The Genetics of The Genetics of CancerCancer

Presenters Presenters

Patrick DayPatrick Day

Rachael HanksRachael Hanks

Leila ShiraziLeila Shirazi

History of CancerHistory of Cancer Cancer has been documented as Cancer has been documented as

early as 3000 B.C.early as 3000 B.C. Recorded treatments of cancer Recorded treatments of cancer

since 1600 B.C.since 1600 B.C. Egyptians would burn or cut off Egyptians would burn or cut off

cancerous tumors, also they would cancerous tumors, also they would mix pig brains and freshly ground mix pig brains and freshly ground dates and insert into the urinary dates and insert into the urinary tract for some internal cancerstract for some internal cancers

By 300 B.C Hippocrates had By 300 B.C Hippocrates had identified several different types of identified several different types of cancercancer

Cancer effects about 1 out of Cancer effects about 1 out of every 3 peopleevery 3 people

Findings of CancerFindings of Cancer In the 1980’s-1990’s researchers In the 1980’s-1990’s researchers

identified parts of the genome that identified parts of the genome that only infected individuals shared, only infected individuals shared, such as chromosomal aberration such as chromosomal aberration or a unique DNA sequence. The or a unique DNA sequence. The research continued on specific research continued on specific genes that’s could effect cell cycle genes that’s could effect cell cycle control. This led to the discovery control. This led to the discovery of more then 100 oncogenes, and of more then 100 oncogenes, and more then 30 tumor suppressing more then 30 tumor suppressing genes.genes.

Oncogenes-Oncogenes- cause cancer cause cancer when they are inappropriately when they are inappropriately activatedactivated

Tumor suppressing genes-Tumor suppressing genes- deletion or inactivation of these deletion or inactivation of these genes causes cancer.genes causes cancer.

Function Of Cancer Genes Function Of Cancer Genes Discovered Discovered

Dutch researcher Sebastian Nijman has discovered new genes which are Dutch researcher Sebastian Nijman has discovered new genes which are involved in the development of cancer. The results of his research have led involved in the development of cancer. The results of his research have led to a new treatment for patients with an inherited form of cancer, to a new treatment for patients with an inherited form of cancer, cylindromatosis. (www.sciencedaily.com)cylindromatosis. (www.sciencedaily.com)

Cylindromatosis- Cylindromatosis- PatientsPatients with the very rarewith the very rare geneticgenetic condition condition

cylindromatosis develop a lot of benign tumours on the skin. These tumours cylindromatosis develop a lot of benign tumours on the skin. These tumours

mainly occur on the head where they can cause serious malformations.mainly occur on the head where they can cause serious malformations.

Difference Between Cancer cells Difference Between Cancer cells and Regular cellsand Regular cells

Cancer cells can divide infinitely if Cancer cells can divide infinitely if provided enough nutrients and provided enough nutrients and spacespace

Cancer cells can produce Cancer cells can produce telomerestelomeres

Cancer cells look much different Cancer cells look much different then a normal cellthen a normal cell

Cancer cells can metastasize Cancer cells can metastasize (Spread)(Spread)

Induce local blood vessel Induce local blood vessel formationformation

Increased mutation rateIncreased mutation rate

Normal cells divide until the Normal cells divide until the telomeres on the cell run outtelomeres on the cell run out

Normal cells do not divide as often Normal cells do not divide as often as cancer cellsas cancer cells

Cell division is controlledCell division is controlled Adhere to the surroundings of the Adhere to the surroundings of the

other cells (Takes the same shape other cells (Takes the same shape as cells around it)as cells around it)

Plasma membrane has less fluid Plasma membrane has less fluid compared to a cancer cellcompared to a cancer cell

Diagram of Cancer cells V.S.Diagram of Cancer cells V.S.Normal cellsNormal cells

How Cancer cells FormHow Cancer cells Form Cancer cells are formed when a Cancer cells are formed when a

normal cell looses its ability to normal cell looses its ability to control it’s division ratecontrol it’s division rate

Cancer can form from Cancer can form from environmental triggers: Smoking, environmental triggers: Smoking, drinking, stressdrinking, stress

Mutations in cells can cause them to Mutations in cells can cause them to become cancerousbecome cancerous

Cancer cells squeeze into the blood Cancer cells squeeze into the blood stream which allow them to travel to stream which allow them to travel to other parts of the bodyother parts of the body

A loss of balance in tissue cells that A loss of balance in tissue cells that can divide continually or frequentlycan divide continually or frequently

Cancer cells could come from stem Cancer cells could come from stem cells or regular cells that have gone cells or regular cells that have gone through a series of mutationsthrough a series of mutations

Other Causes of CancerOther Causes of Cancer

Dedifferentiation reverses Dedifferentiation reverses specializationspecialization

Mutations in a differentiated cell Mutations in a differentiated cell could reactivate latent “stemness” could reactivate latent “stemness” genes, giving the cell greater genes, giving the cell greater capacity to divide while causing it capacity to divide while causing it to lose some of its specialization.to lose some of its specialization.

To much repair may trigger To much repair may trigger tumor formationtumor formation

If the epitheluim is occasionally If the epitheluim is occasionally damaged, resting stem cells can damaged, resting stem cells can become activated and divide to fill become activated and divide to fill the tissue. If the injury is severe, the tissue. If the injury is severe, the present activation of stem cells the present activation of stem cells to renew the tissue can veer out of to renew the tissue can veer out of control, causing an abnormal control, causing an abnormal growthgrowth

DNA MicroarraysDNA Microarrays Some cancer’s look the same as normal cells under a microscope, with the Some cancer’s look the same as normal cells under a microscope, with the

use of DNA microarray analysis, we have been able to refine and even use of DNA microarray analysis, we have been able to refine and even individualize cancer diagnosis and treatment.individualize cancer diagnosis and treatment.

The vertical columns of squares represent tumor samples and the horizontal The vertical columns of squares represent tumor samples and the horizontal rows compare the activities of particular genes- The red tone indicates rows compare the activities of particular genes- The red tone indicates higher-then-normal expression and the blue indicates lower-then-normal higher-then-normal expression and the blue indicates lower-then-normal expression.expression.

Germline V.S. Sporadic CancerGermline V.S. Sporadic Cancer

GermlineGermline In germline cancer, every cell has In germline cancer, every cell has

one gene variant that increases one gene variant that increases the chance of a person getting the chance of a person getting cancer. This type of predisposition cancer. This type of predisposition is known as a Mendelian trait.is known as a Mendelian trait.

This is a cancer that is passed This is a cancer that is passed through generations of people and through generations of people and is hard to avoidis hard to avoid

Sporadic Sporadic Sporadic cancer forms when a Sporadic cancer forms when a

dominate mutation occurs in a cell, dominate mutation occurs in a cell, this is caused by environmental this is caused by environmental triggers such as exposure to triggers such as exposure to radiation or a chemical, can cause radiation or a chemical, can cause the somatic mutations that cause the somatic mutations that cause cancer.cancer.

This cancer is strictly caused by This cancer is strictly caused by environmental factors and can be environmental factors and can be avoidedavoided

Causes of TumorsCauses of Tumors

Angiogenesis nurtures a Angiogenesis nurtures a tumortumor

Cells starved for oxygen deep Cells starved for oxygen deep within a tumor secrete vascular within a tumor secrete vascular endothelial growth factor, which endothelial growth factor, which stimulates nearby capillaries to stimulates nearby capillaries to extend branches towards the extend branches towards the tumor helping it to grow.tumor helping it to grow.

Shifting the balance in a Shifting the balance in a tissue towards cells that tissue towards cells that dividedivide

If a mutation renders a If a mutation renders a differentiated cell able to divide to differentiated cell able to divide to yield other cells that frequently yield other cells that frequently divide, then over time these cells divide, then over time these cells may take over, forming an may take over, forming an abnormal growthabnormal growth

Cancer Stem cellsCancer Stem cells A cancer stem cell can divide to self-renew and give rise to a cancer cell, A cancer stem cell can divide to self-renew and give rise to a cancer cell,

which in turn can also spawn abnormal daughter cells.which in turn can also spawn abnormal daughter cells. Upsetting the balance of stem and progenitor to differentiated cells can Upsetting the balance of stem and progenitor to differentiated cells can

cause cancer as excess, fast dividing cells accumulate.cause cancer as excess, fast dividing cells accumulate. The cancer causing mutations can occur in the cancer stem cell- in this The cancer causing mutations can occur in the cancer stem cell- in this

case, the early progenitor cells form the tumor which may also spawn case, the early progenitor cells form the tumor which may also spawn abnormal daughter cells.abnormal daughter cells.

Genes Associated With CancerGenes Associated With Cancer

Oncogenes- (recessive) Oncogenes- (recessive) activate improper cell division activate improper cell division which leads to cancer. (proto-which leads to cancer. (proto-oncogenes are normal and oncogenes are normal and control cell cycles.)control cell cycles.)

Tumor suppressors- Tumor suppressors- (dominant) normally prevent (dominant) normally prevent cancer, but can mutate so that cancer, but can mutate so that part of a gene is missing, part of a gene is missing, thereby eliminating its function thereby eliminating its function and causing cancer.and causing cancer.

DNA repair genes- normally DNA repair genes- normally repair damaged DNA. Faulty repair damaged DNA. Faulty DNA allows mutations to build DNA allows mutations to build up and mutant cells to divide.up and mutant cells to divide.

The bright blue enlarged cells are carrying oncogenes.

Proto-Oncogenes and OncogenesProto-Oncogenes and Oncogenes Proto-Oncogenes are Proto-Oncogenes are

active when high cell active when high cell division rates are division rates are necessary (like in necessary (like in wounds).wounds).

Oncogenes are point Oncogenes are point mutations of proto-mutations of proto-oncogenes, activated at oncogenes, activated at non-wound sites.non-wound sites.

Rapid cell division in Rapid cell division in undamaged tissue leads undamaged tissue leads to cancerous growths to cancerous growths (also known as tumors). (also known as tumors).

A single base change in a proto-oncogene causes bladder cancer.

The oncogene RET alters growth factors or growth factor receptors and can lead to Thyroid cancer.

Transformations of Gene Transformations of Gene ExpressionsExpressions

Proto-oncogenes can become oncogenes when placed next to Proto-oncogenes can become oncogenes when placed next to virus-infected cells.virus-infected cells.

When a chromosome is inverted or translocated, proto-oncogenes When a chromosome is inverted or translocated, proto-oncogenes can “turn on” and become oncogenes if they are moved near very can “turn on” and become oncogenes if they are moved near very active genes.active genes.

The immune system can contribute to overexpression of oncogenes The immune system can contribute to overexpression of oncogenes by producing an excess of antibodies to accommodate oncogenes.by producing an excess of antibodies to accommodate oncogenes.

Burkitt lymphoma is caused when proto-oncogenes are activated along with antibody genes.

Fusion ProteinsFusion Proteins When proto-oncogenes are read When proto-oncogenes are read

together as a pair, the result is a together as a pair, the result is a double gene product, or a fusion double gene product, or a fusion protein.protein.

Fusion proteins can take control of Fusion proteins can take control of cell division. Rapid cell division cell division. Rapid cell division can cause cancer.can cause cancer.

Fusion proteins are most Fusion proteins are most commonly associated with commonly associated with cancers of the blood, including cancers of the blood, including leukemia.leukemia.

Pieces of chromosomes that are Pieces of chromosomes that are randomly translocated to others randomly translocated to others during cell division can lead to during cell division can lead to fusion proteins, and in turn, to fusion proteins, and in turn, to various cancers.various cancers.

Fusion proteins can cause childhood cancers of the blood such as leukemia.

Excessive Receptor Signals and Excessive Receptor Signals and Her-2/neu Breast CancerHer-2/neu Breast Cancer

25% of women with breast cancer have 1-2 25% of women with breast cancer have 1-2 million copies of an oncogene producer (a million copies of an oncogene producer (a protein) called Her-2/neu. Normal women have protein) called Her-2/neu. Normal women have 20,000-100,000 copies.20,000-100,000 copies.

These proteins bind to tyrosine kinase receptors These proteins bind to tyrosine kinase receptors which, together, send too many signals to tell which, together, send too many signals to tell cells to divide.cells to divide.

A drug called Herceptin can help by stopping A drug called Herceptin can help by stopping some of the receptors from sending out too some of the receptors from sending out too many signals for cell division.many signals for cell division.

Tumor SuppressorsTumor Suppressors

A tumor suppressor can mutate into a gene that causes A tumor suppressor can mutate into a gene that causes cancer. The mutated gene has usually had some kind of cancer. The mutated gene has usually had some kind of deletion which removes part or some of its normal deletion which removes part or some of its normal functions.functions.

Wilms’ tumor is the result of a mutated tumor suppressor. In this form of cancer, a child’s kidney cells divide at the same rate as would an embryo’s, forming a tumor.

Retinblastoma (RB)Retinblastoma (RB)

Retinoblastoma or (RB) is Retinoblastoma or (RB) is a rare childhood eye a rare childhood eye cancer.cancer.

Most RB is the result of a Most RB is the result of a partial deletion on partial deletion on Chromosome 13.Chromosome 13.

In 1987, researchers In 1987, researchers found the RB gene and found the RB gene and have linked it to other have linked it to other cancers such as breast, cancers such as breast, lung, and prostate lung, and prostate cancer.cancer.

RB is a childhood eye cancer that results in one or both of the eyes developing an average of three tumors.

On the left is a normal cell with no Chromosome 13 deletion. On the right is a cancerous cell with deletion.

The “Two-Hit Hypothesis”The “Two-Hit Hypothesis”

Alfred Knudson was one of the Alfred Knudson was one of the first to recognize tumor first to recognize tumor suppressors and form the suppressors and form the “two-hit hypothesis in his “two-hit hypothesis in his observations of RB in children.observations of RB in children.

Two mutations can lead to RB:Two mutations can lead to RB:

- the first mutation is inherited - the first mutation is inherited and can affect a newborn with and can affect a newborn with just a single mutation in one just a single mutation in one somatic eye cell.somatic eye cell.

- the second mutation, in its - the second mutation, in its non-inherited form, appears non-inherited form, appears later in childhood.later in childhood.Alfred Knudson is now widely

recognized for his research on RB and the “two-hit” hypothesis.

The p53 GeneThe p53 Gene p53 is a gene that codes for a p53 is a gene that codes for a

protein which decides whether protein which decides whether a cell should repair DNA copy a cell should repair DNA copy errors or die.errors or die.

Much like the RB gene, if there Much like the RB gene, if there is a slight mutation or deletion is a slight mutation or deletion of the p53 gene, a cell with of the p53 gene, a cell with damaged DNA can be allowed damaged DNA can be allowed to divide, leading to cancer.to divide, leading to cancer.

More than ½ of all cancers More than ½ of all cancers involve some sort of mutation involve some sort of mutation or deletion in the p53 gene.or deletion in the p53 gene.

Environmental triggers such as Environmental triggers such as viruses, radiation, and smoking viruses, radiation, and smoking can lead to mutations in the can lead to mutations in the p53 gene.p53 gene.

The p53 gene.

BRCA-1 and Breast CancerBRCA-1 and Breast Cancer BRCA-1 stands for “breast BRCA-1 stands for “breast

cancer predisposition gene cancer predisposition gene 1.”1.”

It is a mutated tumor It is a mutated tumor suppressor gene that, when suppressor gene that, when inherited, has a late onset of inherited, has a late onset of symptoms for the affected symptoms for the affected individual.individual.

• BRCA-1 codes for a protein that is necessary for DNA repair.

• Mutations in BRCA-2 (a gene that is very similar to BRCA-1) can cause breast cancer, or lead to other kinds of cancer.

A breast cancer survivor.

Series of Genetic ChangesSeries of Genetic Changes

““Gatekeeper” genes control Gatekeeper” genes control mitosis and apoptosis (cell mitosis and apoptosis (cell death).death).

““Caretaker” genes control the Caretaker” genes control the mutation rates of gatekeeper mutation rates of gatekeeper genes.genes.

Series of genetic changes in Series of genetic changes in different stages of cancer can different stages of cancer can help researchers to pinpoint help researchers to pinpoint certain mutations and develop certain mutations and develop prevention treatments.prevention treatments.

Understanding genetic changes in the different stages of colon cancer could potentially lead to preventative treatments.

Brain TumorsBrain Tumors

Astrocytomas are the most common kinds of Astrocytomas are the most common kinds of brain tumors.brain tumors.

They are the result of a series of single-gene They are the result of a series of single-gene and chromosomal changes that occur in and chromosomal changes that occur in different stages of the growth of the tumor.different stages of the growth of the tumor.

On the left is a normal brain, and the blue mass in the right brain is an astrocytoma.

Colon CancerColon Cancer Only 5% of colon cancer cases Only 5% of colon cancer cases

are inherited.are inherited. Colon cancer begins with the Colon cancer begins with the

build-up of tiny colon polyps, build-up of tiny colon polyps, which leads to a condition called which leads to a condition called FAP. Colon lining cells that do not FAP. Colon lining cells that do not die on schedule build up and lead die on schedule build up and lead to cancer.to cancer.

Researchers have pinpointed the Researchers have pinpointed the direct cause of colon cancer to be direct cause of colon cancer to be linked to a deletion in linked to a deletion in Chromosome 5.Chromosome 5.

A kind of chain reaction in this A kind of chain reaction in this mutation leads to others that can mutation leads to others that can spread the cancer (p53, PRL-3, spread the cancer (p53, PRL-3, and TGF).and TGF).

•Mutating genes that help the cancer cells and that strongly affect the person. This can happen in virtually anyone.

Environmental Factors

CarcinogensCarcinogensCarcinogens are any substance, illness Carcinogens are any substance, illness or exposure circumstances that directly or exposure circumstances that directly

raises the risk of cancer. raises the risk of cancer.

There is a four-grouped classifying There is a four-grouped classifying system, one-four of how carcinogenic system, one-four of how carcinogenic

things are to humans.things are to humans.

However many studies only prove However many studies only prove correlations instead of cause and correlations instead of cause and

effect.effect.

LoweringLowering Your Risk Your RiskAvoid certain high-risk factorsAvoid certain high-risk factors

ChemopreventionChemoprevention Taking certain nutrients, plant extracts, or Taking certain nutrients, plant extracts, or

drugs, which include folic acids, vitamin D, drugs, which include folic acids, vitamin D, extracts from green tea and tomatoes, and extracts from green tea and tomatoes, and more.more.

Methods to Study Cancer-Methods to Study Cancer-Environment LinksEnvironment Links

Population StudyPopulation Study Population disease Population disease

incidence in different incidence in different groups of people. groups of people. Yet too many Yet too many variables make it variables make it hard to establish hard to establish solid cause & effects.solid cause & effects.

Case-Control StudyCase-Control Study People with a certain type of cancer are matched People with a certain type of cancer are matched

along with people much like them (weight, age, along with people much like them (weight, age, ethnicity, etc.) but who are healthy. Researchers then ethnicity, etc.) but who are healthy. Researchers then look at significant differences between the two’s look at significant differences between the two’s lifestyle and history.lifestyle and history.

Prospective StudyProspective Study A study that follows two or more groups as they A study that follows two or more groups as they

comply to a specified activity plan. They are comply to a specified activity plan. They are continuously checked on for cancer. However some continuously checked on for cancer. However some forms of cancer may take several years to appear.forms of cancer may take several years to appear.

Diagnosis and TreatmentsDiagnosis and Treatments

After a screening test After a screening test (blood or x-rays), (blood or x-rays), symptoms occurring, symptoms occurring, or patient feels it, or patient feels it, there are several there are several options in which the options in which the person can take for person can take for treatment.treatment.

SurgerySurgery Simply remove the tumor, however if Simply remove the tumor, however if

even one cancer cell is left though, a even one cancer cell is left though, a tumor will return.tumor will return.

Radiation & ChemotherapyRadiation & Chemotherapy Kills all cells that divide rapidly. This Kills all cells that divide rapidly. This

also kills healthy cells. also kills healthy cells.

Newer Types of TreatmentNewer Types of Treatment• Include inhibiting telomeres, blocking Include inhibiting telomeres, blocking

hormone receptors, and drawing the hormone receptors, and drawing the blood out of the cancer cells.blood out of the cancer cells.

Alternative MethodsAlternative Methods• Prayers, herbs, etc.Prayers, herbs, etc.

Genomic ApproachesGenomic Approaches

Breast cancer is a great example of how Breast cancer is a great example of how genes are helping us understand and fix genes are helping us understand and fix the problem. Phenotype and Genotypes the problem. Phenotype and Genotypes are taken into considerationare taken into consideration Depending on the women, the breast cancer either Depending on the women, the breast cancer either

has receptors for estrogen or progesterone. That will has receptors for estrogen or progesterone. That will determine what medicine and recovering therapy she determine what medicine and recovering therapy she will receive.will receive.

Cancer diagnosis will continue to be based Cancer diagnosis will continue to be based more heavily on DNA microarrays, which more heavily on DNA microarrays, which will look at gene expression and genotype.will look at gene expression and genotype.• This will be able to give patients immediate This will be able to give patients immediate

treatments that fit their type of cancer. Also treatments that fit their type of cancer. Also predicts side affects that particular patient will predicts side affects that particular patient will get.get.

ReferencesReferences

Function of Cancer Genes DiscoveredFunction of Cancer Genes Discovered, Science Daily, May 13, 2005, Science Daily, May 13, 2005March7,2007,March7,2007,http://www.sciencedaily.com/releases/2005/05/50513224031.htmhttp://www.sciencedaily.com/releases/2005/05/50513224031.htm

Lewis, Ricki, Lewis, Ricki, Human GeneticsHuman Genetics, New York: McGraw-Hill, , New York: McGraw-Hill, 20052005

The p53 tumor suppressor gene. The p53 tumor suppressor gene. National Center for National Center for Biotechnology Information.Biotechnology Information.

          http://http://www.ncbi.nlm.nih.govwww.ncbi.nlm.nih.gov. Jan 10 2007.. Jan 10 2007.

Wikipedia, March 5, 2007, Free Encyclopedia, March 6, 2007, <Wikipedia, March 5, 2007, Free Encyclopedia, March 6, 2007, <http://http://en.wikipedia.org/wiki/Canceren.wikipedia.org/wiki/Cancer>>

Bonus Question!

Q: What are the most common type of brain tumors?

A: AstrocytomasAstrocytomas