Cancer Genetics 2011

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CANCERGENETICS

Dr. Zeyad Akawi Jreisat, M.D., M.A., Ph.D.


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CANCER

Cancer is a genetic disease becauseit can be traced to alterations within

specific genes, but in most cases, itis not an inherited disease


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Initiation

Irreversible with memory

Requires fixation by cell division

Additive

No readily measurable threshold

For many chemical initiators, dependent uponxenobiotic metabolizing capabilities of the cell

Single initiated cells are not usually identifiable


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Promotion

Reversible Promoted cell population dependent upon

continued presence of the promoting agent fortheir existence

Dose response exhibits a threshold and maximal

effect level Modulated by variety of environmental factors,

including age, diet, hormonal status, andfrequency of administration of promoting agent

Although not carcinogenic, promoting agents

may promote fortuitously initiated cells Promoted lesions are seen microscopically

and/or grossly


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Progression

Irreversibility

Growth of altered cells responsive toenvironmental factors during early phase ofprogression

Discernable alterations in cell genome

Evolving chromosomal abnormality Fortuitous progression of promoted cells can be

demonstrated

Benign and/or malignant neoplasm seen


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CANCER

Genes play an important role in cancer

Cancer can be viewed as a series of geneticchanges that eventually lead to uncontrolled cellgrowth

Cancer usually is a multi-step process A cancerous growth can be considered clonal in

origin 5-10% of cancer patients have an inherited

predisposition to develop the cancer Most cancers 90-95% are not passed from

parents to offspring

Once a cellular growth has became cancerous ormalignant, the cancer cells are invasive andmetastatic


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1. DNA of a normal cell

This piece of DNA is an exact copy of the DNA fromwhich it came. When the parent cell divided tocreate two cells, the cell's DNA also divided,creating two identical copies of the original DNA.


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2. Mutation of DNA

This DNA has suffered a mutation, either through mis-copying (when its parent cell divided), or through thedamaging effects of exposure to radiation or a chemicalcarcinogen.


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3. Genetically altered cell

The DNA of the cell highlighted above has a mutationthat causes the cell to replicate even though this tissuedoesn't need replacement cells at this time or at this

place.


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4. Spread and second mutation

After about a million divisions, there's a good chancethat one of the new cells will have mutated further. Thiscell, now carrying two mutant genes, could have analtered appearance and be even more prone toreproduce unchecked.


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5. Third mutation

Over time and after many cell divisions, a third mutation

may arise. If the mutation gives the cell some furtheradvantage, that cell will grow more vigorously than itspredecessors and thus speed up the growth of the tumour.


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6. Fourth mutation

The new type of cells grow rapidly, allowing for moreopportunities for mutations. The next mutationpaves the way for the development of an even moreaggressive cancer.

At this point the tumour is still contained.


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7. Breaking through the membrane

The newer, wilder cells created by another mutation

are able to push their way through the epithelialtissue's basement membrane, which is a meshworkof protein that normally creates a barrier. Theinvasive cells in this tumour are no longer contained.

At this point the cancer is still too small to be

detected.


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8. Angiogenesis

Often during the development of earlier stages of thetumour, or perhaps by the time the tumour has brokenthrough the basement membrane (as pictured above),angiogenesis takes place. Angiogenesis is therecruitment of blood vessels from the network ofneighbouring vessels.


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9.Invasion and dispersal

The tumour has now invaded the tissue beyond thebasement membrane.


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The Most Common Cancer RiskFactors

Genetic predisposition: Colon and Breast cancer.

High estrogen exposure: Breast and uterinecancer.

Ionizing radiation: X-Rays and nuclear radiation.

Ultraviolet radiation: Skin cancer.

Carcinogenic chemicals: Asbestos, Polycyclicaromatic hydrocarbons, Aromatic amines,Nitrosamines, Various drugs, Inorganic

compounds


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Tobacco smoke: Lung cancer

Alcohol: Mouth, throat, esophagus, stomach, and

liver cancer

Carcinogenic foods: Include salted, and smokedfoods, meats treated with nitrites

Free radicals: Highly reactive chemicalcompounds that can damage DNA

Unhealthy diet: High in saturated fat (colon,rectum and prostate gland cancer)


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Viruses: DNA viruses: Papovavirus (papilomavirus,

polyomavirus, SV40), Adenovirus, Herpesvirus,Hepadna virus family

RNA viruses: Retrovirus type C, Retrovirus typeB

Examples:

- Epstein-Bar virus associated with Burkittslymphoma, nasopharyngeal carcinoma, B celllymphomas

- Hepatitis B virus associated with hepatocellularcarcinoma

- Human papillomaviruses associated with anogenitalcancers


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AMES TEST

This test used to screen for potential carcinogensusing a specially constructed strain of Salmonellatyphimuriumthat has a mutation (His-) in a genethat codes for one of the enzymes involved in thesynthesis of histidine.

Salmonella typhimurium +Histidine Growth Salmonella typhimurium -Histidine No

Growth

Salmonella typhimurium +CarcinogensMutations His- His+Salmonellatyphimurium -Histidine Growth


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DNA is the critical macromoleculein carcinogenesis WHY ?

The essential changes responsible for cancer aretransmitted from mother to daughter cells

Both irradiation and chemical carcinogensdamage DNA and are capable of causingmutations in DNA

A high incidence of cancer in individuals whohave an inherited deficiency in their ability torepair lesions in DNA

Many tumor cells exhibit abnormal chromosomes

Transfection experiments indicate that purifiedDNA (oncogenes) from cancer cells cantransform normal cells into cancer cells

The presence of special genes in the cellsshowed to increase susceptibility to cancer


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Changes shown by cultured cells after beingtransformed into malignant cells

Morphology changes Increased cell density

Loss of anchorage dependence

Loss of contact inhibition

Biochemical changes

Alteration of cytoskeletal structure

Diminished requirement for growth factors


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Cancer Causing Genes Usually

involved In The progression of a cell through the cell cycle.

Adhesion of a cell to its neighbors.

Apoptosis.

DNA repair.


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Types of genes which may mutate tocause cancer

Tumour suppressor genes

Oncogenes

DNA repair genes

Telomerases


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Tumour Suppressor Genes


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Tumor Suppressor Genes

Mutations in both alleles or a mutation in onefollowed by a loss of or reduction tohomozygosity in the second

Loss of function of a protein

Mutation present in germ cell (can beinherited) or somatic cell

Strong tissue preference (effect of RB1 gene inthe retina)


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Knudsens two hit hypothesis


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Proteins which are encoded by tumor-suppressor

genes

1 Intracellular proteins that regulate or inhibit progressionthrough a specific stage of the cell cycle (e.g., p16 and Rb).

2 Receptors or signal transducers for secreted hormones or

developmental signals that inhibit cell proliferation (e.g.,

TGF).3 Checkpoint-control proteins that arrest the cell cycle if

DNA is damaged or chromosomes are abnormal (e.g., p53).

4 Proteins that promote apoptosis.

5 Enzymes that participate in DNA repair.


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Mechanisms for inactivating tumor-

suppressor genes

1) Have deletions, point mutations or gene conversionthat prevent production of any protein or lead toproduction of a non-functional protein.

2) Methylation of cytosine residues in the promoter orother control elements. Such methylation is commonlyfound in non-transcribed regions of DNA.

3) Chromosomal abnormalities

M h i f l i th i i


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Mechanisms of loosing the remaininggood copy of a tumor suppressor gene

Tumor suppressor genes mutations Causing


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Tumor suppressor genes mutations CausingLoss

of Growth-Inhibition and Cell-Cycle Controls

p15: protein which causes cells to arrest in G1.

Binding of TGF to its receptor induces activation

of cytosolic Smad transcription factors

After translocating to the nucleus, Smads canpromote expression of the gene encoding p15.


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p16: binds specifically to CDK4 and CDK6, cyclin-dependent kinases (CDKs), thereby inhibitingtheir kinase activity (whose promotes

progression past the restriction point) andcausing G1 arrest. the p16 gene is inactivatedbyhypermethylation of its promoter region, whichPrevents transcription.

Cyclin D1 :Amplification of the cyclin D1 gene andconcomitant overproduction of the cyclin D1protein is common in human breast cancer.


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Rb:The complete phosphorylation of Rb irreversibly commitsthe cell to DNA synthesis. phosphorylation of Rb protein isinitiated midway through G1 by active cyclin D-CDK4 andcyclin D-CDK6 complexes & completed by other cyclin-CDKcomplexes in late G1, allowing activation of E2F transcriptionfactors, which stimulate transcription of genes encodingproteins required for DNA synthesis.

The kinase activity of cyclinD-CDk phosphorylates Rb,thereby activating E2F; this kinase activity is inhibited by p16.

In human cancers either a positive regulator overproduction

of cyclin D, or negative regulators p16 and Rb.

Rb function can be eliminated by the binding of an inhibitory

protein, designated E7, that is encoded by human

papillomavirus (HPV)


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Interaction between the Rb and E2F protein


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p53:

Is a sensor essential for the checkpoint control thatarrests cells with damaged DNA in G1.

Unlike other cell-cycle proteins, p53 is present atvery low levels in normal cells because it isextremely unstable and rapidly degraded.

DNA damage by -irradiation or by other stresses

somehow leads to the activation of ATM, a serinekinase that phosphorylates and thereby stabilizesp53, leading to a marked increase in itsconcentration.

The stabilized p53 activates expression of the geneencoding p21 CIP, which binds to and inhibitsmammalian G1 cyclin-CDK complexes.


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Oncogenic p53 mutations act as dominant negatives,with mutations in a single allele causing a loss offunction.

The activity of p53 normally is kept low by a proteincalled Mdm2. Mdm2 gene is itself transcriptionallyactivated byp53, Mdm2 functions in anautoregulatory feedback loop with p53, perhapsnormally preventing excess p53 function.

The activity of p53 also is inhibited by a humanpapillo-mavirus (HPV) protein called E6.


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Central role of p53 in preventing the proliferation of


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Central role ofp53 in preventing the proliferation of

cancer cells


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APC protein: inhibits the progression of certaintypes of cells through the cell cycle & it does soby preventing the Wnt signal-transductionpathway from activating expression of proto-oncogenes including the c-myc gene.

The first step in colon carcinogenesis involvesloss of a functional APC gene, resulting in

formation of polyps (precancerous growths)


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Cancer Genetics 2011

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