Chapter 24: Cancer Genetics

Welcome to Last Minute Lecture.

This free chapter overview is designed to help students review and understand key concepts.

These summaries supplement not replaced the original textbook and may not be redistributed or resold.

For complete coverage, always consult the official text.

Welcome back to The Deep Dive.

Today, we're tackling something huge, really fundamental to human health.

Yeah, it's a big one.

Cancer.

I mean, the stats are pretty sobering.

Second most common cause of death in Western countries.

And the lifetime risk.

It's something like one in three people getting a diagnosis.

Exactly.

So our mission today is to look beyond the symptoms and dive into what's happening underneath because fundamentally it's a genetic disease, mostly happening in our somatic cells.

That really is the absolute core idea.

You look at any cancer, doesn't matter the type, and you find these two fundamental properties rooted in genetics.

Okay, what are they?

First, you got abnormal cell growth, proliferation.

The cells just keep dividing when they shouldn't.

Right, uncontrolled growth.

And second, there are these defects that let the cells, well, escape.

They break away, spread and set up shop elsewhere in the body.

Metastasis.

So we're going to trace how that happens today, how a normal cell gets corrupted basically from these tiny single mutations, maybe all the way up to massive chromosomal screw ups, and how the very systems designed to protect us, DNA repair, cell death, keeping the cell cycle in check how they get broken.

And it's important to remember, while people worry about inheriting cancer, and that does happen.

Yeah, you hear about genes like BRCA.

Exactly.

But that only accounts for maybe five to 10 % of all cancers.

Most of the time, the mutations that really drive the cancer, they pop up randomly later in life, just in regular body cells, somatic mutations.

Okay, let's start with this idea of clonal origin, because when you see a tumor, it's billions of cells.

Looks chaotic, but it's not, is it?

Not at all.

That's a key concept.

Every single cell in that primary tumor, and even in the secondary ones, the metastasis, they all trace back to one single ancestral cell.

One cell.

One cell that got that first critical hit, that first set of cancer causing mutations.

It's the founder.

And we can actually see the proof of this.

Oh yeah, definitely.

We can use genetic markers like fingerprints,

take Birkitt lymphoma.

It often involves what's called a reciprocal translocation.

Pieces of chromosome 8 and say 14 get swapped.

The clincher is, every single lymphoma cell in that one patient has the exact same break point where the swap happened.

That proves they all came from that one original cell where the translocation occurred first.

Wow, okay, so if they all come from one cell, but we sequence a tumor and find like tens of thousands of mutations, how do we know which ones actually caused the cancer?

That's the million dollar question.

It's like finding needles in a haystack.

You have to distinguish between driver mutations and passenger mutations.

Driver versus passenger.

The drivers are the important ones.

They're usually only a few, maybe two to eight in a typical tumor.

These are the mutations that actually give the cell a growth advantage that push it towards becoming cancerous.

And the passengers.

They're the vast majority.

Just sort of collateral damage, you know.

They build up because the cells repair systems might be faulty, but they don't initially cause the cancer phenotype.

So they're just noise, initially at least.

Pretty much.

Although interestingly, a passenger mutation could, down the line, maybe help the cancer cells survive chemotherapy or something.

So they can become relisant later through selection.

That makes so much sense.

And it explains why cancer risk increases so dramatically with age.

Exactly.

If just one driver mutation was enough, cancer would be common in kids.

But it's not.

It takes time.

It takes time because it's a multi -step process.

You need several hits, an accumulation of these driver mutations, often over many years, with each one getting the cell a slight edge, leading to waves of clonal expansion.

Right.

One clone takes over, then a cell within that clone gets another hit, and that clone expands.

Precisely.

And the classic example we study, the one where we can see the steps most clearly, is colorectal cancer.

That progression can take like 40 years or more.

And there are specific genes linked to each step.

Yep.

You start with normal gut lining, the epithelium.

Step one, getting a small benign growth in adenoma almost always involves knocking out the APC gene.

That's a tumor suppressor.

Okay, lose APC, you get a small adenoma.

What's next?

To get to an intermediate adenoma, you often see a mutation pop up in the cross gene.

Now cross is a proto -oncogene.

Proto -oncogene, meaning it normally promotes growth.

Right.

It's usually carefully controlled.

But the cancer mutation basically jams the cross proteins on switch.

So it's constantly signaling divide, divide, divide, even when it shouldn't be.

It's like flooring the gas pedal.

Unregulated division.

Got it.

And then the final step,

to full malignancy.

That needs more hits.

You often see mutations in other key genes like TP53, we'll definitely talk more about that one, and things like PI3K and TGFB.

It's this whole cascade of genetic failures accumulating.

Which leads us right into the idea of genomic instability.

Because how do all these mutations pile up so fast?

That's the engine driving it.

Cancer cells develop what we call a mutator phenotype.

Their basic ability to repair DNA damage gets broken.

So mistakes happen more often and they don't get fixed.

Exactly.

Leading to higher mutation rates, big chromosomal rearrangements like translocations, bits getting deleted, extra copies of genes, and aploidy.

The whole genome gets destabilized.

And the classic visual for that instability is the Philadelphia chromosome, isn't it?

Oh, absolutely.

That's the T922 translocation swap between chromosome 9 and 22.

It fuses part of the BCR gene with the CABL proto -oncogene.

And the result is?

The result is this Frankenstein protein, BCRABL.

Normal ABL is a kinase, an enzyme that adds phosphate groups, but it needs signals to turn on.

This BCRABL fusion protein, it's constantly active.

So it's always on, always telling the cell to grow.

Relentlessly.

It doesn't need external growth factors anymore.

It's a direct result of that massive chromosomal screw -up driving proliferation.

And we know these DNA repair defects are causal because of certain inherited diseases, right?

Perfect examples.

Look at xeroderma pigmentosum, XP.

People with XP have faulty nucleotide excision repair.

They can't fix DNA damage caused by UV light, like thymine dimers from sunlight.

And the result is incredibly high skin cancer rates.

Exactly.

Or HNPCC, hereditary non -polyposis colorectal cancer.

That's caused by defects in mismatched repair genes, like MSH2 or MLH1.

Their job is to fix typos made during DNA replication.

When they fail, the mutation rate across the entire genome just skyrockets.

Accelerating that whole multi -step process we talked about.

Massively accelerating it.

Okay.

So we have changes in the DNA sequence, but what about changes to the DNA or around it?

Epigenetics.

Right.

Epigenetic alterations.

These are changes in gene expression that don't involve changing the actual DNA code itself.

And cancer messes these up too.

How so?

Well, it's a bit complex.

Overall, cancer cells often have less DNA methylation, less of these chemical tags on the DNA.

But crucially, they use hypermethylation, too much methylation, very specifically at the promoter regions of certain genes.

Promoter regions.

Those are the switches that turn genes on or off.

Exactly.

And guess which genes they often silence this way.

Let me guess.

Tumor suppressors.

Bingo.

They shut down the guardian genes using epigenetic marks.

And it's not just methylation.

The proteins that package DNA, histones, and the enzymes that modify them,

acetylases, those are often mutated or messed up too.

But the key thing about epigenetic changes is they can be reversed, right?

Unlike a DNA sequence mutation.

That's the exciting part clinically.

Because they are reversible, they're a huge target for developing new cancer therapies.

Drugs that can strip away those silencing marks, for instance.

Okay.

So, genome's unstable, repair is shot, epigenetics are haywire.

What about basic cell division control?

The cell cycle.

That's the next domino to fall.

Normal specialized cells usually exit the division cycle and enter a resting state called G0.

They're alive and working, just not dividing cancer cells.

They typically lose the ability to enter G0.

They're stuck in drive.

Constantly cycling.

Constantly cycling.

Which means they have to blow past the safety checkpoints.

Checkpoints, like quality control.

Sort of.

There are critical points, G1S, G2M, and one within M phase where the cell normally pauses to check.

Is the cell big enough?

Is the DNA damaged?

Are the chromosomes aligned properly?

Cancer cells just ignore these red flags.

And what controls those checkpoints?

The main players are proteins called cyclins and cyclin -dependent kinases, or CDKs.

Think of cyclins like timers or triggers.

Their levels rise and fall through the cycle.

When a cyclin builds up, it binds to its partner's CDK and activates it.

And the CDK does what?

The activated CDK is a kinase, so it phosphorylates other proteins, basically pushing the cell machinery forward into the next phase of the cycle.

If you mess with the genes controlling these cyclins or CDKs, making them overactive, the cell just keeps getting pushed forward cycle after cycle.

Okay, so uncontrollable division.

But what if the DNA damage gets really bad?

Isn't there a self -destruct mechanism?

Yes, there is.

Apoptosis.

Programmed cell death.

It's the cell's way of committing suicide gracefully when things are beyond repair, especially DNA damage.

To prevent a damaged cell from potentially becoming cancerous.

Exactly.

And this process is also genetically controlled.

There's a balance between proteins that promote apoptosis, like the BAX group, and proteins that inhibit it, like the BCL2 group.

And in cancer.

Often that balance is tipped towards survival.

You might see really high levels of the anti -epoptotic BCL2 or low levels of the pro -epoptotic BAX.

This allows cells with dangerous levels of DNA damage to survive, keep dividing, and accumulate even more mutations.

Okay, this really clarifies the two main types of cancer genes you hear about.

Right.

You've got the proto -oncogenes and the tumor suppressor genes.

Proto -oncogenes are the normal genes involved in driving growth, like you said, with CRESS.

Correct.

They're the gas petals.

When they get mutated into oncogenes, it's a gain of function.

The gene becomes hyperactive, or it makes too much protein, or makes a protein that's always on.

And because it's a gain of function, you only need one copy, one allele, of the gene to be mutated to have an effect, right?

It's dominant at the cell level.

Precisely.

Just one bad copy is enough to start causing trouble.

Then you have the tumor suppressor genes.

These are the breaks.

Their normal job is to regulate those checkpoints we talked about, or to initiate apoptosis if needed.

Think APC, or the big one, TP53.

So for these to contribute to cancer, you need to lose the function.

Right.

It's a loss of function.

And because you have two copies of most genes, you typically need to knock out both copies, both alleles, to completely lose that breaking function.

Let's dig into the specific examples.

Ras proto -oncogenes.

You said they're mutated in something like 30 % of cancers.

Yeah, they're incredibly common culprits.

Ras proteins are key signal transducers.

They sit near the cell surface and act like a molecular switch.

They relay signals from outside growth factors to the inside of the cell.

And the switch is GTP versus GDP.

Exactly.

When Ras finds GTP, it's on and signals for growth.

When it hydrolyzes GTP to GDP, it switches off.

So the cancer mutation.

They break that off switch.

The mutated Ras protein can't hydrolyze GTP properly, or it swaps GDP for GDP too readily.

Either way, it gets stuck in the GTP bound on state.

Constantly signaling divide, even without any external growth factor telling it to.

That's the essence of it.

Unregulated, constitutive signaling.

Okay, if Ras is the stuck gas pedal, then TP53.

That sounds like the master break failure.

You called it the guardian of the genome.

It really is.

It's mutated in over half of all human cancers.

It's incredibly central.

So what does P53, the protein made by TP53, normally do?

P53 is a transcription factor.

It controls the expression of other genes.

Normally its levels are kept low because it's bound and targeted for destruction by another protein called MDM2.

But when there's trouble, DNA damage, stress.

Ah, then signals are sent.

P53 gets modified, often by phosphorylation, and it breaks free from MDM2.

It becomes stable and active.

And now the cell faces a critical decision.

What does P53 do once it's active?

It has two main paths.

Path one, it can turn on genes like P21, which halts the cell cycle, usually at that G1S checkpoint.

This gives the cell time to repair the DNA damage.

Pause and repair.

Okay, and path two.

If the damage is just too severe, too widespread, P53 switches gears and triggers apoptosis.

It does this by activating pro -death genes like BAX and simultaneously repressing anti -death genes like BCL2.

So it enforces either repair or suicide.

Exactly.

That's why losing P53 is so catastrophic.

A cell without functional P53 is essentially blind to DNA damage.

It can't pause the cycle effectively, and it can't trigger self -destruction when it should.

It just keeps dividing with all those errors.

Guardian of the genome, indeed.

Okay, so a cell is dividing like crazy, ignoring damage, refusing to die.

The next step for the disease is spread, right?

Metastasis.

How does a tumor cell actually get mobile and invade other tissues?

That requires acquiring yet more abilities.

Lignin cells start secreting powerful enzymes called proteolytic enzymes.

Think of things like matrix metalloproteinases MMP1 and MMP2.

What do they do?

They literally digest the surrounding environment, the extracellular matrix, the basal lamina, which is like the scaffolding holding tissues together.

They chew through the barriers.

Clearing a path.

Clearing a path to invade nearby tissues or get into blood vessels or lymphatic channels.

And often, they also downregulate or lose cell adhesion molecules, like echidherin.

Echidherin, that's like the glue holding cells together.

Yeah, helps keep epithelial cells tightly bound.

If you lose echidherin, the cells become less sticky, more able to detach from the primary tumor and drift away.

Wow.

Okay, let's circle back quickly to inherited risk.

You mentioned people inheriting one faulty tumor suppressor gene, like RB1 for retinoblastoma or BRCA12.

They don't get cancer immediately, right?

Correct.

They inherit one bad copy, but they still have one good functional copy in all their cells, their heterozygous.

So cancer only develops if?

If, in one particular cell somewhere in the body, that second good copy gets lost or mutated through a random somatic event.

This is called loss of heterozygosity, or LOH.

You lose the remaining good copy.

You lose the remaining protection.

Now that cell has no functional copies of that critical tumor suppressor, and it can start down the path to cancer much more easily.

Like an FAP, familial adenomatous polyposis, where you inherit one bad APC gene.

Perfect example.

Those individuals develop thousands of polyps, because it's relatively easy for colon cells to undergo LOH and lose the second APC copy.

But turning one of those polyps into a full -blown invasive cancer still requires accumulating those other driver mutations, like in CROS and TP53.

It's that multi -hit process again, just with a head start.

Exactly.

The inherited mutation is the first hit, present from birth.

Okay.

Besides inherited mutations and random errors, what else kicks off this process?

What external triggers introduce the mutations?

Viruses.

Viruses are definitely a factor contributing to maybe 12 % or so of human cancers globally.

They have RNA viruses, retroviruses like HTLV1.

They can cause trouble in a few ways.

They integrate their genetic material into the host cell's DNA as a provirus.

If this happens near one of the host's proto -oncogenes, it can accidentally activate it.

Or the virus itself might carry a hijacked, mutated version of a proto -oncogene called a VEONT.

Or the viral proteins might just interfere with the normal cell cycle regulation.

And DNA viruses, like HPV or hepatitis.

They often work differently.

Many DNA viruses encode proteins whose job is specifically to seek out and inactivate the host's tumor suppressor proteins like P53 or RBA.

Why would they do that?

To force the host cell into the S phase, the DNA replication phase.

The virus needs the cell's replication machinery to copy its own DNA.

So it disables the breaks to make the cell start dividing.

Clever in a sinister way.

And finally, the big one, environmental carcinogens.

Right, these are the chemicals or radiation that directly damage DNA and cause mutations.

And they're everywhere.

Even natural sources.

Absolutely.

Aflatoxin, produced by mold on peanuts and corn.

Natural radiation like UV from the sun or radon gas from the earth.

Even just normal metabolism creates damaging byproducts, reactive oxygen species.

Eskimos suggest maybe 10 ,000 DNA lesions happen per cell, per day, just from basic chemistry.

Wow, our repair systems must be busy.

Incredibly busy.

But the one we've studied the most, of course, is tobacco smoke.

Of the classic carcinogens.

Contains over 60 known carcinogens.

And the effects are measurable.

Smoking a pack a day for a year can cause, on average, something like 150 new mutations in every single lung cell.

150 mutations per cell per year.

Yeah.

Specific types, too.

Like base substitutions and bulky chemical adducts stuck onto the DNA.

Over 40 years of smoking, you're virtually guaranteeing that some cells will accumulate that deadly combination of two to eight driver mutations.

Okay, so wrapping this all up.

What's the big takeaway for you, the listener?

It seems the core lesson is that cancer isn't usually one single event.

It's this accumulation, maybe just two to eight key driver mutations over a long time.

And it often starts because the cell's own safety mechanisms, DNA repair, the cell cycle checkpoints, the apoptosis suicide program, they start to fail.

That affects both the gas pedals, oncogenes like res, and the brakes.

Tumor suppressors like TP53.

That's really it.

You can't overstate how central genomic instability is.

It's not just a side effect.

It's the engine driving the whole process, allowing the cancer to evolve and become more aggressive.

And digging deeper, there's this idea of cancer stem cells.

Right.

That maybe only a small fraction of cells in a tumor can actually start new tumor.

Exactly.

A subpopulation that might be responsible for maintaining the tumor and driving relapse.

So here's something to think about.

Traditional treatments, chemo, radiation, they work largely by causing massive DNA damage, hoping to kill rapidly dividing cells faster than normal cells.

Right.

They exploit that proliferation.

But if the real root of the problem is this underlying genomic instability, possibly maintained by those cancer stem cells,

what kind of future therapies, maybe genetic or epigenetic ones, could actually target that mechanism?

Could we fix the instability itself or selectively kill those stem cells without causing so much damage to healthy resting cells?

That's the million dollar question, isn't it?

Shifting focus from just killing dividing cells to actually correcting the fundamental genetic and epigenetic corruption.

That's really the frontier.

A fascinating and hopefully ultimately optimistic frontier.

Thank you for joining us for this deep dive into cancer genetics.