genomics for obstetrics & gynecology
DESCRIPTION
Genomics could be difficult to understand for gynecologists. In this talk we will try to make it simple .TRANSCRIPT
Human Genome Project
Potential Applications
In March, 2002
Doctors successfully screened embryos for gene mutation linked to early onset Alzheimer's
JAMA, March, 2002
A Great Success
BasicsInside the nucleus of every cell in the body, a complex set of genetic instructions, known as the human genome, contained on pairs of chromosomes.
Chromosomes are long chains of DNA-deoxyribonucleic acid.
Base codeHereditary instructions are written in a four-letter code, with each letter corresponding to one of the chemical constituents of DNA: A, G, C, T.
GeneA gene is a chromosomal region capable of making a functional transcript.
ThusA genome is all the DNA in the cell, including its genes. Errors in genes--the smallest units of heredity-- may cause or contribute to disease
HoweverMany genes are co-expressed with their own antagonist
The resultAll diseases have a genetic component, whether inherited or resulting from the body's response to environmental stresses like viruses or toxins
GenomicsStructural genomics: to identify all the approximate 30,000 genes in human DNA Functional genomics: to understand gene-gene interaction
Objectivesdetermine the sequences of the 3 billion chemical base pairs that make up human DNA, store this information in databases explore potential application in
practical life
The concept
How & Which genes play a role in disease
causation
ToolsAn increasing number of gene tests are becoming available commerciallyMicro-array composed of five separate array each of which has about 10,000 target
Genomic MedicineDiagnosisMonitoring of progresstreatment of disease
Prevention
ExampleUsing tools emerging from the Human Genome Project, an international team tracked the gene for hereditary nonpolyposis colon cancer to a region of chromosome 2.
ButThe road from gene identification to effective treatments is long and full of challenges
So Why?!!!We as Doctors must be aware about the new genetic era and its potential impacts on our specialty so as to offer our patients the most appropriate and informed care.
Implantation : the model
Repeated failure of implantation was linked to Leukemia inhibitory Factor gene (LIF)However,
ImplantationMicro-array analysis has shown 36 up-regulated genes and 27 down-regulated genes at the implantation site.
Reese J et al, 2001
Categorised ingenes with recognized roles in implantation, genes with potential roles in this processgenes whose functions have yet to be defined in this event
Polycystic Ovary Syndrome
the insulin gene called variable number tandem repeat (VNTR) gene appears to be a promising candidate
Polycystic Ovary Syndrome
follistatin gene as a potential disease locus implicated in ovarian follicular development
Polycystic ovary syndrome
CYP11a gene -encoding P450 side chain cleavage-appears to be a major susceptibility locus for steroidogenic abnormalities
Franks et al, 2001
MUC 1: a genetic link to infertility?
Women with unexplained infertility were found to have a genetic susceptibility to failure of embryo implantation due to small MUC 1 allele size.
Horne A, et al,2001
Inherited breast and ovarian cancer (BRCA 1 and 2; early-onset tumors of breasts and ovaries)
Pre-eclampsiaA polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia
Zusterzeel et al 2001
Women with the glutathione S-transferase P1b-1b genotype, which could result in lower glutathione S-transferase detoxification capacity, has been linked to higher susceptibility to preeclampsia
Zusterzeel 2000
Gynecological oncology
The increased ovarian cancer risk associated with the high-activity of human EPHX gene (epoxide hydrolase)
Cystic Fibrosis
three hundred affected children born each year in UK
Although improvements in care and treatment mean that people with cystic fibrosis can now live for up to twenty-five years,
there is no cure
Currently Available DNA-Based Gene Tests
Some Alpha-1-antitrypsin deficiencyAlzheimer's diseaseCystic fibrosis
Ataxia telangiectasia Gaucher disease Inherited breast and ovarian cancerHereditary nonpolyposis colon cancerCharcot-Marie-Tooth Congenital adrenal hyperplasia
Duchenne muscular dystrophy/Becker muscular dystrophy Fanconi anemia Factor V-Leiden Fragile X syndrome Hemophilia A and B Huntington's disease Myotonic dystrophy Neurofibromatosis type 1
PhenylketonuriaAdult Polycystic Kidney DiseasePrader Willi/Angelman syndromes Sickle cell disease Spinocerebellar ataxiaSpinal muscular atrophy Thalassemias Tay-Sachs Disease
Gene TherapyIt means modification of the genetic material of living cells
This applies to genetically determined diseases but also to diseases that occur later in life
Highly promisingTreatmentPreventionImmunity enhancing (e.g., by adding a gene that suppresses tumor growth).
Still experimentalmore technological barriers are encountered than foreseen and therefore, the clinical success up to now is limited.
HowCells may be modified ex vivo for subsequent administration to patients, or may be altered in vivo by gene therapy given directly to the subject.
Germ cell gene therapy
Two techniquesDeposit corrective genes in the cell’s nucleus, integrate genes into the chromosomes..
Somatic cell gene therapy
VectorViral genes targeting
the cell's nucleus are retained in the vector, while harmful viral genes are removed and replaced with the corrective gene.
StepsViruses recognize and attach to receptors (a) and work their way through, into the cell (b). Once inside, the virus discharges its contents (c). Viral genes progress through the cell and into the nucleus (d).
Specific TargetEach virus is particularly adapted to use one or a few specific receptors, which limits the range of cells each one can infect.
Familial Hypercholesterolemia
A corrective low-density lipoprotein (LDL) receptor gene. A piece of the patient's liver was removed, and the cells were treated with a retrovirus carrying a good copy of the gene. Cells with the corrective gene were reimplanted into the patients's liver.
Is it the future!!!gene therapy for single-gene diseases may be routine and successful in 20 years.
Role in oncology• It has been proven that many cancers are
caused by the mutation of certain genes or lack of gene function
• The introduction of those genes into cancer cells where gene function is compromised, can work to restore gene function and stop tumor progression
Cancer Gene Therapy
• The RIZ1 gene is the best example • has potent tumor suppressive activities in
causing apoptosis, G2/M arrest, or both. • Preclinical animal studies have shown that
a recombinant adenovirus expressing the gene, AdRIZ1, can suppress
the growth of colon cancer Canote 2002
May be in the futurePatients with cancer may receive combination chemotherapy together with gene therapy for six cycles of treatment and, at that point, the chemotherapy is stopped and patients continue with chronic maintenance biologic therapy
Ozols 2002
Gene Therapy: Simple in Theory but Difficult
in Practice
Obstacles
SafetyCostsEthics : Baby designers
all of the current approaches to gene therapy seek to
introduce the good gene into the so-called somatic cells
of a child or an adult.