Chapter 24 cancer genetics

Approximately —% of men and women will be diagnosed with cancer of any site at some point during their lifetime. Cancer is the — most common cause of death in —- countries exceeded only by heart disease.

40, second, western

Cancer is a — disease of some — cells. Somatic cells are — cells that are not sperm and egg and — can build up in these cells overtime which change how cells grow, —, and survive. Most cancers are not —- only about 5 to 10% are caused by inherited germline mutations and the rest come from mutations acquired during life in somatic cells.

Genetic, somatic, body, mutations, divide, inherited

The 4 main types of genomic alterations in cancer

1) single nucleotide substitution is a change in one DNA base imagine A becoming G this can activate cancer genes and disable tumor suppressor genes

2) chromosome rearrangements are when large chromosome pieces move around this includes translocation and inversion. It can create abnormal fusion proteins, and misregulated genes

3) amplification is when a gene gets copied many extra times and sometimes too much protein is produced this affects gene that stimulate growth

4) deletions are when DNA sections are lost it usually removes tumor suppressor genes and results in loss of growth control

What are the two fundamental properties of cancer cells?

Unregulated cell proliferation: cancer cells divide when they should not but normal cells obey checkpoints, growth signals, contact inhibition, and apoptosis signals, but cancer cells Ignore all these controls.

2) abilities to spread known as metastasis. Cancer cells can detach from primary tumor and enter blood stream invade other tissues and form secondary tumors primary tumor is known as original tumor site and metastasis is when secondary tumors are formed after cancer spreads

Mutation lead to —- cellular function, which lead to — behavior these mutations affect cell cycle regulation, DNA repair, apoptosis, signaling pathways and movement

— mutations are acquired during life and not inherited. They cause most cancers .germline are inherited from parents present in — cells and count for 5 to 10% of cancers.

Altered, cancer, somatic, all

What cancer cells must do to metastasize

To leave the primary tumor cancer cells must break through barriers known as extracellular matrix (ECM) and basal lamina (BL). Normally these structures, separate tissues, hold cells in place and prevent migration, but cancer cells digest these barriers using enzymes

Steps of metastasis

1) cancer cells detached they lose adhesion to nearby cells

2) digest ECM and basal lamina: using proteolytic enzymes to cut through tissue barriers

3) enter blood or length this allows travel through the body

4) invade distant tissues : they leave circulation and colonize new tissue

5) formed, secondary tumors, called metastases

Only about —% of metastatic cells actually succeed in forming metastatic tumors metastasis is extremely —

0.01, inefficient

Genes important in metastasis that you should know

1) cell adhesion molecules control whether cells stick together

2) cytoskeleton regulators help cells move

3) proteolytic enzymes digest ECM and basal lamina

Benign versus malignant tumors

Benign tumors are localized, do not metastasize, and usually removable by surgery. They are not life-threatening.

Malignant tumor spread, metastasize, invade tissues and often life-threatening think of malignant as metastatic potential

What is clonal origin of cancer and evidence that cancer is clonal?

Clonal means all cancer cells came from one original mutated cell. That first cell accumulated mutations and divided repeatedly so primary tumor cells are genetically related and metastatic. Tumor cells are genetically related.

There’s two evidence that cancer is clonal one is reciprocal translocation, and other is X inactivation pattern

1) reciprocal translocation is when chromosome pieces swap places

2) X inactivation pattern is when female tumor cells often show the same inactive X chromosome. This indicates all cells descent from one ancestor.

Reciprocal translocation

Very common in leukemia and lymphoma. An important example is Burkitt lymphoma involves translocation between chromosome eight and chromosome 2, 14, or 22 this activates growth promoting genes..

Drivers versus passenger mutations

Drivers mutation actually contributes to cancer they give growth advantage and promote survival, but usually only 2 to 8 driver mutations for cancer. These are important mutations.

Passenger mutations do not help cause cancer. They accumulate accidentally because cancer cells have lots of DNA damage think of them as passengers along for the ride.

Cancer stem cell hypothesis

Only a small subset of tumor cells are continuously proliferate and maintain the tumor, these cells self renew, and generate more cancer cells

The idea is that not all cancer cells are equally important inside a tumor many cancer cells exist, but only a small group may actually keep the tumor growing. These special cells are called cancer stem cells. They make more stem cells and produce specialized cells so the hypothesis is that only certain tumor cells can continuously regenerate the tumor.

Cancer develops in multiple steps

Cancer usually does not happen from one mutation instead multiple mutations accumulate overtime. This is why cancer risk increases with age and older people get cancer more often.

Cancer incidents increased with age because cancer requires several independent mutations occurring in the same cell lineage that takes time so the older you get the more mutations accumulated

Tumorigenesis

Development of a malignant tumor. these occurs when mutations progressively remove normal growth controls, and the cell becomes more and more abnormal overtime

Imagine a mutation occurs that slightly increases division, but the cell isn’t cancer yet it just grows a little faster then another mutation disables apoptosis now damage cells survive longer than they should. Then another mutation comes and affects DNA repair and so on.

Cancer progression is

Gradual

APC gene

APC is tumor suppressor gene it normally suppresses cell division which means it acts like cellular breaks that stop excessive . It helps ensure that cells divide appropriately and stop dividing when necessary so they mature at the right time.

What happens when APC is lost

If a PC gets inactivated self begin dividing more than they should organization of intensinal tissue breaks down and polyps form.

A polyp is an overgrowth of abnormal cells

Early cancer development often starts with loss of growth control

What is KRAS MUTATION

KRAS activation is involved in signaling pathways that tell cells to divide. Normally KRAS turns on briefly when growth is needed, and then turns off. Mutated KRAS becomes permanently active so now the cell constantly receives divide divide divide so APC loss removes the brakes and KRAS jams the gas pedal now the tumor grows much more aggressively.

A normal cell does not randomly divide it waits for —-. Outside the cell are —- —- which are chemical signals from nearby cell saying we need more cells. these signals bind to receptors on the cell membrane that signal then travels through proteins inside the cell. One of the proteins is KRAS.

Mutated KRAS instead of turning on only briefly becomes —- on. now even if no growth factors is present KRAS keeps sending messages saying to divide

APC IS PART OF THE SYSTEM THAT MONITORS AND RESTRAINTS GROWTH AND HELPS PREVENT —- DIVISION THINK OF IT AS QUALITY CONTROL. In certain tissues, cells constantly divide because the intestine renews itself rapidly, but this division must stay organized, which is what the APC helps do. APC mutation removes growth — the cell loses part of the system that normally limits excessive division.

Signals, growth factors, permanently, excessive, restraints

Sometimes cancer is not caused by just small mutations, but by entire chromosome pieces moving around this happens in chronic myelogenous leukemia CML. So what actually happens

Part of chromosome 9 breaks off also part of chromosome 22 breaks off they swap places this is called reciprocal translation. The altered chromosome 22 becomes the Philadelphia chromosome.

This is dangerous because the translocation accidentally fuses two jeans together, which are BCR and ABL creating BCR-ABL

Why do fusion proteins matter?

ABL gene normally makes a protein that’s involved in cell signaling, grow regulation and division control. Normally ABL is regulated so it’s turned on when needed and turned off after. when reciprocal translocation happens between chromosome nine and 22, the abnormal chromosome 22 known as Philadelphia chromosome is produced

When the chromosome swap pieces part of ABL gene gets physically attached to BCR gene so now DNA sequence becomes BCR-ABL this is called a fusion gene because two different genes become FUSED together abnormally

Fusion gene make fusion proteins the BCRABL fusion protein is very dangerous because the BCR part makes the ABL signaling activity to become permanently active the white blood cell pre-cursor keep receiving signal saying grow divide and survive, which causes chronic myolegenus leukemia

Why was BCRABL discovery huge

Scientist discovered that specific genetic abnormalities can directly cause cancer one chromosome abnormality creates one abnormal protein, which then drives uncontrolled division

Scientist realized if BCRABL is driving the cancer maybe we can block that protein which led to gleevec a drug that specifically inhibits BCRABL activity. Traditional chemotherapy kills rapidly dividing cells, but also harmed normal tissues too but this drug specifically targets the cancer driving protein

Xeroderma pigmentosum

XP is UV light that damages DNA by creating thymine dimmers. Nucleotide excision repair usually removes the damage created by UV light but people with XP lack proper repair so every time sunlight damage is skin DNA mutation remains and damage accumulates

HNPCC Lynch syndrome

Mismatch repair. During DNA replication DNA polymers sometimes inserts the wrong base mismatch repair normally fixes those mistakes but without it replication errors, accumulate rapidly, and mutation rates explode

Epigenetics

Two cells can have identical DNA sequence, but behave completely different because different genes are turned on or off that’s Epigenetics. Imagine DNA as a giant library. Every cell has the same library, but different cells read different books. A neuron reads neuron genes while liver cell reads liver genes.

Epigenetic controls, which genes are accessible and active

DNA methylation

One way cell silence genes is through DNA methylation. Methyl groups attached to DNA and usually prevent transcription so methylation often turns genes off.

This matters in cancer because a tumor suppressor gene has normal DNA sequence, but when Promotor becomes heavily methylated, the gene cannot be expressed

Histone acetylation

DNA wraps around proteins called histones. if DNA is wrapped tightly transcription machinery cannot access genes if DNA is loose genes can be expressed. histone modifications control this packaging

Acetylation generally loosens chromatin and increases transcription while deacetylatiom tightens chromatin and reduces transcription. Cancer is not only mutated DNA, but also abnormal regulation of genes.

The cell cycle

The cell cycle is the core of cancer biology. It is the sequence of events a cell goes through to divide into two new cells because a normal cell does not divide randomly.

The cell cycle has two major parts, interphase and M phase, also known as mitosis. Most of the cells life is spent in interphase.

Interphase

Interface is the period between cell division. This is when the cell grows performed normal functions and copies It’s DNA. It has three stages.

G1: this is when cells grow and make proteins and organelles

S: this is when DNA is replicated and each chromosome is copied

G2: cells prepare for mitosis and more growth and protein production occur

G0

Some cells leave the cell cycle and enter G0 a resting and nondividing state. Cells do not divide and are still metabolically active. Normal cells can stop dividing and enter G0 but cancer cells often cannot enter and keep cycling continuously this causes uncontrolled cell division.

Signal transduction pathways

Cells respond to external growth signals through signaling pathways and these pathways tell them to divide or to stop. cancer cells often have defects in these pathways so they keep receiving divide signals

cyclins and CDK’s

Cell cycle progression is controlled, mainly by:

Cyclins are protein, whose levels rise and fall during the cycle

CDK or cyclin independent kinesis, which are enzymes activated by Cyclins. together they control movement through checkpoints and progression of the cell cycle. If this system malfunctions uncontrolled division can occur.

Apoptosis

Program cell death it is a controlled process that removes damage cells

It’s important because if DNA damage is too severe, the cell stop dividing and apoptosis is triggered, which helps prevent cancer

The steps are nuclear breaks apart. Organelles and cytoskeleton disassemble. Cells breaking into small membrane bound pieces. phagocytes engolf them.

Define proto-oncogenes, oncogenes, tumor suppressor genes and metastasis suppressor genes

1) proto-onco genes are normal genes that promote cell growth division. They are necessary for normal cell function. examples or growth, signaling proteins, Cyclins , and transcription factors.

2) oncogenes are mutated or overactive proto-oncogenes they cause excessive cell growth or uncontrolled division

3) tumor suppressor genes are genes that slow or stop the cell cycle. They repair DNA and trigger apoptosis. They act like brakes on cell division if mutated or inactivated damage cells may continue dividing.

4) metastasis suppressor genes are genes that help prevent cancer spread. They often control cell adhesion, cytoskeleton, and enzymes involved in tissue invasion. If these genes fail cancer cells can spread to other tissues.

Proto-oncogenes

Normal gene that help cells grow and divide. They’re not bad normally they’re necessary for life. They make proteins involved in growth, signals cell cycle, progression and telling cell to divide so they’re basically the go signal for cell cycle.

When protooncogenes mutate, they become onco genes. Think of them as gas pedals that are stuck down the cells keep dividing.

RAS gene

it is a famous proto-oncogene. Normally RAS turn cell division signaling on temporarily and then turns off RAS binds GTP then hydrolyzes it to GTP and makes it inactive. Mutated RAS cannot convert so it gets stuck on on meaning the self constantly receives divide divide divide signals.

P 53

Known as guardian of the genome, this is probably the most important cancer gene. It is a tumor suppressor gene meaning it stops damaged cells from dividing. think of it like breaks. cancer often involves gas pedals that are stuck on on and brakes that are failing when DNA damage occurs P 53 levels increase then it can stop the cell cycle allow DNA repair and trigger apoptosis.

If DNA is damaged and not repaired, mutations accumulate and cancer risk rises cells without working P 53 don’t stop at checkpoints they don’t repair damage properly and don’t undergo apoptosis so damage cells keep dividing

50% of cancers have mutated P 53 and things that increase P 53 or DNA damage UV radiation or double strand that break this signals something is wrong

Somatic versus hereditary cancer

Most cancers are somatic, mutations meaning mutations acquired during life. They are not inherited, and it could be from smoking damage or UV exposure. We have hereditary cancers, too, which are smaller percentages. They are inherited mutations that are already present from birth. A person starts life with a higher cancer risk.

Carcinogens

Things that caused DNA damage and mutations these mutations can affect protoncogenes, and tumor suppressor genes which lead to cancer

Examples of tobacco smoke, which are the biggest environmental carcinogen and contain many mutagens. There’s also UV radiation that damages, DNA alcohol that can promote inflammation and liver, cancer and red meat that’s associated with some cancers.

Natural carcinogens

Natural does not automatically mean safe it means naturally occurring substances that can damage DNA. an example is Aflatoxin. It is produced by mold on foods like bread or corn and very cARCINOGENIC

another example is nitrosamine they are found in some preserved meat and can damage DNA and increased cancer risk

Both are natural chemicals and synthetic chemicals so cancer risk depends on DNA damage and not whether something is natural

Radiation and cancer

UV light damages, DNA specially causes thiming dimmers and DNA mutations that can lead to skin cancer

Ionizing radiation are like x-rays or gamma rays. These are more powerful. They can cause double stranded DNA to break, which is very dangerous.

Radon gas is radioactive gas, naturally released from rocks or soil. It can accumulate in buildings and associated with lung cancer.

herceptin

A targeted therapy drug, especially targets HER2 positive cancer cells. Instead of killing all rapidly, dividing cells, modern treatments target, specific mutations and specific protein this is personalized medicine treatment based on patient specific tumor genetics.

Neo antigens

New abnormal antigens produced by tumor mutations immune system may recognize them as a non-self

Cytotoxic T cells. These are a killer T cells they have destroy abnormal cells using perforin and granzymes which induced apoptosis’

Cancer cells are not always invisible to immune system. The immune system often does recognize them. Problem is tumors evolved ways to evade destruction.

Tumor infiltrating lymphocytes

These are T cells found inside tumors meaning the immune system already attempted to attack the cancer. The problem is the response isn’t strong enough so tumor survives.

Adoptive cell transfer ACT

This is another modern immunotherapy approach the idea remove T cells from tumor. Find best tumor fighting T cells. So select T cells that recognize tumor antigens Best. grow huge numbers of it in lab amplify them and then put them back into the patient so now patient has army of tumor targeting T cells