Cancer Biomarkers - Volume 9, issue 1-6

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