You'll notice here, on the flow chart thus far,
we've walked through our box on the left
in which we talked about chemicals, viruses and
radiation. When a normal cell has been exposed
increases the risk of carcinogens. Our next topic,
which is a very short topic is that if there is
failure of your DNA repair which we already kind
of discussed with xeroderma pigmentosa.
Upon exposure to UVB rays may then develop cancer.
DNA repair defects. Let's talk about this in great detail.
What you find here on the right, is the fact that
you have your DNA, and you have a double helix.
Next, you find depurination and then you have a, what's
known as a endonuclease. And then finally DNA polymerase
in which it then helps you put back a part of the strand
which is then been removed. You'll notice here please,
that on the bottom strip, from 5' to 3', that you have
a nucleotide endonuclease taking out the G.
And then you have a polymerase and along with
the ligase which puts it all together.
Now what ends up happening on the right, is the fact
that you are not able to properly do it. Deaminase.
Then you have DNA glycosylase. Then you have endonuclease and
DNA polymerase. So these are the enzymes that you want to know,
in general from genetics. I'm not going to go into
greater detail about this apart from the fact that
some of this enzymes may then become mutated. Mistakes made
in DNA replication are corrected by DNA repair genes usually.
Often detected by what's known as microsatellite instability.
What is a microsatellite instability and why do you want to
know this. If you are not able to properly remove a microsatellite
instability, you might develop a condition known as,
HNPCC, hereditary non-polyposis colorectal cancer. This
may then give rise to a right sided colorectal cancer.
Clinical application of what we are looking at here,
i'm not giving you information that is trivial.
Every single point has serious clinical significance. So,
what then happens is that if there is a mutation
in the DNA repair enzymes, then this then becomes fixed.
What becomes fixed? The microsatellite. What's a microsatellite?
The 1 to 6 nucleotide tandems that should normally be
removed by the enzymes. The mutation is in one of the genes.
At least want to know MSH 2, MLH 1. Memorise that. The mutations
in MSH and MLH result in a condition called Lynch syndrome.
What is another name for Lynch? Hereditary non-polyposis
colorectal cancer. Giving rise to what kind of colorectal cancer?
More so right of left side? Right. Another condition
which we talked about earlier with DNA repair mutations,
is your thymine dimer, with xeroderma pigmentosa.
Walked through this in greater detail earlier.
Upon exposure to UVB rays, may develop certain types
of skin cancers. Be familiar with the enzymes
that we are seing here on the right and what it's
responsible for doing in terms of proper replacement
Our next big topic is the fact that we are
going to take each one of this boxes,
i'm going to first read them through you or to you
and then we'll walk through them to show you that
if you are able to satisfy each one of the criteria in
this boxes, what are you doing? You are developing cancer.
The first box on your left is oncogenes. If i gave you
t(8;14), you tell me, Burkitt. And you would tell me
what kind of oncogene? C-myc. Lots of c-myc, gives rise
to cancer. What kind? Burkitt. The middle box.
Remember the tumor suppressor genes are security
guards. They are the guardians of your cell cycle.
As you walk through your cell cycle, our major
point of arrest would be between G1 and S phase.
Remember G1 and S. Your focus on your boards will be
between G1 and S. The guardians for G1 to S will be
Rb and p53. If the guardians have been removed for whatever
reason. p53 being very common. It is the most common
mutated gene isn't it. And if p53 has been removed there
is nothing stopping the cell from going to a cell cycle.
We'll talk about this in greater detail. And finally we
will talk about apoptosis in which if a cell is able to
successfully evade apoptosis, then the cancer cell is never
going to die. Clear? Each one of this boxes, clinically significant.
Talk about the types of mutation here. We will have to go
through in great detail, RAS. You have heard of KRAS, NRAS, HRAS.
Our focus will be KRAS. You have heard of TP53? And actually
from henceforth, whenever you see the letter 'P', in front of a
number and such, that to you should indicate that tumor suppressor
gene. And we have RB. RB being another big point of mutation
Translocations (9;22), well apart from CML I want
to add another cancer that you need to know.
Would you tell me what is the most common leukaemia in a
child between the ages of 1 to approximately 15?
Acute Lymphoblastic Leukaemia. t(8;14) Burkitt, t(14;18)
Good. Follicular. t(15;17) AML type 3. We will talk about this later.
Deletions, amplifications, ERBB2. ERBB2 is synonymous with
HER2/neu. So what we will do, and don't memorise this right now.
I'm just giving you types of mutations that are to come.
And they will come. And we will keep repeating, reinforcing
you will be sick and tired of me if you are not already, of all
the different mutations that we have to go through including BCL2.
The genes involved in cancer. Proto-oncogenes we will
talk about. Remember, proto-oncogenes are actually normal.
We require for proper growth. If then these become mutated
this then become oncogenes. The suppressor genes, p53 and RB.
Anti-apoptotic gene will be BCL2. And we already did
our DNA repair gene in which we had mismatch repair
and we talked about MLH1 and MSH2. And we will talk about
apoptosis as well. Must know. Either between BCL2 and BAX.
Nice little introduction of high yield list of genes
and mutations that you have to know for your boards.
The topic on this table. These tables are big time. Neoplastic
molecular markers and when do you want to use it.
Let's first begin with the first row and with ABL I want
you to jump over to t(9;22). So whenever you hear t(9;22)
you should be thinking about Philadelphia chromosome. That
t(9;22) that translocation gives rise to and codes for an
enzyme called tyrosine kinase. And whenever this
translocation takes place you will automatically have CML.
And if it's a young patient I was talking to you
about leukaemia, and then it would be ALL.
So what's a non-receptor TK activity. TK stands for tyrosine
kinase. In pharmacology, you have learned of a drug
in which it knocks out the tyrosine kinase activity of
t(9;22). Welcome to imatinib. Next, we have HER.
HER. Now interesting enough the marker gives you the
gender. So it's a she. Now with this gender,
what does HER actually stands for? Human epidermal
growth factor receptor. Epidermal growth factor receptor.
So what does that mean. It means that the
receptor autonomously undergoes amplification,
and with all this receptor activity what kind of cancer
is your patient going to develop? Breast cancer.
And this type of breast cancer with HER2/neu positive, you
are going to use a drug called? Good. Trastuzumab.
MYC. With MYC it's a nuclear transcription t(8;14) Burkitt.
So down in the area of the nucleus, inside the nucleus,
you have an oncogene, specifically focusing upon
C-myc and this then gives rise to Burkitt.
Then you have something called N-myc. N-myc. N as in N-myc,
N as in neuroblastoma. Also responsible for nuclear transcription.
We will be spending quite a bit of time with RAS. You
need to know everything about RAS. 40-50% of your cancers
has a RAS mutation involved. At this point, I would
like for you to connect and forever memorise the RAS
associated with GTP signal transduction. GTP, RAS. When
we get into GI, we will talk about what's known as
familial adenomatous polyposis. With familial adenomatous
polyposis there is a gene, a mutation with APC.
At some point, I will give you the interaction between
APC and beta catenin. If this then becomes mutated,
what's your risk of going on to colorectal cancer in familial
adenomatoud polyposis? 100%. What are you going to find in the colon?
A carpet of polyps. And associations of familial adenomatous
polyposis, might have heard of Gardner and you know about the Turcot.
Next we have BRCA1 and BRCA2. BRCA, breast cancer. Not
only could it be breast, it could also be the ovary.
Both will be involved. One and two. RB.
Retinoblastoma. This is a normal tumor suppressor gene,
that guards a cell or guards, monitors, supervises the
quality of a cell as it goes from G1 to S phase.
G1 to S phase, that is perfectly normal. If there is a
mutation in chromosome 13 and retinoblastoma has been removed,
you remove the break. Worried about retinoblastoma, and later
on in life genetically may develop osteosarcoma.
TP53 is all over the place. Also controls and
monitors the quality of your cell between G1 and S.
If you have'nt already, you put together p53 and RB
they will work together. If those are become mutated,
these then give rise to all kinds of cancer. p53 is
the most common mutation that results in cancer development.