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Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 7, Number 1, February 2007
Contents
Cancer Genetics
Guest Editor: Anirban Maitra
Editorial Pp. 1-2
Sudhir Srivastava
Genetics of Preneoplasia: Lessons from Lung Cancer
Pp. 3-14
Ignacio I. Wistuba
[Abstract] [Full
text article]
Early Onset Gastric Cancer: On the Road to Unraveling
Gastric Carcinogenesis Pp. 15-28
Anya N. Milne, Robert Sitarz, Ralph Carvalho, Fatima Carneiro
and G. Johan A. Offerhaus
[Abstract] [Full
text article]
Gastrointestinal Polyposis Syndromes Pp.
29-46
Lodewijk A.A. Brosens, W. Arnout van Hattem, Marnix Jansen,
Wendy W.J. de Leng, Francis M. Giardiello and G. Johan A.
Offerhaus
[Abstract] [Full
text article]
Fusions Involving PAX and FOX Genes in the Molecular
Pathogenesis of Alveolar Rhabdomyosarcoma: Recent Advances
Pp. 47-61
Gabriela E. Mercado and Frederic G. Barr
[Abstract] [Full
text article]
Modeling INK4/ARF Tumor Suppression in the Mouse
Pp. 63-75
Justin H. Berger and Nabeel Bardeesy
[Abstract] [Full
text article]
Tyrosine Kinase Mutations in Human Cancer
Pp. 77-84
Ernst Lengyel, Kenjiro Sawada and Ravi Salgia
[Abstract] [Full
text article]
DNA Methylation in Health, Disease, and Cancer
Pp. 85-102
David S. Shames, John D. Minna and Adi F. Gazdar
[Abstract] [Full
text article]
The Application of Microarray Technology to the Analysis
of the Cancer Genome Pp. 103-120
John K. Cowell and Lesleyann Hawthorn
[Abstract] [Full
text article]
Mitochondria and Human Cancer Pp. 121-131
Josephine S. Modica-Napolitano, Mariola Kulawiec and Keshav
K. Singh
[Abstract] [Full
text article]
Bioinformatics Approaches in the Study of Cancer
Pp. 133-141
David A. Hanauer, Daniel R. Rhodes, Chandan Sinha-Kumar
and
Arul M. Chinnaiyan
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
Sudhir Srivastava
Cancer Genetics in the Post Genomic Era
From a simple observation of Austrian monk Gregor Mendel in
1865, the history of genetics has transitioned from Mendelian
genetics, to post-Mendelian genetics, to classical genetics,
to molecular genetics. Molecular genetics is driving cancer
research and is an integral part of cancer biology. Since
the completion of over 90% of the human genome sequence in
2001, a new frontier in molecular medicine has begun to emerge:
personalized medicine based on individual molecular profiles.
Scientific advances and major discoveries from areas such
as genomics, nanotechnology, proteomics, metabolomics, immunology,
molecular imaging, and bioinformatics allow us to envision
a future when a patient’s genetic, lifestyle, and environmental
risks for cancer can be combined with effective prevention
and early intervention strategies, especially for those at
high risk.
In the past two decades, remarkable progress has been made
in cancer genetics, which has provided an opportunity for
exponential progress fighting the disease. Cancer genetics
has a rich history of discoveries and innovations that continue
to benefit combinatorial approaches in cancer detection, diagnosis
and treatment. Lessons learned from model systems, such as
yeast or mouse, have enabled us to understand the carcinogenic
process in humans. Mouse models, in particular, have provided
biological “footprints” of many human cancers,
and are increasingly being used in pre-clinical development
of cancer drugs and toxicity assessment.
New technologies and increased interest of medical practitioners
to utilize molecular genetics in early detection, diagnosis,
therapeutic treatments, and predicting the clinical outcomes,
have accelerated efforts by the drug discovery communities
(pharmaceutical industry) to develop novel molecular biomarkers
for several human diseases, including cancer. Development
of molecular biomarkers also enables us to develop a new generation
of diagnostic products and to integrate diagnostics and therapeutics.
This integrated approach will aid in “individualizing”
the medical practice.
The current issue of Molecular Medicine on Cancer
Genetics appears to embody this integrated approach towards
fulfilling the needs for “personalized medicine”
for cancer patients. A number of drugs like Iressa™
(gefitinib) are targeting a specific molecule, such as EGFR-tyrosine
kinase. Recently, the presence of EGFR mutations was found
to correlate with a significant proportion of the clinical
responses to EGFR inhibitors, such as gefitinib, in non-small
cell lung carcinoma. The review on Tyrosine Kinome mutations
by Salgia is timely and useful for the field.
Molecular-based cancer diagnosis and treatment appears to
be the potential beneficiary of genetics. The definition of
pre-cancer, or preneoplasia, is being redefined in terms of
molecular changes that precede clinical detection of precancerous
lesions (see the articles by Wistuba, Milne and Barr). Since
pathology of precancerous lesions is subject to the observer’s
training and experience, molecular profiles are aiding in
removing such subjectivity and enhancing the detection of
preneoplastic lesions. Offerhaus’ article on inheritable
cancers, such as familial polyposis, an inherited condition
in which numerous polyps form on the inside walls of the colon
and rectum and increase the risk of colorectal cancer, provides
a perspective on gene-environment interaction. It also provides
insights into the exposures, genetic risk factors, and lifestyles
that have significant impacts on the majority of non-familial
cancers. Genetic changes along with epigenetic alterations
are good examples of gene-environment interactions.
In this issue, Gazdar talks about how epigenetic changes could
be used as potential biomarkers for cancer detection and diagnosis.
Among epigenetic markers, methylation is thought to be one
of the best studied in mammalian cells to modify gene function.
Aberrant DNA methylation can confer a selective growth advantage
to the respective cell. This occurs when the promoter regions
of genes, involved in the control of cell proliferation, are
subjected to DNA methylation in their CpG islands, thus silencing
gene expression. Hypermethylation of the promoter region CpG
islands in cancer cells is frequently observed concomitant
with the inhibition of gene function.
Environmental and genetic signals can trigger eukaryotic cells
to commit a suicide, a process known as programmed cell death
(apoptosis). Cancer causes changes not only in the nuclear
and cytoplasmic DNA and proteins, but also in specific organelles,
such as Golgi and mitochondria. Mitochondria are known to
play a pivotal role during apoptosis. A number of mutations,
deletions and insertions in the mitochondria genome have been
associated with specific cancers. The D-loop mtDNA region
seems to be a hotspot for mutations . The D loop region is
a non-coding region that contains short poly-pyrimidine tracts
and is thought to be involved in mtDNA replication. The article
by Singh and his colleagues describes a number of changes
that are associated with mitochondria in cancer cells. These
findings are encouraging because they offer the opportunity
to develop a non-invasive means to detect these cancers in
mtDNA isolated from cells in body fluids. The abundance of
mitochondria in each cell (in the thousands) offers an advantage
because there is only a single nucleus in each cell. For example,
a smoker at a higher risk of bladder cancer might provide
his or her doctor with a urine sample for protein profile
analysis of urothelial cells at the initial visit; this will
serve as a baseline for identification of future changes.
Changes that were previously associated with malignant or
pre-malignant lesions may suggest the development of malignancy,
and may warrant additional tests.
In summary, I applaud the editor of this special issue on
his effort for bringing to the fore timely research issues
and challenges in cancer genetics and its profound impact
on all facets of cancer biology. Advances in bioinformatics
are digitizing our discoveries in genomics, proteomics and
epigenomics to better understand complex data systems and
fulfilling our hopes of “cybermedicine” that will
one day provide its users the ability to assess their personal
risk and treatment options for disease, including cancer.
Sudhir Srivastava
Chief, Cancer Biomarkers Research Group
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Suite 3142
Rockville, MD 20852
USA
E-mail: srivasts@mail.nih.gov
[Back to top]
Genetics of Preneoplasia: Lessons from Lung Cancer
Ignacio I. Wistuba
[Full
text article]
From biological, histopathologic, and clinical perspectives,
lung cancer is a highly complex neoplasm probably having multiple
preneoplastic pathways. The sequence of histopathologic changes
in the bronchial mucosa that precedes the development of squamous
carcinomas of the lung has been identified. For the other
major forms of lung cancer, however, such sequences have been
poorly documented. This review summarizes the current knowledge
regarding the molecular and histopathologic pathogenesis of
lung cancer and discusses the complexity of identifying novel
molecular mechanisms involved in the development of the lung
premalignant disease, and their relevance to the development
of new strategies for early detection and chemoprevention.
Although our current knowledge of the molecular pathogenesis
of lung cancer is still meager, work over the last decade
has taught several important lessons about the molecular pathogenesis
of this tumor, including the following: a) Better characterization
of the high-risk population is needed. b) There are several
histopathologic and molecular pathways associated with the
development of the major types of non-small cell lung cancer.
c) Although there is a field effect phenomenon for lung preneoplastic
lesions, recent data suggest that there are at least two distinct
lung airway compartments (central and peripheral) for lung
cancer pathogenesis. d) Inflammation may play an important
role in lung cancer development and could be an important
component of the field effect phenomenon. e) For lung adenocarcinoma,
at least two pathways (smoking-related and nonsmoking-related)
have been identified. f) Finally, the identification of deregulated
molecular signaling pathways in lung cancer preneoplasias
may provide a rationale for designing novel strategies for
early detection and targeted chemoprevention of lung cancer.
[Back to top]
Early Onset Gastric Cancer: On the Road to Unraveling
Gastric Carcinogenesis
Anya N. Milne, Robert Sitarz, Ralph Carvalho, Fatima Carneiro
and G. Johan A. Offerhaus
[Full
text article]
Gastric cancer is thought to result from a combination of
environmental factors and the accumulation of specific genetic
alterations due to increasing genetic instability, and consequently
affects mainly older patients. Less than 10% of patients present
with the disease before 45 years of age (early onset gastric
carcinoma) and these patients are believed to develop gastric
carcinomas with a molecular genetic profile differing from
that of sporadic carcinomas occurring at a later age. In young
patients, the role of genetics is presumably greater than
in older patients, with less of an impact from environmental
carcinogens. As a result, hereditary gastric cancers and early
onset gastric cancers can provide vital information about
molecular genetic pathways in sporadic cancers and may aid
in the unraveling of gastric carcinogenesis.
This review focuses on the molecular genetics of gastric cancer
and also focuses on early onset gastric cancers as well as
familial gastric cancers such as hereditary diffuse gastric
cancer. An overview of the various pathways of importance
in gastric cancer, as discovered through in-vitro,
primary cancer and mouse model studies, is presented and the
clinical importance of CDH1 mutations is discussed.
[Back to top]
Gastrointestinal Polyposis Syndromes
Lodewijk A.A. Brosens, W. Arnout van Hattem, Marnix Jansen,
Wendy W.J. de Leng, Francis M. Giardiello and G. Johan A.
Offerhaus
[Full
text article]
Colorectal cancer is one of the leading causes of cancer-related
death in the Western society, and the incidence is rising.
Rare hereditary gastrointestinal polyposis syndromes that
predispose to colorectal cancer have provided a model for
the investigation of cancer initiation and progression in
the general population. Many insights in the molecular genetic
basis of cancer have emerged from the study of these syndromes.
This review discusses the genetics and clinical manifestations
of the three most common syndromes with gastrointestinal polyposis
and an increased risk of colorectal cancer: familial adenomatous
polyposis (FAP), juvenile polyposis (JP) and Peutz-Jeghers
syndrome (PJS).
[Back to top]
Fusions Involving PAX and FOX Genes in the Molecular
Pathogenesis of Alveolar Rhabdomyosarcoma: Recent Advances
Gabriela E. Mercado and Frederic G. Barr
[Full
text article]
Rhabdomyosarcoma is the most frequent soft tissue sarcoma
in the pediatric population. Two main histopathologic variants
have been described, embryonal (ERMS) and alveolar (ARMS),
which demonstrate clinical and genetic differences. In particular,
most ARMS but not ERMS tumors are characterized by the presence
of recurrent chromosomal translocations, which have been cytogenetically
defined as t(2;13)(q35;q14) and t(1;13)(p36;q14). These translocations
form PAX3-FKHR and PAX7-FKHR gene fusions, which encode chimeric
transcription factors. These chimeric proteins are hypothesized
to generate a novel transcriptional program in the target
cell, thereby contributing to multiple aspects of ARMS tumorigenesis.
This review highlights recent advances in numerous areas of
biomedical investigation that are providing new insights into
the biology, molecular pathology, and translational science
of ARMS: the identification of downstream targets of PAX3-FKHR
and collaborating events in the process of tumorigenesis and
metastasis; generation of animal models based on the gene
fusion and collaborating events; development of new assays
for diagnosis, prognosis, and detection of minimal disseminated
disease; and exploration of immune recognition of this tumor
and the fusion protein. These findings highlight the continued
importance of the fusion proteins in understanding the biology
of this tumor and developing improved diagnostics for this
tumor, and have led to the initiation of efforts to explore
therapeutic strategies based on the increasing understanding
of the biology of these fusion proteins.
[Back to top]
Modeling INK4/ARF Tumor Suppression in the Mouse
Justin H. Berger and Nabeel Bardeesy
[Full
text article]
The INK4/ARF locus encodes the p15INK4B,
p16INK4A and p14ARF tumor suppressor
proteins whose loss of function is associated with the pathogenesis
of many human cancers. Dissecting the relative contribution
of these genes to growth control in vivo is complicated
by their physical contiguity and the frequency of homozygous
deletions that inactivate all three components of this locus.
While genetically engineered mouse models provide a rigorous
system for elucidating cancer gene function, there is some
evidence to suggest there are cross-species differences in
regulating tumor biology. Given the prevalence of mouse models
in cancer research and the potential contribution of such
models to preclinical studies, it is important determine to
what degree the function of these critical tumor suppressors
is conserved between organisms. In this review, we assess
the relative biological roles of INK4A, INK4B and ARF in mice
and humans with the aim of determining the faithfulness of
mouse models and also of obtaining insights into the pattern
of specific tumor types that are associated with germline
and somatic mutations at components of this locus. We will
discuss 1) the contribution of INK4A, INK4B and ARF to growth
control in vitro in a series of cell types, 2) the
in vivo phenotypes associated with germline loss
of function of this locus and 3) the study of Ink4a and Arf
in different cancer-specific mouse models.
[Back to top]
Tyrosine Kinase Mutations in Human Cancer
Ernst Lengyel, Kenjiro Sawada and Ravi Salgia
[Full
text article]
A subset of tyrosine kinases are activated by mutations which
contribute to the malignant transformation, growth, and metastasis
of human cancers. Mutations change the expression, conformation
and/or stability of tyrosine kinases, often leading to constitutive
activation of the signaling pathways the kinases regulate.
Given that tyrosine kinases are key members of signaling cascades,
mutations have multiple effects on various cellular proteins.
This review will focus on four kinases (EGFR, c-Met, c-Kit,
and PI3-kinase) known to be mutated in human cancer. It will
discuss the effects that these mutations have on the biology
of tumors, and how our understanding of the structure and
function of kinases and their mutations is currently being
used to design targeted treatments.
[Back to top]
DNA Methylation in Health, Disease, and Cancer
David S. Shames, John D. Minna and Adi F. Gazdar
[Full
text article]
The spatial arrangement and three-dimensional structure of
DNA in the nucleus is controlled through the interdigitation
of DNA binding proteins such as histones and their modifiers,
the Polycomb-Trithorax proteins, and the DNA methyltransferase
enzymes. DNA methylation forms the foundation of chromatin
and is crucial to epigenetic gene regulation in mammals. Disease
pathogenesis mediated through infectious agents, inflammation,
aging, or genetic damage often involves changes in gene expression.
In particular, cellular transformation coincides with multiple
changes in chromatin architecture, many of which appear to
affect genome integrity and gene expression. Infectious agents,
such as viruses directly affect genome structure and induce
methylation of particular sequences to suppress host immune
responses. Hyperproliferative tissues such as those in the
gastrointestinal tract and colon have been shown to gradually
acquire aberrant promoter hypermethylation. Here we review
recent findings on altered DNA methylation in human disease,
with particular focus on cancer and the increasingly large
number of genes subject to tumor-specific promoter hypermethylation
and the possible role of aberrant methylation in tumor development.
[Back to top]
The Application of Microarray Technology to the Analysis
of the Cancer Genome
John K. Cowell and Lesleyann Hawthorn
[Full
text article]
The identification of genetic events that are involved in
the development of human cancer has been facilitated through
the development and application of a diverse series of high
resolution, high throughput microarray platforms. Essentially
there are two types of array; those that carry PCR products
from cloned nucleic acids (e.g. cDNA, BACs, cosmids) and those
that use oligonucleotides. Each has advantages and disadvantages
but it is now possible to survey genome wide DNA copy number
abnormalities and expression levels to allow correlations
between losses, gains and amplifications in tumor cells with
genes that are over- and under-expressed in the same samples.
The gene expression arrays that provide estimates of mRNA
levels in tumors have given rise to exon-specific arrays that
can identify both gene expression levels, alternative splicing
events and mRNA processing alterations. Oligonucleotide arrays
are also being used to interrogate single nucleotide polymorphisms
(SNPs) throughout the genome for linkage and association studies
and these have been adapted to quantify copy number abnormalities
and loss of heterozygosity events. To identify as yet unknown
transcripts tiling arrays across the genome have been developed
which can also identify DNA methylation changes and be used
to identify DNA-protein interactions using ChIP on Chip protocols.
Ultimately DNA sequencing arrays will allow resequencing of
chromosome regions and whole genomes. With all of these capabilities
becoming routine in genomics laboratories, the idea of a systematic
characterization of the sum genetic events that give rise
to a cancer cell is rapidly becoming a reality.
[Back to top]
Mitochondria and Human Cancer
Josephine S. Modica-Napolitano, Mariola Kulawiec and Keshav
K. Singh
[Full
text article]
The better part of a century has passed since Otto Warburg
first hypothesized that unique phenotypic characteristics
of tumor cells might be associated with an impairment in the
respiratory capacity of these cells. Since then a number of
distinct differences between the mitochondria of normal cells
and cancer cells have been observed at the genetic, molecular,
and biochemical levels. This article begins with a general
overview of mitochondrial structure and function, and then
outlines more specifically the metabolic and molecular alterations
in mitochondria associated with human cancer and their clinical
implications. Special emphasis is placed on mtDNA mutations
and their potential role in carcinogenesis. The potential
use of mitochondria as biomarkers for early detection of cancer,
or as unique cellular targets for novel and selective anti-cancer
agents is also discussed.
[Back to top]
Bioinformatics Approaches in the Study of Cancer
David A. Hanauer, Daniel R. Rhodes, Chandan Sinha-Kumar
and
Arul M. Chinnaiyan
[Full
text article]
A revolution is underway in the approach to studying
the genetic basis of cancer. Massive amounts of data are now
being generated via high-throughput techniques such
as DNA microarray technology and new computational algorithms
have been developed to aid in analysis. At the same time,
standards-based repositories, including the Stanford Microarray
Database and the Gene Expression Omnibus have been developed
to store and disseminate the results of microarray experiments.
Bioinformatics, the convergence of biology, information science,
and computation, has played a key role in these developments.
Recently developed techniques include Module Maps, SLAMS (Stepwise
Linkage Analysis of Microarray Signatures), and COPA (Cancer
Outlier Profile Analysis). What these techniques have in common
is the application of novel algorithms to find high-level
gene expression patterns across heterogeneous microarray experiments.
Large-scale initiatives are underway as well. The Cancer Genome
Atlas (TCGA) project is a logical extension of the Human Genome
Project and is meant to produce a comprehensive atlas of genetic
changes associated with cancer. The Cancer Biomedical Informatics
Grid (caBIG™), led by the NCI, also represents a colossal
initiative involving virtually all aspects of cancer research
and may help to transform the way cancer research is conducted
and data are shared.
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