intraepithelial neoplasia, cervical intraepithelial neoplasia, adenomatous polyps, ductal carcinoma in situ, lobular carcinoma in situ, inflammation, radiation, viral infections, carcinogens, dysplasia, actinic keratosis, repair, angiogenesis, LOCDIR

DOI: 10.3233/CBM-2011-0172

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 21-39, 2011

Authors: Srivastava, Sudhir | Grizzle, William E.

Article Type: Research Article

Abstract: It has become increasingly evident that the study of DNA is inadequate to explain many, if not most, aspects of the development and progression of neoplastic lesions from pre-invasive lesions to metastasis. Thus, the term "genetic" can no longer refer to just the study of the genome. Much of the action in genetic research now shifts to the methods by which the pre-mRNA from one gene is processed to yield multiple different proteins, different quantities of the same protein as well as other forms of regulating RNA. Thus, the age of post-transcriptional processing and epigenetic control of the transfer of …information from the genome has arrived. The mechanisms of post-transcriptional processing and epigenetic control that must be characterized in greater detail including alternate splicing, regulation of mRNA degradation, RNA regulatory factors including those factors which extensively edit mRNAs, control of translation, and control of protein stability and degradation. This chapter reviews many of the processes that control information from the genome to proteins and how these factors lead from less than 40,000 genes to more than an order of magnitude increase more proteins which actually control the phenotypes of cells – normal or neoplastic. It is usually the products of genes (e.g., mRNA, microRNA and proteins) that are the molecular markers that will control translational research and ultimately, individualized (personal) medical approaches to disease. This chapter emphasizes how the process of neoplasia “hijacks” the normal processes of cellular operations, especially those processes that are important in the normal development of the organisms – including proliferation, cellular death, angiogenesis, cellular mobility and invasion, and immunoregulation to ensure neoplastic development, survival and progression. This chapter reviews the wide range of processes controlling the information that flows from the genome to proteins and emphasizes how molecular steps in pure processes can be used as biomarkers to study prevention, treatment and/or management of diseases. Show more

Keywords: Intraepithelial neoplasia, dysplasia, methylation, microsatellite instability, mutations, insertions, deletions, oncogenes, suppressor genes, aneuploidy, translocations, caretakers, gatekeepers, landscapers, mismatch repair genes, LOCDIR, epigenetics, immunoregulation, tumor associated fibroblasts, exosomes, angiogenesis, clonal selection, viral insertions, biomarkers, validation

DOI: 10.3233/CBM-2011-0204

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 41-64, 2011

Authors: Natarajan, Thanemozhi G. | Ganesan, Natarajan | FitzGerald, Kevin T.

Article Type: Research Article

Abstract: In an effort to improve our understanding and treatment of cancer, a new model of tumorigenesis is being developed – the cancer stem cell model. Building upon traditional concepts of cancer and stem cells, this model is intended to shed new light on the continuing struggle with treatment challenges such as tumor drug-resistance and recurrence. This review describes the cancer stem cell model with an emphasis on delineating markers that represent a "stemness" phenotype within certain tumor cells. The objective of this delineation is to develop targeted therapies for the selective elimination of cancer stem cells with minimal toxicity to …normal stem cells and tissues. However, this specific targeting of cancer stem cells has proved to be a significant challenge due to the similarity of markers expressed by both normal and cancer stem cells. Still, research in the area of cancer biomarkers is steadily progressing. Show more

Keywords: Cancer, stem cells, markers, stemness, asymmetric division, stem cell niche, immortality, canonical pathways, signaling pathways, surface antigens, transcription factors, detoxifying proteins, communication, clinical implications

DOI: 10.3233/CBM-2011-0173

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 65-99, 2011

Authors: Carmona, F. Javier | Esteller, Manel

Article Type: Research Article

Abstract: Life expectancy rises steeply when a tumor is diagnosed at an early stage. Therefore, diagnosing cancer before it turns into an aggressive, barely curable disease is one of the main goals of oncological research in the 21st century. This is of vital importance for certain types of cancer for which survival rates drastically drop as primary tumors are detected by currently available screening procedures. Aberrant DNA methylation is a common hallmark of human cancer. This epigenetic mark is altered in instructive ways in the distinct stages of multistep tumorigenesis from the early onset of malignant transformation. Therefore, the possibility of …detecting precise methylation signatures associated with particular cancers and the development of methodologies increasingly sensitive at detecting them, makes DNA methylation biomarkers attractive predictors for the development of effective diagnostic tests for the early detection of human neoplasia. Show more

Keywords: DNA methylation, cancer, biomarker, early detection, screening

DOI: 10.3233/CBM-2011-0184

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 101-111, 2011

Authors: Sen, Subrata | Hopwood, Vicki

Article Type: Research Article

Abstract: There is strong evidence that multistep tumorigenesis begins with the acquisition of somatic mutations which promote genomic instability. Genomic instability is an important malignant trait because genomic instability can generate the genetic diversity that is necessary for the transforming cell to acquire increasingly variable and aggressive tumor phenotypes. Genomic instability often manifests in the form of chromosomal instability (CIN) leading to the induction of aneuploidy, a phenomenon identified by high resolution molecular cytogenetic techniques. Fluorescent in situ hybridization (FISH) and Array Comparative Genomic Hybridization (aCGH) are two high resolution molecular cytogenetic techniques that allow detection of chromosomal aneuploidy and structural …rearrangements occurring in pre-malignant and malignant lesions during tumor progression and invasion. These high resolution molecular cytogenetic techniques are used for genetic screening of single cells in pre-malignant and precursor malignant lesions as well as in exfoliated cells from body fluids and excreta. Consequently, molecular cytogenetic testing offers the promise of an extremely powerful method of risk assessment and early detection of cancer. Show more

Keywords: Chromosomal instability (CIN), aneuploidy, genetic mutation, microenvironment, chromosomal rearrangements, gene amplification, gene fusion, chromosome deletion, spindle assembly checkpoint, Fluorescence in situ hybridization (FISH), Array Comparative Genomic Hybridization (aCGH)

DOI: 10.3233/CBM-2011-0171

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 113-132, 2011

Authors: Wang, Wendy | Srivastava, Sudhir

Article Type: Research Article

Abstract: Molecular biomarkers are widely recognized as having tremendous utility in cancer early detection, prediction, and prevention. Huge efforts have been put into searching of various molecular biomarkers for these purposes, yet there are few molecular biomarkers that have been approved by the Food and Drug Administration for clinical use. Discovery of novel molecular biomarkers is still urgently needed to create biological insights into early events of carcinogenesis and to predict the aggressiveness of early cancer. Noncoding RNAs (ncRNAs) are relatively unexplored molecules identified only one decade ago. With research on the basic biology and mechanisms of ncRNAs, they have rapidly …been linked to etiology of diseases, particularly cancer. In this chapter, we will summarize ncRNAs, particularly microRNAs (miRNAs), a type of ncRNAs, as a new frontier for the discovery of cancer biomarkers in preneoplastic lesions and their usefulness as markers for the risk assessment, early detection, and diagnosis of cancer. Show more

Keywords: Noncoding RNAs (ncRNAs), microRNAs (miRNAs), cancer, biomarkers, early detection, diagnosis, biomarker validation, cancer risk assessment, oncogene, tumor suppressor

DOI: 10.3233/CBM-2011-0179

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 133-140, 2011

Authors: Liu, Alvin Y. | Pascal, Laura E. | Vêncio, Ricardo Z. | Vêncio, Eneida F.

Article Type: Research Article

Abstract: In prostate tumors, both the epithelial and stromal mesenchyme compartments show gene expression changes from their respective normal counterpart. In fact, there are more such changes in the stroma than the epithelium. These include down-regulated expression of genes involved in smooth muscle cell differentiation and those differentially expressed between prostate and bladder, i.e., organ-restricted. In development, the stromal cell type mediates tissue formation from differentiation of stem or progenitor cells. Diseases like cancer may arise as a result of defective stromal signaling. Stromal signaling can be demonstrated by co-culture of stromal cells and embryonal carcinoma NCCIT cells used as a …stem cell substitute. In co-culture, stromal cells induce NCCIT cells through diffusible molecules to lose stem cell gene expression, gain expression of prostate genes, alter cytomorphology, and lower proliferation. This NCCIT response is varied as co-cultured bladder stromal cells induce a different gene expression. At the same time, NCCIT factors also affect gene expression of co-cultured stromal cells. NCCIT induces normal prostate tissue (NP) stromal cells to become more like cancer-associated (CP) stromal cells in both mRNA and microRNA expression. In contrast, NCCIT shows minimal effect on CP stromal cells. CP stromal cells may represent a less differentiated state in the prostate stromal cell lineage. Show more

Keywords: Prostate cancer, cell type transcriptomes, CD26+ cancer cells, CD90+ cancer-associated stromal cells, Gleason patterns, stromal induction of stem cells, NCCIT embryonal carcinoma cells, in vitro co-culture, cell-cell interaction, intercellular signaling molecules, mRNA and miRNA expression changes

DOI: 10.3233/CBM-2011-0174

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 141-155, 2011

Authors: Czerniak, Bogdan

Article Type: Research Article

Abstract: Bladder cancer originates in the epithelial lining of the bladder's mucosa and develops in association with several habitual, industrial, and environmental risk factors via papillary and non-papillary pathways. In this chapter we review novel concepts concerning the molecular mechanisms of early field change in bladder neoplasia stemming from whole-organ genomic mapping studies. These mechanisms are discussed in the context of molecular pathogenesis of bladder cancer and in relation to treatment and biomarker-based detection strategies.

Keywords: Bladder cancer, dual-track pathway, genomic map, biomarkers, risk factors, forerunner genes, precursor lesions, field effect, molecular profiling, diagnosis and treatment of bladder cancer

DOI: 10.3233/CBM-2011-0175

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 159-176, 2011

Authors: Cole, Kimberly | Tabernero, Maria | Anderson, Karen S.

Article Type: Research Article

Abstract: Breast cancer is the second leading cause of cancer death in women in the United States. While mammography and breast magnetic resonance imaging (MRI) improve detection of early disease, there remains an unmet need for biomarkers for risk stratification, early detection, prediction, and disease prognosis. A number of early breast lesions, from atypical hyperplasias to carcinomas in situ, are associated with an increased risk of developing subsequent invasive breast carcinoma. The recent development of genomic, epigenomic, and proteomic tools for tissue biomarker detection, including array CGH, RNA expression microarrays, and proteomic arrays have identified a number of potential biomarkers that …both identify patients at increased risk, as well as provided insights into the pathology of early breast cancer development. This chapter focuses on the detection and application of tissue and serum biomarkers for the identification and risk stratification of early breast cancer lesions. Show more

Keywords: Breast cancer, benign breast disease, biomarkers

DOI: 10.3233/CBM-2011-0187

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 177-192, 2011

Authors: Adamson, D. Cory | Rasheed, B. Ahmed K. | McLendon, Roger E. | Bigner, Darell D.

Article Type: Research Article

Abstract: Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past …decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients – medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome. Show more

Keywords: Central nervous system, brain, glioma, astrocytoma, glioblastoma, glioblastoma multiforme, GBM, oligodendroglioma, medulloblastoma, EGFR, EGFRvIII, MGMT, PTEN, TP53, VEGF, PDGFR, TGF-b, Myc, Otx2, PTCH, glioma stem cell, CD133, Olig2

DOI: 10.3233/CBM-2011-0177

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 193-210, 2011

Authors: Rushton, Jennifer | López-Terrada, Dolores

Article Type: Research Article

Abstract: Pediatric malignancies are a spectrum of biologically diverse cancers different from those seen in adults. Malignant solid tumors diagnosed in children are often, and at least partly the result of developmental pathways dysregulation, and may recapitulate stages of organogenesis. Significant insight into their pathogenesis came from studying normal embryonal and fetal organ development, as well as mechanisms responsible for developmental disorders and congenital syndromes associated with these tumors. Systematic integration of pathology, genetic and molecular analyses of pediatric solid tumors is allowing the recognition of distinct clinical tumor subtypes, as well as potential therapeutic targets for some of …these neoplasms. From the diagnostic point of view, some pediatric solid tumors represent examples of clinical translation, as genetic and molecular markers are being incorporated into clinical algorithms, and used for tumor classification, risk stratification, theragnostics or disease monitoring. The on-going comprehensive analysis of some pediatric tumor types using genomic, expression and epigenetic profiling technologies, and the development of experimental tumor model systems, are fastly improving our understanding of their biology. However, further and comprehensive characterization of other pediatric solid tumors, particularly aggressive or chemoresistant cancer types, is still necessary, and should result in the development of new integrated clinical testing, improved therapeutic strategies and better outcomes for these patients. Show more

Keywords: Childhood, cancer, molecular, genetic, pathology, tumor markers, embryonal tumors, developmental pathways, profiling, epigenetics, risk stratification, molecular diagnostics, prognosis

DOI: 10.3233/CBM-2011-0199

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 211-234, 2011

Authors: Manne, Upender | Shanmugam, Chandrakumar | Katkoori, Venkat R. | Bumpers, Harvey L. | Grizzle, William E.

Article Type: Research Article

Abstract: A variety of genetic and molecular alterations underlie the development and progression of colorectal neoplasia (CRN). Most of these cancers arise sporadically due to multiple somatic mutations and genetic instability. Genetic instability includes chromosomal instability (CIN) and microsatellite instability (MSI), which is observed in most hereditary non-polyposis colon cancers (HNPCCs) and accounts for a small proportion of sporadic CRN. Although many biomarkers have been used in the diagnosis and prediction of the clinical outcomes of CRNs, no single marker has established value. New markers and genes associated with the development and progression of CRNs are being discovered at an accelerated …rate. CRN is a heterogeneous disease, especially with respect to the anatomic location of the tumor, race/ethnicity differences, and genetic and dietary interactions that influence its development and progression and act as confounders. Hence, efforts related to biomarker discovery should focus on identification of individual differences based on tumor stage, tumor anatomic location, and race/ethnicity; on the discovery of molecules (genes, mRNA transcripts, and proteins) relevant to these differences; and on development of therapeutic approaches to target these molecules in developing personalized medicine. Such strategies have the potential of reducing the personal and socio-economic burden of CRNs. Here, we systematically review molecular and other pathologic features as they relate to the development, early detection, diagnosis, prognosis, progression, and prevention of CRNs, especially colorectal cancers (CRCs). Show more

Keywords: Early detection, molecular diagnosis, prognosis, molecular staging, colorectal cancer

DOI: 10.3233/CBM-2011-0160

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 235-265, 2011

Authors: Bogenrieder, Thomas | Herlyn, Meenhard

Article Type: Research Article

Abstract: Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogen-associated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target …of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit from agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease. Show more

Keywords: Melanoma, cell cycle, pRb pathway, p16INK4A, p14ARF, cyclins, CDKs, Apaf1, Bcl2, MAPK pathway, Ras, BRAF, PTEN, PI3K/AKTpathway, SCF, ckit, HGF, cmet, cmyc, Notch

DOI: 10.3233/CBM-2011-0164

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 267-286, 2011

Authors: Merritt, Melissa A. | Cramer, Daniel W.

Article Type: Research Article

Abstract: Pregnancy, breastfeeding, and oral contraceptive pill use interrupt menstrual cycles and reduce endometrial and ovarian cancer risk. This suggests the importance of turnover within Mullerian tissues, where the accumulation of mutations in p53 and PTEN has been correlated with number of cycles. The most common type of endometrial cancer (Type I) is endometrioid and molecular abnormalities include mutations in PTEN, KRAS and β-catenin. The Type I precursor is Endometrial Intraepithelial Neoplasia which displays PTEN defects. Type II endometrial cancer (whose precursors are less clear) includes serous and clear cell tumors and the most common alteration is p53 mutation. For ovarian …cancer, histopathologic types parallel endometrial cancer and include serous, mucinous, endometrioid, and clear cell; some molecular features are also shared. The most frequent type of ovarian cancer is high grade serous that often displays p53 mutation and its precursor lesions may originate from normal-appearing fallopian tube epithelium that contains a p53 “signature”. Mutations in KRAS, BRAF and PTEN are described in mucinous, endometrioid and low grade serous cancers and these may originate from ovarian cortical inclusion cysts. A consideration of molecular and other pathogenetic features, like epidemiology and histopathology, may provide a better understanding of endometrial and ovarian cancer. Show more

Keywords: Ovarian cancer, Endometrial cancer, p53, PTEN, KRAS, Precursor lesions, Endometrial intraepithelial neoplasia, Fallopian tube, Cortical inclusion cysts, mullerian, epidemiology, risk factors, Type I, Type II, serous, mucinous, endometrioid, clear cell

DOI: 10.3233/CBM-2011-0167

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 287-305, 2011

Authors: Reid, Brian J.

Article Type: Research Article

Abstract: Barrett’s esophagus is a condition in which the stratified squamous epithelium of the distal esophagus is replaced by specialized intestinal metaplasia. Clinical management of Barrett’s esophagus, like many other “premalignant” conditions, is characterized by overdiagnosis of benign early changes that will not cause death or suffering during the lifetime of an individual and underdiagnosis of life-threatening early disease. Recent studies of a number of different types of cancer have revealed much greater genomic complexity than was previously suspected. This genomic complexity could create challenges for early detection and prevention if it develops in premalignant epithelia prior to cancer. Neoplastic progression …unfolds in space and time, and Barrett’s esophagus provides one of the best models for rapid advances, including “gold standard” cohort studies, to distinguish individuals who do and do not progress to cancer. Specialized intestinal metaplasia has many properties that appear to be protective adaptations to the abnormal environment of gastroesophageal reflux. A large body of evidence accumulated over several decades implicates chromosome instability in neoplastic progression from Barrett’s esophagus to esophageal adenocarcinoma. Small, spatial scale studies have been used to infer the temporal order in which genomic abnormalities develop during neoplastic progression in Barrett’s esophagus. These spatial studies have provided the basis for prospective cohort studies of biomarkers, including DNA content abnormalities (tetraploidy, aneuploidy) and a biomarker panel of 9p LOH, 17p LOH and DNA content abnormalities. Recent advances in SNP array technology provide a uniform platform to assess chromosome instability. Show more

Keywords: Barrett’s esophagus, esophageal adenocarcinoma, clonal evolution, genome instability, chromosome instability, aneuploidy, biomarkers, SNP arrays, telomeres, nonsteroidal anti-inflammatory drugs, genetic diversity, clonal expansion, hitchhikers ("passengers"), gastroesophageal reflux disease (GERD), dysplasia, Peter Nowell

DOI: 10.3233/CBM-2011-0162

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 307-324, 2011

Authors: Park, Brian J. | Chiosea, Simion I. | Grandis, Jennifer R.

Article Type: Research Article

Abstract: Head and neck squamous cell carcinomas (SCCHN) arise in the mucosa of the upper aerodigestive tract at multiple anatomic sites. While tobacco and alcohol exposure remain the primary risk factors for this malignancy, infection with the human papilloma virus is emerging as a major contributing factor to cancers that arise primarily in the oropharynx. Despite therapeutic advances, survival has remained relatively unchanged over the past few decades. Increased understand of the cellular and molecular biology of these cancers will improve our understanding of this malignancy and facilitate the development of more effective therapeutic strategies. Alterations that have been studied to …date include genetic and epigenetic changes. While the epidermal growth factor receptor (EGFR) is the only established molecular therapeutic target, other proteins and pathways are under active investigation to determine their contribution to SCCHN carcinogenesis and progression. Show more

Keywords: Head and neck cancer, molecular pathogenesis, squamous cell carcinoma, leukoplakia, premalignant, human papilloma virus

DOI: 10.3233/CBM-2011-0163

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 325-339, 2011

Authors: Zhao, X. Frank | Reitz, Marvin | Chen, Qing Ching | Stass, Sanford

Article Type: Research Article

Abstract: In the past several decades, great progress has been made in our understanding of normal hematopoiesis and its malignant transformation. This article provides a comprehensive and up-to-date review of pathogenesis of leukemia and lymphoma, with an emphasis on early molecular events. Current concepts of normal hematopoiesis and its key regulatory processes are summarized. Various environmental and infectious factors that play a causative role in hematopoietic malignancies are described. In particular, several causative viruses, i.e. HTLV1, HHV8 and EBV, are discussed in depth. Numerous genetic abnormalities have been identified in leukemia and lymphoma, including chromosomal translocations, gene deletions, amplifications, and point …mutations. Synopses are included for the most frequently encountered aberrations, and their relation to normal and malignant hematopoiesis, disease classification and prognosis. Major molecular mechanisms and signal transduction pathways involved in the leukemogenesis are depicted; these include blockage of differentiation, self-sustainable proliferation, abnormal cell cycle progression and impaired apoptosis. Also included are the recently discovered microRNAs, and their potential role in the pathogenesis of leukemia and lymphoma. Future directions in leukemia and lymphoma research are presented, including several modern molecular technologies and their importance in developing new biomarkers for early detection of leukemia and lymphoma. Show more

Keywords: Leukemia, lymphoma, hematopoiesis, stem cells, pathogenesis, leukemogenesis, chromosomal translocation, Philadelphia chromosome, oncogene, tumor suppressor, microRNA, retrovirus, herpes virus, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloproliferative neoplasm, gene expressing profiling

DOI: 10.3233/CBM-2011-0178

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 341-374, 2011

Authors: Block, Timothy | Mehta, Anand S. | London, W. Thomas

Article Type: Research Article

Abstract: Primary cancer of the liver, hepatocellular carcinoma (HCC), is an extremely deadly cancer, with very poor 5 year survivals, following diagnosis. The poor outcomes are believed to be due, in part, to the late times in which the cancers are usually first detected. Improved methods for early detection have thus become a top priority in the management of liver cancer. This Chapter reviews current methods of detection as well as leading new methods. Possible explanations as to why there are so many markers that are being discovered, but so few that make it to validation are discussed.

Keywords: Liver Cancer, Hepatocellular carcinoma, hepatitis B, hepatitis C, early detection, early diagnosis, biomarkers

DOI: 10.3233/CBM-2011-0165

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 375-383, 2011

Authors: Gazdar, Adi F. | Brambilla, Elisabeth

Article Type: Research Article

Abstract: As with other epithelial cancers, lung cancer develops over a period of several years or decades via a series of progressive morphological changes accompanied by molecular alterations that commence in histologically normal epithelium. However the development of lung cancer presents certain unique features that complicates this evaluation. Anatomically the respiratory tree may be divided into central and peripheral compartments having different gross and histological anatomies as well as different functions. In addition, there are three major forms of lung cancer and many minor forms. Many of these forms arise predominantly in either the central or peripheral compartments. Squamous cell and …small cell carcinomas predominantly arise in the central compartment, while adenocarcinomas predominantly arise peripherally. Large cell carcinomas are not a single entity but consist of poorly differentiated forms of the other types and, possibly, some truly undifferentiated “stem cell like” tumors. The multistage origin of squamous cell carcinomas, because of their central location, can be followed more closely than the peripherally arising adenocarcinomas. Squamous cell carcinomas arise after a series of reactive, metaplastic, premalignant and preinvasive changes. However, long term observations indicate that not all tumors follow a defined histologic course, and the clinical course, especially of early lesions, is difficult to predict. Peripheral adenocarcinomas are believed to arise from precursor lesions known as atypical adenomatous hyperplasias and may have extensive in situ growth before becoming invasive. Small cell carcinomas are believed to arise from severely molecularly damaged epithelium without going through recognizable preneoplastic changes. The molecular changes that occur prior to the onset on invasive cancers are extensive. As documented in this chapter, they encompass all of the six classic Hallmarks of Cancer other than invasion and metastasis, which by definition occur beyond preneoplasia. A study of preinvasive lung cancer has yielded much valuable biologic information that impacts on clinical management. Show more

Keywords: Lung cancer, squamous cell carcinoma, adenocarcinomas, small cell lung carcinoma, preneoplasia, carcinoma in situ, atypical adenomatous hyperplasia, tumor suppressor genes, oncogenes, apoptosis, telomerase, angiogenesis

DOI: 10.3233/CBM-2011-0166

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 385-396, 2011

Authors: Balic, Marija | Williams, Anthony | Dandachi, Nadia | Cote, Richard J.

Article Type: Research Article

Abstract: Metastatic disease is the most important determinant in the clinical management of patients with cancer. Disseminated tumor cells are regarded as a surrogate for early metastatic spread of disease. These cells can be detected in bone marrow aspirates, lymph nodes and peripheral blood, where we refer to them as circulating tumor cells. Detection of disseminated tumor cells represents a great technical challenge, and many different technologies have been developed to enhance the sensitivity and specificity of the testing for these rare events. Different characteristics of tumor cells have been used to establish enrichment methods, including the differential expression of tumor-specific …markers on the surface of the cells, the size-based selection of the cells, and other physical properties. Despite technical obstacles, the detection of circulating tumor cells in particular have emerged in recent years as a biomarker with outstanding predictive and prognostic capacity in a number of malignancies including breast, prostate, lung and colorectal cancer. In this text, we provide a comprehensive review of different approaches for enrichment of disseminated and circulating tumor cells and elucidate additional molecular methods for their detection. Further, the clinical significance of disseminated tumor cells detected in various compartments is discussed. Based on recent findings on the biology and heterogeneity of tumor cells, along with development of robust enrichment techniques, we believe that future research will focus less on pure detection but more importantly on detailed molecular characterization of these rare events with the potential impact on design of novel therapeutics. Show more

Keywords: Metastasis, circulating tumor cells (CTC), disseminated tumor cells (DTC), CTC enrichment, membrane microfilter device, microfiltration, cancer stem cells, breast cancer, prostate cancer, colorectal cancer, bladder cancer

DOI: 10.3233/CBM-2011-0161

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 397-419, 2011

Authors: Remmers, Neeley | Bailey, Jennifer M. | Mohr, Ashley M. | Hollingsworth, Michael A.

Article Type: Research Article

Abstract: We describe the pathology of early pancreatic cancer and present an overview of known molecular alterations that occur in these lesions. There are three defined precursor lesions in current models of pancreatic cancer: pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasms (MCN), and intraductal papillary mucinous neoplasms (IPMN). Molecular alterations detected in these lesions include: telomeres, K-ras and downstream targets, p16/CDKN2A, p53, SMAD4/DPC4, microRNAs, mucins and their post-translational processing, inflammatory cytokines, CEACAM, and epigenetic alterations. We summarize previous analyses of these markers as diagnostic markers of disease, and suggest areas of future study.

Keywords: Pancreatic cancer, pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), mucin, K-ras, p16/CDKN2A, p53, SMAD4/DPC4, microRNA, CEACAM, MIC1, CA19-9

DOI: 10.3233/CBM-2011-0168

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 421-440, 2011

Authors: Cazares, L.H. | Drake, R.R. | Esquela-Kirscher, A. | Lance, R.S. | Semmes, O.J. | Troyer, D.A.

Article Type: Research Article

Abstract: This chapter includes discussion of the molecular pathology of tissue, blood, urine, and expressed prostatic secretions. Because we are unable to reliably image the disease in vivo, a 12 core method that oversamples the peripheral zone is widely used. This generates large numbers of cores that need to be carefully processed and sampled. In spite of the large number of tissue cores, the amount of tumor available for study is often quite limited. This is a particular challenge for research, as new biomarker assays will need to preserve tissue architecture intact for histopathology. Methods of processing and reporting pathology are …discussed. With the exception of ductal variants, recognized subtypes of prostate cancer are largely confined to research applications, and most prostate cancers are acinar. Biomarker discovery in urine and expressed prostatic secretions would be useful since these are readily obtained and are proximate fluids. The well-known challenges of biomarker discovery in blood and urine are referenced and discussed. Mediators of carcinogenesis can serve as biomarkers as exemplified by mutations in PTEN and TMPRSS2:ERG fusion. The use of proteomics in biomarker discovery with an emphasis on imaging mass spectroscopy of tissues is discussed. Small RNAs are of great interest, however, their usefulness as biomarkers in clinical decision making remains the subject of ongoing research. The chapter concludes with an overview of blood biomarkers such as circulating nucleic acids and tumor cells and bound/free isoforms of prostate specific antigen (PSA). Show more

Keywords: Prostate Cancer, Prostate Pathology, Predictive Biomarkers, Molecular Markers of Cancer, Prostate Histopathology, Cytogenetics and Prostate Cancer, Proteomics and Prostate Cancer, microRNAs and Prostate Cancer, Expressed prostatic secretions and prostate cancer

DOI: 10.3233/CBM-2011-0181

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 441-459, 2011

Authors: Cairns, Paul

Article Type: Research Article

Abstract: Renal Cell Carcinoma (RCC) has the highest mortality rate of the genitourinary cancers and the incidence of RCC has risen steadily. If detected early, RCC is curable by surgery although a minority are at risk of recurrence. Increasing incidental detection and an ageing population has led to active surveillance as an option for patients with small renal masses. RCC is heterogeneous and comprises several histological cell types with different genetics, biology and behavior. The identification of the genes predisposing to inherited syndromes with RCC has provided much of our knowledge of the molecular basis of early sporadic RCC. Many of …the oncogenes and tumor suppressor genes that are mutated leading to pathway dysregulation in RCC remain to be elucidated. Global studies of copy number, gene sequencing, gene expression, miRNA expression and gene methylation in primary RCC will lead towards this goal. The natural history of RCC indicated by candidate precursor lesions, multifocal or bilateral disease, growth rate of small renal masses under surveillance, and high risk populations provide insight into the behavior of this disease. The use of molecular markers for early detection and prognosis merits more attention with ongoing advances in omics technologies. This review focuses on early RCC, that is disease confined within the renal capsule. Show more

Keywords: Renal cell carcinoma (RCC), clear cell, papillary, chromophobe, small renal masses (SRM), genetics, epigenetics, hypermethylation, natural history, precursor lesion, multifocal, end stage renal disease (ESRD), diagnosis, prognosis, therapy

DOI: 10.3233/CBM-2011-0176

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 461-473, 2011

Authors: Powers, Martin | Zhang, Wei | Lopez-Terrada, Dolores | Czerniak, Bogdan A. | Lazar, Alexander J.

Article Type: Research Article

Abstract: Sarcomas are rare malignancies of mesenchymal lineage with more than 100 specific types and many benign potential mimics. In situ and precursor lesions are generally not described and thus much of molecular pathology in this field concentrates on molecular diagnosis, prognosis and determination of therapeutic targets. This chapter discusses the applications of molecular methodologies that provide insight into pathogenesis of sarcoma, and of molecular methods which are currently applied to, or will likely soon influence, the clinical management of this complex array of tumors.

Keywords: Sarcoma, translocation, EWSR1, reverse transcriptase-polymerase chain reaction (RT-PCR), fluoresence in-situ hybridization (FISH), fusion transcript, molecular diagnostics, pigmented villonodular synovitis, Ewing sarcoma, gastrointestinal stromal tumor (GIST), KIT, PDGRA, karyotype, desmoid fibromatosis, beta-catenin (CTNNB1), malignant peripheral nerve sheath tumor (MPNST), leiomyosarcoma, genomic profiling

DOI: 10.3233/CBM-2011-0170

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 475-491, 2011

Authors: David, Stefan | Meltzer, Stephen J.

Article Type: Research Article

Abstract: Gastric cancer is one of the most common neoplasias in the world and remains an important cause of cancer-related mortality. Vast resources have been invested in the study of the molecular events driving the development and progression of gastric tumors. Gastric cancer is known to result from an interaction between host and environmental factors. The present review will discuss the most how genetic and epigenetic changes contribute to gastric carcinogenesis and their potential for developing novel diagnostic and therapeutic tools.

Keywords: Gastric cancer, genetics, epigenetics, microsatellite instabilitychromosomal instability, mutation, deletion, translocation, methylation, oncogene, tumor suppressor gene

DOI: 10.3233/CBM-2011-0169

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 493-507, 2011

Authors: Crichton, Daniel J. | Mattmann, Chris A. | Thornquist, Mark | Anton, Kristen | Hughes, J. Steven

Article Type: Research Article

Abstract: Capturing, sharing, and publishing cancer biomarker research data are all fundamental challenges of enabling new opportunities to research and understand scientific data. Informatics experts from the National Cancer Institute's (NCI) Early Detection Research Network (EDRN) have pioneered a principled informatics infrastructure to capture and disseminate data from biomarker validation studies, in effect, providing a national-scale, real-world successful example of how to address these challenges. EDRN is a distributed, collaborative network and it requires its infrastructure to support research across cancer research institutions and across their individual laboratories. The EDRN informatics infrastructure is also referred to as the EDRN Knowledge Environment, …or EKE. EKE connects information about biomarkers, studies, specimens and resulting scientific data, allowing users to search, download and compare each of these disparate sources of cancer research information. EKE's data is enriched by providing annotations that describe the research results (biomarkers, protocols, studies) and that link the research results to the captured information within EDRN (raw instrument datasets, specimens, etc.). In addition EKE provides external links to public resources related to the research results and captured data. EKE has leveraged and reused data management software technologies originally developed for planetary and earth science research results and has infused those capabilities into biomarker research. This paper will describe the EDRN Knowledge Environment, its deployment to the EDRN enterprise, and how a number of these challenges have been addressed through the capture and curation of biomarker data results. Show more

Keywords: EDRN knowledge environment, data intensive systems, biomarker research, informatics infrastructure, e-science, metadata, data curation, data sharing, biomarker database, Data Grid

DOI: 10.3233/CBM-2011-0180

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 511-530, 2011

Authors: Grizzle, William E. | Bell, Walter C. | Sexton, Katherine C.

Article Type: Research Article

Abstract: The availability of human tissues to support biomedical research is critical to advance translational research focused on identifying and characterizing approaches to individualized (personalized) medical care. Providing such tissues relies on three acceptable models – a tissue banking model, a prospective collection model and a combination of these two models. An unacceptable model is the "catch as catch can" model in which tissues are collected, processed and stored without goals or a plan or without standard operating procedures, i.e., portions of tissues are collected as available and processed and stored when time permits. In the tissue banking model, aliquots of …tissues are collected according to SOPs. Usually specific sizes and types of tissues are collected and processed (e.g., 0.1 gm of breast cancer frozen in OCT). Using the banking model, tissues may be collected that may not be used and/or do not meet specific needs of investigators; however, at the time of an investigator request, tissues are readily available as is clinical information including clinical outcomes. In the model of prospective collection, tissues are collected based upon investigator requests including specific requirements of investigators. For example, the investigator may request that two 0.15 gm matching aliquots of breast cancer be minced while fresh, put in RPMI media with and without fetal calf serum, cooled to 4°C and shipped to the investigator on wet ice. Thus, the tissues collected prospectively meet investigator needs, all collected specimens are utilized and storage of specimens is minimized; however, investigators must wait until specimens are collected, and if needed, for clinical outcome. The operation of any tissue repository requires well trained and dedicated personnel. A quality assurance program is required which provides quality control information on the diagnosis of a specimen that is matched specifically to the specimen provided to an investigator instead of an overall diagnosis of the specimen via a surgical pathology report. This is necessary because a specific specimen may not match the diagnosis of the case due to many factors such as necrosis, unsuspected tumor invasion of apparently normal tissue, and areas of fibrosis which are mistaken grossly for tumor. Aliquots for quality control (QC) may or may not be collected at the time of collection and in some cases, QC may not occur until specimens are distributed to investigators. In establishing a tumor repository, multiple issues need to be considered. These include the available resources, long term support, space and equipment. The needs of the potential users need to be identified as to the types of tissues and services needed and the annotation expected. Other specific issues to be considered include collection of specimens potentially infected with blood borne pathogens (e.g., hepatitis B), charge back mechanisms, informatics needs and support, and investigator requirements (e.g., recognition of repository contributions in publications). In general, the repository should not perform the research of the investigators, but should provide the infrastructure necessary to support the research of the investigator. Thus, the goals of the repository must be established. Similarly, ethical and regulatory issues must be evaluated. In general, tissue repositories need ethical (e.g., IRB) and privacy (e.g., HIPAA) review. Also, safety issues need to be considered as well as how biohazards will be addressed by investigator-users. Considerations involving the transfer of specimens to other organization usually require a material transfer agreement (MTA). A MTA should address biohazards as well as indemnification. Thus, many issues must be considered and addressed in order to establish and operate successfully a biorepository. Show more

Keywords: Tissue repositories, tissue banking, prospective collections, quality control, quality assurance, repository science, bias, clinical trials, epidemiology, annotation, material transfer agreement, shipping, informatics, safety, biohazards, security, difficult requests, caBIG, vocabulary, common data elements, chemical hazards, cost recovery, HIPAA, informed consent, demographics, clinical information, training, audits, good manufacturing practice, storage, specimen identification, services

DOI: 10.3233/CBM-2011-0183

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 531-549, 2011

Article Type: Other

DOI: 10.3233/CBM-2011-91-630

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 551-552, 2011