Most everyone in this room has

been affected in one way or

another by it, but what is it?

All information is up to date and referenced to Sam Rhine’s

Genetic Update Conference, University of Nebraska & SIUC

cancer research conferences

Oncogenes

• Oncogenes are the genes that cause cancer.

• Onco = Cancer

• Oncology = the study of cancer and its cures

• There are 164 individual cancer causing genes and 544 total suppressing genes that cause cancer

• Total 708 possible genetic causes of cancer

Is cancer hereditary?• Cancer itself is NOT hereditary, if it was

we would see it every generation.

• The tendency for cancer is hereditary.– This means that you can have genes that

increase your cells chances for mistakes

– This increase chance is what makes cancer seem hereditary

– However, it CAN NOT be hereditary, because it occurs in somatic cells

• You can inherit the predisposition for cancer. – You can inherit the tendency to get cancer, but only in

rare occasions is the disease inherited (TSG breast

cancer).

Cancer in the USA

• Females:

• Breast-31%

• Lung -12%

• Colon-11%

• Uterine-6%

• DEATHS

• Lung-26%

• Breast 15%

• Colon-10%

• Pancreas -6%

• Ovary-6%

• Males:

• Prostate- 33%

• Lung- 13%

• Colon- 10%

• Deaths

• Lung -31%

• Colon -10%

• Prostate- 9%

• Pancreas- 6%

Tumor Paint

(Derived from Scorpion Venom)

If not cigarettes… Pot??

• Smoking a joint is equivalent to 20

cigarettes in terms of lung cancer risk,

scientists in New Zealand have found, as

they warned of an "epidemic" of lung

cancers linked to cannabis.

• CARCINOGENS- there are 55 different

carcinogens found in a single cigarette

All cancer is genetic!

• All cancer is “genetic” (meaning it has to

do with genes).

• It is all an abnormal phenotype

• (Not having cancer is normal)

• But, most cancer is not inherited!!

• Inherited means it is passed from parent

to child through their germ line.

(Heredity)

• All the non germ line cells are Somatic

cells

All in the family

• Sporadic cancer is cancer that just appears within a family.

– 90-95% of cancer is sporadic

• Most cancer comes from perfectly normal genes given to you by your parents

• Most cancer occurs when a somatic cell mutates somewhere in the body.

• This is called transformation…

– This will NOT be passed on, it is in your SOMATIC cells!

Point mutations

• Those 40,000 transcripting (protein producing) genes make up about 1.5% of the total DNA in your cells.

• Those genes are all made of bases (A,T,G,C) which act like the letters in the book of life

– We have about 2,851,330,913 bases in our DNA

• One single change in any of those 2,851,330,913 are a point mutation

Genes don’t cause cancer!

• Genes do NOT cause cancer.

• Genes do not do anything but sit in the

nucleus doing nothing.

• Genes direct the creation of protein.

(Transcription and translation)

• Proteins do all the work.

• Essentially, proteins cause cancer

Those darn amino acids

• Proteins (created from the genes found in

your DNA) have multiple functions within a

cell

• Generally enzymes act as the motor

proteins that turn things off and on

• Indicator proteins are released into the

blood stream to notify receiver proteins of

important changes in the body

• Essentially, every system in your body is

reliant on proteins…

This

Protein

may be

released

into the

blood at

the end of

S1 phase

These 2

new

proteins

may be

required to

start M

phase

What about the other 98.5% of our

DNA

• If 1.5% of our DNA makes ALL of the

proteins in our bodies, what does the other

98.5% do?

• The other 98.5% is called “junk DNA”

because it is non-coding.

• IT IS NOT GARBAGE! GARBAGE

YOU THROW OUT! Junk you store away

in the attic somewhere.

• This junk –called Mysterious dark matter

Lysogenic Virus

The new genome project• Jan 22, 2008 we started a new genome project

in which we will look for their SNPS (Single

Nucleotide Polymorphisms)

• SNPS are located in your non-transcripts

• We will sequence 1,000 individual peoples

genomes.

• This will help us understand predispositions

better (for cancer, heart disease, asthma, and

other common ailments).

• Expected to take 2 years. (Is it done yet?**)

– We expected thousands… we currently have found

1,419,190…

What’s it worth to you?• Sequencing your own human genome

would sequence YOUR OWN SNPS.

• Knowing your SNPS is knowing your

predispositions

• Right now, human genome sequence =

about 5,000 bucks

• 5 years ago it was about 100,000 bucks

• In 5 years = about 1,000 bucks

• In 10 years = about 100 bucks

• Think what that means to your children…

The present of SNPs• Currently, geneticists are racing to map

and compare the genomes of large groups

of individuals who are suffering from

genetic disorders

• Then these “disorder groups” are

compared to the genomes of healthy

individuals

• This is called a Genome Wide

Association Study (GWA) or (GWAS)

• The more GWAS we conduct the more

pinpointed the SNP cause becomes

Individualized Medicine

• Because the strength of

your liver, pain tolerance

differences, and even

your medical allergies are

all genetically controlled,

someday your

prescriptions and medical

treatment will be tailored

specifically for you.

• To do this… we need

to understand all of

the SNPs

Your Chip

• In the very NEAR

future, each of us will

carry a “chip” about

the size of a credit

card that will contain

ALL OF our SNPs

• This can be

sequenced at any

hospital to tell a

doctor EXACTLY how

to treat you.

Know your OMES:

• Genome we said… Sum total of all your DNA

• Total of all your transcripts –Transcriptome

• Total of all your proteins – Proteome

• How all your proteins interact with everything in your body… - Interactome

– The reason we mapped the human genome was because we wanted the human interactome

Human interactome• Fix an interactome, cancer goes to 0…

• we have done this for CML leukemia…

• 10 years ago, CML leukemia’s only fix was a

bone marrow transplant with a 50% failure rate,

and at best, would give you 2 years…

• NOW… the fix is… a daily pill… that’s it, one pill

a day with no known human side affects…

• CML leukemia went from a 95% fatality rate

to a 95% remission rate in America in one

year

chronic myelogenous leukemia

Introns and Exons

Exons and Introns

• The gene that causes muscular dystrophy contains 189 introns and 190 exons

• Use exons 1 and 2 you have a gene

• Use exon 1 skip exon 2 move to exon 3 and you have a different gene…

• Gene numbers don’t actually matter… we can make a billion different proteins from our 20,000 genes by reorganizing exons.

• Introns help in this organization

The light switch

• If you stop the production of a protein, you turn a gene off…

• Turning a gene off or on is the basis of genetics

– If we can do this, we can cure cancer, fix diseases like muscular dystrophy, and Parkinson's disease

• Point mutations can turn a gene on or off…

• Epigenetics – imprinting (can do it)

Epigenetics

• Add methyl groups (CH3) to DNA

• You can do this with Methylase which adds CH3 turning the gene off

• Demethylase can remove the CH3 and turn it on

Epigenetics (Methylation of

DNA)

Repression Through

Compression

The next step…

• In the non-coding DNA genes we have (within the last 2 years) found a mechanism to turn the genes off and on

• These genes can not code for protein… but they can make RNA

• They will be transcribed and not translated.

• We have currently found 1,000+ (we are finding them at about the rate of 150 per semester)

sncRNAs

• sncRNAs =Small non-coding RNA

• (Also called microRNAs

• Also called miRNA

• Also called miRs)

• These are tiny, only ~22 nucleotides long

• They are negative regulators = turn DNA off

• We have found that they control 20-30% of our coding genes

Small non-coding RNA• They are endogenous (meaning they are

made normally in your body everyday)

• They work post transcriptionally.

• They affect the transcript (the RNA) by homologous interaction (base pairing) with UTR (nontrascripting DNA at the ends of the transcript)

• By doing this, they stop translation, it is never made into a protein, it is succesffuly turned off…

• The gene is silenced (called gene silencing)

Current Genome

• State of the Genome - September 2013:•

• 1.5% Coding DNA - Exons = EXOME

•

• 98.5% Non-Coding DNA

• 28.5% - Introns = INTROME

•

• 51.5% - 500 sncRNA genes + 13,000 lncRNA genes

• plus…..2,890,000 ‘Docking Sites’20.0 % - Yet to be determined

•

• 30% - Exons and Introns of the 21,000 Coding DNA Genes

RNAi

• This RNA molecule control is called RNAi.

Which means Inhibitor or interference

RNA

• Fire and Mello, the doctors who figured

this out published in 1998 won the nobel

prize in 2006… 8years….

• One year faster than Watson and Crick.

RNAi & sncRNA

• dsRNA = Double Stranded RNA

• dsRNA Induces a protein called DICER.

• DICER cuts the double stranded RNA into

a 22 nucleotide long RNA strand, throws

one of the strands away, and the other…

• Becomes sncRNA (miRNA), the inhibitor

molecule

Non-coding Hairpins

• All of the non coding mRNA’s can form

hairpin molecules.

• Which makes dsRNA (double stranded

RNA)… When this happens, it induces a

special enzyme called DICER!

• Dicer will chop the promoter, making a 22

nucleotide miRNA.

Where are they?• This is where we have gotten our 1,000+

non-coding miRNA.

• Where do we find them?

• Most are intergenic (found in-between the

coding DNA genes)

• Some are intragenic (found within the

coding DNA gene)

• Have we ever heard of non-coding

DNA within coding DNA???

• Of course, introns!

The Switch for Every Gene???

• The current scientific thought is that every

gene has a UTR regulator

• This regulator can suppress an abnormal

protein from being synthesized from an

abnormal gene.

• If the sncRNA sequence is found for the

gene, essentially we could control if the

protein is produced (silencing the gene)

sncRNA and Cancer

• In fact every stage of tumor development

has various miRNA’s turned off…

• We can use miRNA to not only lead us to

preventing the cancer

• …but also, by evaluating the miRNA

present will tell us the stage the cancer is

in.

Cancer Vocab• Neoplasia –New growth, a rapidly growing

abnormal growth. Gives rise to a tumor

• Tumor : an abnormal mass of cells growing more rapidly than normal cells

• Transformation: Normal somatic cell mutates to become a cell with Malignant potential … Transforms into a cancer cell

• Founder cell: The one single mutated cell that will develop over time into a tumor

• Primary tumor: the original tumor that forms at the site of transformation

• Metastasis: Migration of cells from the primary tumor ino remote tissue… generally seed secondary tumors

Human Cancer

• Avg. human tumor will take 15-25 years with multiple mutations.

• Once cancer hits telomerase, it gains cellular immortality and can grow forever. Cellular immortality!

• CARCINOGENS- there are 55 different carcinogens found in a single cigarette

• Most carcinogens are mutagens – cause mutations in your DNA

Cancer

• Tumor = too much mitosis

• Mitosis = cell birth

• Cancer generally starts during interphase

• Cyclin proteins control the cell cycle.

• Cells go through mitosis when the cyclin

proteins are present…

• Cancer happens when the cyclin proteins

occur at the wrong time.

Cancer and cyclin• Cancer is a mutated gene in a somatic cell

that makes a mutated protein…that turns on the cyclin

• What turns on cyclin normally? (How does a cell know to go through mitosis normally)

• Mitosis cell signal relay

• Peptide growth factor is the signal in the relay.

• It signals the cell nucleus (likely passed from a different cell) which turns on the cyclin, which starts mitosis. (This has 43 steps within the relay)

Cell signal relay

• The gene mutation causes the relay to interpret the translated protein as cyclin, starts the relay…

• mitosis starts when it shouldn’t… = cancer

• This relay can be started at any of the 43 relay points within the relay.

• These are interacting proteins. They are interactomes.

ATP and cancer• Scientists recently found within the relay of

many cancer cells, ATP, supplying the energy for the relay within the cancer cells.

• Can we find a molecule to inhibit the ATP???

• We did, it is called, Imatinib Mesylate (Gleevec)…

• It is what is in that little pill that stops the leukemia. It is actually used in two cancer remissions… (CML leukemia & GastroIntestinal Stromal Tumor)

Is all cancer too much mitosis?

• 2001 a man (Robert Horvitz) studying C. elegans (same worm as before, different research)

• He understood all 959 cells within the body of that worm. They found that every developing fertilized egg for the worm has 1090 cells… 131 die before adulthood

• These deaths are programmed cell death and called apoptosis– This is exactly what happens to a tadpole’s tail…

same thing that happened to all of our webbed fingers and toes (literally takes about a week)

Homeostasis• When the body falls out of balance

(homeostasis)… cancer occurs

• Too much mitosis out of balance

Cancer

• Not enough apoptosis out of balance

to many cells left over cancer

• CANCER IS BOTH!

– Figured out, because if those 131 cells in C.

elegans don’t apoptose, they become

cancerous.

Cancer’s future• The fact is, both of these versions of

cancer are directly controlled by both your operator and the UTR at the other end

• As we learn more about these non-transcripting DNA strands we learn ways to manipulate them

– Such as dicer and sncRNA

• To turn these on and off is to control the fate of cancer cells…

The Guardian Angel

• For years it was believed that chemo. and

rad. Treatment killed the actual tumor cell.• And to some extent it does kill some cells

– Remarkably it was found that most of the

destruction of the cancer cells was actually

done after the chemo by a protein called p53.

– This protein locates damaged DNA (caused

by chemo) and either prevents the cell from

replicating or destroys the cell

• This is how chemo and rad. treatment can

cause cancer to go into remission

Tumor Removal• The obvious fix to any cancer issue is to

remove all of an infected area

– This is very common with the treatment of

breast cancer (Mastectomy)

• And, yes guys, the same is true for the treatment

of penis cancer

• However, this can become much more

difficult when concerning organs required

for survival

– Currently, partial removal or tissue removal is

the safest option, but this does not guarantee

complete cancer removal

Have another…

• Remarkable new science breakthroughs

have occurred in the field of organ

replacement therapy

– We have successfully cloned a wide variety of

organisms (from sheep to albatross)

• Could I be cloned so that if I needed an

organ transplant I could take it from a

clone? (Movie: The Island)

• Is it an option to clone just the organ I

need?

Cell Replacement Therapy

• With the discovery of dedifferentiation it

has now become possible to revert a

normal body cell back into a stem cell

– Called an Induced Pluripotent Stem Cell

(iPS) Remarkably takes only 4 signals

• Using iPS cells we have the potential to

make any of the bodies 220 cell types

• Currently we are making the necessary

scaffolding to attach this tissue so that it

can eventually replace defective tissue

Endless Options

• We have already successfully made a

functioning kidney, heart, and liver in the

laboratory (as 2012 we have made 4 parts

of the brain)

– While there is still a ways to go to perfect this

science, the strides we have made are

amazing

• This could allow us to not only replace a

failing organ, but to remove ALL of a

cancerous tissue and replace it with

healthy cells, tissue, and even organs!