Where we are here with carcinogenesis is finally,
well, the inactivation of tumor suppressor gene
and now give you tables and we'll talk further about
what this means to you. So tumor suppressor genes,
what are these? They encode proteins that regulate and
suppress the two that we already talked about include
Rb and p53. Both of this tumor suppressor gene
so that you prevent the cell and we focused upon
getting through G1 and to S phase. Here, p53 prevents
two things or has two functions. Number 1,
if the cell can be repaired it can be, you can recruit your
DNA repair genes and then p53 will do that, repair the cell
and put it back in the cell cycle. If that is not possible,
then p53 will then recruit those enzymes necessary to bring about
apoptosis. So it will guard the cell properly. Rb. Can you
picture Rb for me. The Rb is bound to E2F, here it literally
guards the arrest points between G1 and S phase. With the
help of whom? E2F. What's the name of the enzyme that causes
phosphorylation of Rb. That's a kinase. Which one do
we focus upon specifically, cyclin D/CDK4.
All of this should speak volumes to you when I'm reading
this. Inactivation of tumor suppressor gene
there is something called the 'two hit hypothesis'. Now this
is not a big deal but, well nothing is a big deal,
once you are actually knowledgeable of what's going on. So
let's bring you knowledge. 'Two hit hypothesis'.
You want to think about mother and father. In order for a
patient to then or progeny to develop a cancer
then both of the allelles have to be hit. Once they have
been hit in the progeny, unfortunately the child is going to
or the progeny will develop whatever type of cancer. That's a
theory between Knudson's 'two hit hypothesis'.
Both copies of gene must be inactivated for oncogenesis is
the theory behind Knudson's 'two hit hypothesis'.
What if you were to inherit one. If you were to inherit
what? A mutation. If you inherit one mutation
how many more mutations you need to hit so that you can
then develop your cancer. One more. The first hit
if it's already inherited, then the other hit takes place
somewhere down the line, well this is then called your familial.
Whereas say that you have a second hit. Now what this means
is that no hits. What hit mean? A mutation. No mutation
was inherited. One hit in mutation took place sporadically,
and a second hit took place sporadically.
And this is then referred to as being your acquired or
sporadic type of mutation. It is important that you know
the term familial versus sporadic. Lot of times, you will
find your cancers either behaving in a familial manner
or behaving in a sporadic manner. It is important that you
understand which one is inherited and which one will be
sporadic. Once again, one that has been inherited is
then called your familial. All you need is one more 'hit'
to then bring about your oncogenesis. Whereas if it's sporadic,
you need to have hits taking place somewhere in your progeny.
Let's talk about examples of inherited or familial type of hits.
So this would mean that you only require one more mutation
somewhere in the lineage of the family tree to develop
the cancer. We have familial retinoblastoma.
One hit already took place, inherited. A second hit will
take place. Now, take a child, you do a funduscopic examination.
What are you going to see in the eye. Leucocorrhoea. What
colour is the tumor in the retina of this child. Retinoblastoma.
White. The prefix leuco means what? White. Leucocorrhoea upon
funduscopic examination. Think about what a normal
retinal examination should look like. Should never look white.
So germ line mutation of Rb, you must memorise chromosome 13.
Another very important familial type of germline mutation would
be, here is a patient and patient is losing weight drastically.
He's coughing out blood. In addition, there is going to be
early satiety. In addition, there is also going to be
infertility. There are a lot of issues in this patient.
Now you start doing investigations and you end up finding
increased levels of the following. Maybe there is going to be
the left supraclavicular lymph node that's been affected
and you find the patient be e-cadherin negative, that's your
gastric adenocarcinoma. I said there was hemoptysis
and early satiety. I'm talking about referring to your
primary gastric adenocarcinoma. I said e-cadherin negative
because it does'nt want to adhere it spreads up into
left supraclavicular. It's called your Virchow's node.
Next, I said that the patient was coughing out blood. And
here you end up finding upon histology, well chest X-ray
shows you one primary nodule and it's by the mediastinum.
One primary nodule. I'll just leave it at that right now.
And I told you about infertility and such. And then here
you might be thinking about on a cut section of the testicle
you might find a non hemorrhagic type of seminoma in this
male. This is interesting. Same patient Dr. Raj? Yeah.
And you said primary gastric adenocarcinoma. Correct. You
said one nodule in the lung by the mediastinum. One nodule.
Yes that is primary. So you have two primary cancers in the
same patient? Yes. And just to make sure we are clear,
I've given you a third one with the seminoma and non hemorrhagic.
Same patient? Yeah. All primary cancers? Yes. What is this?
Li-Fraumeni syndrome. A familial mutation on chromosome 17 which
knocks out p53 giving you multiple primary cancers in your patient.
My topic is familial type of oncogenesis. Where one hit
already took place, inherited. A second hit,
then results in major types of cancers.
Li-Fraumeni, Familial Retinoblastoma.