Tumor Suppressor Genes: Definition and Inactivation – Carcinogenesis

by Carlo Raj, MD

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    00:02 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.

    01:23 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'.

    01:49 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'.

    02:12 Both copies of gene must be inactivated for oncogenesis is the theory behind Knudson's 'two hit hypothesis'.

    02:19 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.

    02:43 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.

    03:02 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.

    03:39 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.

    03:59 One hit already took place, inherited. A second hit will take place. Now, take a child, you do a funduscopic examination.

    04:08 What are you going to see in the eye. Leucocorrhoea. What colour is the tumor in the retina of this child. Retinoblastoma.

    04:19 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.

    04:38 Another very important familial type of germline mutation would be, here is a patient and patient is losing weight drastically.

    04:46 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.

    05:33 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.

    05:47 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.

    06:07 And you said primary gastric adenocarcinoma. Correct. You said one nodule in the lung by the mediastinum. One nodule.

    06:17 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.

    06:48 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.

    About the Lecture

    The lecture Tumor Suppressor Genes: Definition and Inactivation – Carcinogenesis by Carlo Raj, MD is from the course Cellular Pathology: Basic Principles.

    Included Quiz Questions

    1. p53
    2. Rb
    3. E2F
    4. Cyclin D
    5. MDM2
    1. Second hit: inherited germline mutation
    2. Both gene copies must be inactivated
    3. First hit: inherited germline mutation
    4. First hit: inherited somatic mutation
    5. Second hit: acquired somatic mutation
    1. Germline mutation of Rb on chromosome 13
    2. Germline mutation of p53 on chromosome 17
    3. Sporadic mutation of Rb on chromosome 13
    4. Germline mutation of p53 on chromosome 13
    5. Germline mutation of Rb on chromosome 17
    1. Lymphocytic retinal tumor
    2. Weight loss
    3. Mediastinal nodule
    4. Infertility
    5. Multiple primary cancers

    Author of lecture Tumor Suppressor Genes: Definition and Inactivation – Carcinogenesis

     Carlo Raj, MD

    Carlo Raj, MD

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