Current Genomics - Volume 9, Issue 1, 2008

The concept of the adenoma-carcinoma sequence, as first espoused by Morson et al. whereby the development of colorectal cancer is dependent on a stepwise progression from adenomatous polyp to carcinoma is well documented. Initial studies of the genetics of inherited colorectal cancer susceptibility concentrated on the inherited colorectal cancer syndromes, such as Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (also known as HNPCC). These syndromes, whilst easily characterisable, have a well understood sequence of genetic mutations that predispose the sufferer to developing colorectal cancer, initiated for example in FAP by the loss of the second, normal allelle of the tumour supressor APC gene. Later research has identified other inherited variants such as MUTYH (MYH) polyposis and Hyperplastic Polyposis Syndrome. Recent research has concentrated on the pathways by which colorectal adenomatous polyps not due to one of these known inherited susceptibilities undergo malignant transformation, and determination of the types of polyps most likely to do so. Also, why do individuals in certain families have a predisposition to colorectal cancer. In this article, we will discuss briefly the current state of knowledge of the genomics of the classical inherited colorectal cancer syndromes. We will also discuss in detail the genetic changes in polyps that undergo malignant transformation as well as current knowledge with regards to the epigenomic changes found in colorectal polyps.

There is an increasingly growing interest world-wide for the genomics, transcriptomics and proteomics of saliva and the oral cavity, since they provide a non-invasive source of unprecedently rich genetic information. The complexity of oral systems biology goes much beyond the human genome, transcriptome and proteome revealed by oral mucosal cells, gingival crevicular fluid, and saliva, and includes the complexity of the oral microbiota, the symbiotic assembly of bacterial, fungal and other microbial flora in the oral cavity. In our review we summarize the recent information on oral genomics, transcriptomics and proteomics, of both human and microbial origin. We also give an introduction and practical advice on sample collection, handling and storage for analysis. Finally, we show the usefulness of salivary and oral genomics in early diagnosis of cancer, as well as in uncovering other systemic diseases, infections and oral disorders. We close the review by highlighting a number of possible exploratory pathways in this emerging, hot research field.

Carcinogenesis involves the inactivation or inhibition of genes that function as tumor suppressors. Deletions, mutations, or epigenetic silencing of tumor suppressor genes can lead to altered growth, differentiation, and apoptosis. DNA methylation and histone modifications are important epigenetic mechanisms of gene regulation and play essential roles both independently and cooperatively in tumor initiation and progression. Realization that many tumor suppressor genes are silenced by epigenetic mechanisms has stimulated discovery of novel tumor suppressor genes. One of the most useful of these approaches is an epigenetic reactivation screening strategy that combines treatment of cancer cells in vitro with DNA methyltransferase and/or histone deacetylase (HDAC) inhibitors, followed by global gene expression analysis using microarrays, to identify upregulated genes. This approach is most effective when complemented by microarray analyses to identify genes repressed in primary tumors. Recently, using cancer cell lines treated with a DNA methylation inhibitor and/or a HDAC inhibitor in conjunction with cDNA microarray analysis, candidate tumor suppressor genes, which are subject to epigenetic silencing, have been identified in endometrial, colorectal, esophageal, and pancreatic cancers. An increasing number of studies have utilized epigenetic reactivation screening to discover novel tumor suppressor genes in cancer. The results of some of the most recent studies are highlighted in this review.

Cancer metastasis is a complex processes, associated with the invasion to tissues with extensive degradation of the surrounding normal components, penetration into vessels, circulation, and then invasion to normal tissues in body. It would be not surprising that tumor cells usurp pathways critical to the developing embryo during metastasis. For the better understanding of tumor metastasis, this review will highlight the recent progress and significance of the signal transduction pathways, relevant to developmental biology.

A family history of atherosclerosis is independently associated with an increased incidence of cardiovascular events. The genetic factors underlying the importance of inheritance in atherosclerosis are starting to be understood. Genetic variation, such as mutations or common polymorphisms has been shown to be involved in modulation of a range of risk factors, such as plasma lipoprotein levels, inflammation and vascular calcification. This review presents examples of present studies of the role of genetic polymorphism in atherosclerosis.

Theodore Boveri, eminent German pathologist, observed aneuploidy in cancer cells more than a century ago and suggested that cancer cells derived from a single progenitor cell that acquires the potential for uncontrolled continuous proliferation. Currently, it is well known that aneuploidy is observed in virtually all cancers. Gain and loss of chromosomal material in neoplastic cells is considered to be a process of diversification that leads to survival of the fittest clones. According to Darwin's theory of evolution, the environment determines the grounds upon which selection takes place and the genetic characteristics necessary for better adaptation. This concept can be applied to the carcinogenesis process, connecting the ability of cancer cells to adapt to different environments and to resist chemotherapy, genomic instability being the driving force of tumor development and progression. What causes this genome instability? Mutations have been recognized for a long time as the major source of genome instability in cancer cells. Nevertheless, an alternative hypothesis suggests that aneuploidy is a primary cause of genome instability rather than solely a simple consequence of the malignant transformation process. Whether genome instability results from mutations or from aneuploidy is not a matter of discussion in this review. It is most likely both phenomena are intimately related; however, we will focus on the mechanisms involved in aneuploidy formation and more specifically on the epigenetic origin of aneuploid cells. Epigenetic inheritance is defined as cellular information—other than the DNA sequence itself—that is heritable during cell division. DNA methylation and histone modifications comprise two of the main epigenetic modifications that are important for many physiological and pathological conditions, including cancer. Aberrant DNA methylation is the most common molecular cancer-cell lesion, even more frequent than gene mutations; tumor suppressor gene silencing by CpG island promoter hypermethylation is perhaps the most frequent epigenetic modification in cancer cells. Epigenetic characteristics of cells may be modified by several factors including environmental exposure, certain nutrient deficiencies, radiation, etc. Some of these alterations have been correlated with the formation of aneuploid cells in vivo. A growing body of evidence suggests that aneuploidy is produced and caused by chromosomal instability. We propose and support in this manuscript that not only genetics but also epigenetics, contribute in a major fashion to aneuploid cell formation.

Idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, affecting ∼3% of children worldwide. AIS significantly impacts national health in the U. S. alone, creating disfigurement and disability for over 10% of patients and costing billions of dollars annually for treatment. Despite many investigations, the underlying etiology of IS is poorly understood. Twin studies and observations of familial aggregation reveal significant genetic contributions to IS. Several features of the disease including potentially strong genetic effects, the early onset of disease, and standardized diagnostic criteria make IS ideal for genomic approaches to finding risk factors. Here we comprehensively review the genetic contributions to IS and compare those findings to other well-described complex diseases such as Crohn's disease, type 1 diabetes, psoriasis, and rheumatoid arthritis. We also summarize candidate gene studies and evaluate them in the context of possible disease aetiology. Finally, we provide study designs that apply emerging genomic technologies to this disease. Existing genetic data provide testable hypotheses regarding IS etiology, and also provide proof of principle for applying high-density genome-wide methods to finding susceptibility genes and disease modifiers.

Grb7 and their related family members Grb10 and Grb14 are adaptor proteins, which participate in the functionality of multiple signal transduction pathways under the control of a variety of activated tyrosine kinase receptors and other tyrosine-phosphorylated proteins. They are involved in the modulation of important cellular and organismal functions such as cell migration, cell proliferation, apoptosis, gene expression, protein degradation, protein phosphorylation, angiogenesis, embryonic development and metabolic control. In this short review we shall describe the organization of the genes encoding the Grb7 protein family, their transcriptional products and the regulatory mechanisms implicated in the control of their expression. Finally, the alterations found in these genes and the mechanisms affecting their expression under pathological conditions such as cancer, diabetes and some congenital disorders will be highlighted.