Disease Markers - Volume 23, issue 1-2

Authors: Widschwendter, Martin

Article Type: Other

Keywords: DNA methylation, epigenetics, 5-methylcytosine, biomarkers

Citation: Disease Markers, vol. 23, no. 1-2, pp. 1-3, 2007

Authors: Kerr, Keith M. | Galler, Janice S. | Hagen, Jeffrey A. | Laird, Peter W. | Laird-Offringa, Ite A.

Article Type: Research Article

Abstract: Lung cancer, caused by smoking in ∼87% of cases, is the leading cause of cancer death in the United States and Western Europe. Adenocarcinoma is now the most common type of lung cancer in men and women in the United States, and the histological subtype most frequently seen in never-smokers and former smokers. The increasing frequency of adenocarcinoma, which occurs more peripherally in the lung, is thought to be at least partially related to modifications in …cigarette manufacturing that have led to a change in the depth of smoke inhalation. The rising incidence of lung adenocarcinoma and its lethal nature underline the importance of understanding the development and progression of this disease. Alterations in DNA methylation are recognized as key epigenetic changes in cancer, contributing to chromosomal instability through global hypomethylation, and aberrant gene expression through alterations in the methylation levels at promoter CpG islands. The identification of sequential changes in DNA methylation during progression and metastasis of lung adenocarcinoma, and the elucidation of their interplay with genetic changes, will broaden our molecular understanding of this disease, providing insights that may be applicable to the development of targeted drugs, as well as powerful markers for early detection and patient classification. Show more

Keywords: AAH, adenocarcinoma, BAC, CpG island, DNA methylation, hypermethylation, hypomethylation

Citation: Disease Markers, vol. 23, no. 1-2, pp. 5-30, 2007

Authors: Costa, Vera L. | Henrique, Rui | Jerónimo, Carmen

Article Type: Research Article

Abstract: Prostate cancer is a highly prevalent malignancy, which is clinically silent but curable while organ-confined. Because available screening methods show poor sensitivity and specificity, the development of new molecular markers is warranted. Epigenetic alterations, mainly promoter hypermethylation of cancer-related genes, are common events in prostate cancer and might be used as cancer biomarkers. Moreover, the development of quantitative, high-throughput techniques to assess promoter methylation enabled the simultaneous screening of multiple clinical samples. …From the numerous cancer-related genes hypermethylated in prostate cancer only a few proved to be strong candidates to become routine biomarkers. This small set of genes includes GSTP1, APC, RARβ2, Cyclin D2, MDR1, and PTGS2. Single and/or multigene analyses demonstrated the feasibility of detecting early prostate cancer, with high sensitivity and specificity, in body fluids (serum, plasma, urine, and ejaculates) and tissue samples. In addition, quantitative hypermethylation of several genes has been associated with clinicopathologic features of tumor aggressiveness, and also reported as independent prognostic factor for relapse. The identification of age-related methylation at specific loci and the differential frequency of methylation among ethnical groups, also provided interesting data linking methylation and prostate cancer risk. Although large trials are needed to validate these findings, the clinical use of these markers might be envisaged for the near future. Show more

Keywords: Prostate cancer, epigenetics, methylation, molecular markers, biomarkers

Citation: Disease Markers, vol. 23, no. 1-2, pp. 31-41, 2007

Authors: Strathdee, Gordon

Article Type: Research Article

Abstract: The last ten years has seen an explosion in interest in epigenetic mechanisms of control of gene expression. This is particularly true in the field of cancer research where epigenetic alterations are now regarded as equally important as genetic alterations in the development and progression of cancer. Of particular interest is altered DNA methylation, which is a key feature of essentially all tumour types. Aberrant methylation of CpG islands represents an ideal candidate for both diagnostic …and prognostic markers in cancer. It is highly prevalent, very largely tumour specific and potentially far more readily detectible than most genetic alterations. This review will discuss the genes already identified as potential epigenetic markers of drug response, as well as the rapidly improving technology for detection of methylation which has greatly expanded the potential sources of tumour specific DNA that can be used for epigenetic marker analysis. Show more

Keywords: Epigenetics, drug resistance, chemotherapy, DNA methylation

Citation: Disease Markers, vol. 23, no. 1-2, pp. 43-49, 2007

Authors: Zitt, Marion | Zitt, Matthias | Müller, Hannes M.

Article Type: Research Article

Abstract: Colorectal cancer (CRC) is a common malignancy. It arises from benign neoplasms and evolves into adenocarcinomas through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations have been associated with specific steps in this adenoma-carcinoma sequence and are believed to drive the histological progression of CRC. Recently, epigenetic alterations (especially DNA methylation) have been shown to occur in colon polyps and CRC. The aberrant methylation of …genes appears to act together with genetic alterations to drive the initiation and progression of colon polyps to CRC. DNA methylation changes have been recognized as one of the most common molecular alterations in human tumors, including CRC. Because of the ubiquity of DNA methylation changes and the ability to detect methylated DNA in several body fluids (blood, stool), this specifically altered DNA may serve, on the one hand, as a possible new screening marker for CRC and, on the other hand, as a tool for therapy monitoring in patients having had neoplastic disease of the colorectum. As many CRC patients present with advanced disease, early detection seems to be one of the most important approaches to reduce mortality. Therefore, an effective screening test would have substantial clinical benefits. Furthermore, early detection of progression of disease in patients having had CRC permits immediate commencement of specific treatment regimens (e.g. curative resection of liver and lung metastases) and probably longer survival and better quality of life. Show more

Keywords: Colorectal cancer, DNA methylation, stool, screening, therapy monitoring, review

Citation: Disease Markers, vol. 23, no. 1-2, pp. 51-71, 2007

Authors: Hesson, Luke B. | Cooper, Wendy N. | Latif, Farida

Article Type: Research Article

Abstract: Tumour suppressor gene inactivation is critical to the pathogenesis of cancers; such loss of function may be mediated by irreversible processes such as gene deletion or mutation. Alternatively tumour suppressor genes may be inactivated via epigenetic processes a reversible mechanism that promises to be more amenable to treatment by therapeutic agents. The CpG dinucleotide is under-represented in the genome, but it is found in clusters within the promoters of some genes, and methylation of these CpG …islands play a critical role in the control of gene expression. Inhibitors of the DNA methyltransferases DNMT1 and DNMT3b have been used in a clinical setting, these nucleotide analogues lack specificity but the side effects of low dose treatments were minimal and in 2004 Vidaza (5-azacitidine) was licensed for use in myelodysplastic syndrome. Methylation inhibitors are also entering trials in conjunction with another class of epigenetic modifiers, the histone deacetylase inhibitors and this epigenetic double bullet offers hope of improved treatment regimes. Recently there has been a plethora of reports demonstrating epigenetic inactivation of genes that play important roles in development of cancer, including Ras-association domain family of genes. Epigenetic inactivation of RASSF1A (Ras-association domain family 1, isoform A) is one of the most common molecular changes in cancer. Hypermethylation of the RASSF1A promoter CpG island silences expression of the gene in many cancers including lung, breast, prostate, glioma, neuroblastoma and kidney cancer. Several recent studies have illustrated the diagnostic and prognostic potential of RASSF1A methylation. This presents RASSF1A methylation as an attractive biomarker for early cancer detection which, for most cancers, results in improved clinical outcome. DNA methylation analysis is applicable to a range of body fluids including serum, urine, bronchioalveolar lavage and sputum. The ease with which these body fluids can be acquired negates the need for invasive procedures to obtain biopsy material. This review will discuss the feasibility of using RASSF1A methylation as a diagnostic and prognostic marker in cancer management. Show more

Keywords: RASSF1A, tumour suppressor gene, 3p21.3, ras association domain, methylation, cancer

Citation: Disease Markers, vol. 23, no. 1-2, pp. 73-87, 2007

Authors: Fiegl, Heidi | Elmasry, Karim

Article Type: Research Article

Abstract: Epigenetic alterations are heritable changes in gene expression without an accompanying change in primary DNA sequence. Two major mechanisms that cause epigenetic changes are post-translational histone modifications and DNA methylation at cytosine bases within a CpG dinucleotide. Epigenetic defects have turned out to be one of the most common molecular alterations in human neoplasia. Promoter hypermethylation is associated with loss of expression of tumour suppressor genes in cancer. The analysis of aberrant DNA methylation is …gaining strength in the fields of cancer risk assessment, diagnosis, and therapy monitoring in different cancer types. These issues are discussed in this review. Show more

Keywords: Methylation, cancer risk assessment, diagnostics, prediction

Citation: Disease Markers, vol. 23, no. 1-2, pp. 89-96, 2007

Authors: Hau, Peter | Stupp, Roger | Hegi, Monika E.

Article Type: Research Article

Abstract: Glioblastomas are the most malignant gliomas with median survival times of only 15 months despite modern therapies. All standard treatments are palliative. Pathogenetic factors are diverse, hence, stratified treatment plans are warranted considering the molecular heterogeneity among these tumors. However, most patients are treated with "one fits all" standard therapies, many of them with minor response and major toxicities. The integration of clinical and molecular information, now becoming available using new tools such as gene …arrays, proteomics, and molecular imaging, will take us to an era where more targeted and effective treatments may be implemented. A first step towards the design of such therapies is the identification of relevant molecular mechanisms driving the aggressive biological behavior of glioblastoma. The accumulation of diverse aberrations in regulatory processes enables tumor cells to bypass the effects of most classical therapies available. Molecular alterations underlying such mechanisms comprise aberrations on the genetic level, such as point mutations of distinct genes, or amplifications and deletions, while others result from epigenetic modifications such as aberrant methylation of CpG islands in the regulatory sequence of genes. Epigenetic silencing of the MGMT gene encoding a DNA repair enzyme was recently found to be of predictive value in a randomized clinical trial for newly diagnosed glioblastoma testing the addition of the alkylating agent temozolomide to standard radiotherapy. Determination of the methylation status of the MGMT promoter may become the first molecular diagnostic tool to identify patients most likely to respond that will allow individually tailored therapy in glioblastoma. To date, the test for the MGMT-methylation status is the only tool available that may direct the choice for alkylating agents in glioblastoma patients, but many others may hopefully become part of an arsenal to stratify patients to respective targeted therapies within the next years. Show more

Keywords: Glioblastoma, predictive factors, personalized therapy, targeted therapy, MGMT

Citation: Disease Markers, vol. 23, no. 1-2, pp. 97-104, 2007

Authors: Cui, Hengmi

Article Type: Research Article

Abstract: IGF2 is the first gene discovered to be imprinted and expressed exclusively from the paternal allele in both human and mouse. IGF2 is also the first imprinted gene displaying loss of imprinting (LOI) or aberrant imprinting in human cancers. Evidently, LOI or reactivation of the maternal allele of IGF2 is associated with an increase of IGF2 expression that may subsequently play an important role in the onset of human cancers. The most important discovery was the …association of LOI of IGF2 with the risk of developing human colorectal cancer. LOI occurs not only in colon cancer tissues, but also in matched normal tissues and peripheral blood cells. A pilot study indicated a significant relationship between LOI of IGF2 and family history as well as personal history of colorectal cancer, suggesting that LOI of IGF2 might be a valuable biomolecular marker of predicting an individual's risk for colon cancer. A recent epigenetic progenitor model suggested that human cancers might have a common basis that involves an epigenetic disruption of progenitor cells mediated by "tumor progenitor genes" and proposed that non-neoplastic but epigenetically disrupted progenitor cells might be an important target for cancer risk assessment and prevention. Show more

Keywords: IGF2, loss of imprinting, cancer, biomarker

Citation: Disease Markers, vol. 23, no. 1-2, pp. 105-112, 2007

Authors: Alonzo, Todd A. | Siegmund, Kimberly D.

Article Type: Research Article

Abstract: We summarize standard and novel statistical methods for evaluating the classification accuracy of DNA methylation markers. The choice of method will depend on the type of marker studied (qualitative/quantitative), the number of markers, and the type of outcome (time-invariant/time-varying). A minimum of two error rates are needed for assessing marker accuracy: the true-positive fraction and the false-positive fraction. Measures of association that are computed from the combination of these error rates, such as the odds …ratio or relative risk, are not informative about classification accuracy. We provide an example of a DNA methylation marker that is strongly associated with time to death (logrank p=0.0003) that is not a good classifier as evaluated by the true-positive and false-positive fractions. Finally, we would like to emphasize the importance of study design. Markers can behave differently in different groups of individuals. It is important to know what factors may affect the accuracy of a marker and in which subpopulations the marker may be more accurate. Such an understanding is extremely important when comparing marker accuracy in two groups of subjects. Show more

Keywords: Sensitivity, specificity, ROC curves, survival data

Citation: Disease Markers, vol. 23, no. 1-2, pp. 113-120, 2007