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Current
Genomics
ISSN: 1389-2029
Current Genomics
Volume 9, Number 1, March 2008
Contents
The Genomics of Colorectal Cancer: State of the Art
Pp. 1-10
A.D. Beggs and S.V. Hodgson
[Abstract]
Salivary Genomics, Transcriptomics and
Proteomics: The Emerging Concept of the Oral Ecosystem and
their Use in the Early Diagnosis of Cancer and other Diseases
Pp. 11-21
T.K. Fábián, P. Fejérdy and P. Csermely
[Abstract]
Array-Based Approaches for the Identification of Epigenetic
Silenced Tumor Suppressor Genes Pp. 22-24
N. Takai and H. Narahara
[Abstract]
Cancer Metastasis as Disrupted Developmental Phenotype
Pp. 25-28
H. Ishii and T. Saito
[Abstract]
Genetic Variation and Atherosclerosis Pp. 29-42
E. Biros, M. Karan and J. Golledge
[Abstract]
The Epigenetic Origin of Aneuploidy Pp. 43-50
L.A. Herrera, D. Prada, M.A. Andonegui and A. Dueñas-González
[Abstract]
Understanding Genetic Factors in Idiopathic Scoliosis, a Complex
Disease of Childhood Pp. 51-59
C.A. Wise, X. Gao, S. Shoemaker, D. Gordon and J.A. Herring
[Abstract]
Genomic Organization and Control of the Grb7 Gene
Family Pp. 60-68
E. Lucas-Fernández, I. García-Palmero and
A. Villalobo
[Abstract]
Abstracts
[Back to top]
The Genomics of Colorectal Cancer: State
of the Art
A.D. Beggs and S.V. Hodgson
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.
[Back to top]
Salivary Genomics, Transcriptomics and Proteomics:
The Emerging Concept of the Oral Ecosystem and their Use in
the Early Diagnosis of Cancer and other Diseases
T.K. Fábián, P. Fejérdy and P. Csermely
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.
[Back to top]
Array-Based Approaches for the Identification of Epigenetic
Silenced Tumor Suppressor Genes
N. Takai and H. Narahara
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.
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Cancer Metastasis as Disrupted Developmental Phenotype
H. Ishii and T. Saito
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.
[Back to top]
Genetic Variation and Atherosclerosis
E. Biros, M. Karan and J. Golledge
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.
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The Epigenetic Origin of Aneuploidy
L.A. Herrera, D. Prada, M.A. Andonegui and A. Dueñas-González
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 cancercell
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.
[Back to top]
Understanding Genetic Factors in Idiopathic Scoliosis,
a Complex Disease of Childhood
C.A. Wise, X. Gao, S. Shoemaker, D. Gordon and J.A. Herring
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.
[Back to top]
Genomic Organization and Control of the Grb7 Gene
Family
E. Lucas-Fernández, I. García-Palmero and
A. Villalobo
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.
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