Retinoblastoma: Proliferation and Types

00:01 What do we mean by that? Okay.

00:03 In the lower left hand corner is the normal wheel of fortune or the wheel of the cell cycle.

00:09 And at each stage along the way where the arrows stop, and there's a gap, there's a pause that is involved in the cell deciding whether to go forward or to stop.

00:21 And one of the first pauses that occur in the normal cell cycles between the growth phase, G1, and the synthesis phase, S.

00:29 That G1, S transition is actually regulated by retinoblastoma gene products or the retinoblastoma protein.

00:42 Till a little bit more involved, very briefly, we need to cause the breakdown, retinoblastoma is kind of a break on the entire system.

00:52 It's saying, "Nope, we're not going to go anywhere, we're not going to go beyond G1 into S, until I say so." So we need to make retinoblastoma go away, or the Rb protein go away.

01:02 To do that, we have to have upregulated activity of Cyclin-dependent kinase 2, Cdk2.

01:09 And that happens because we increase the activity of cyclin E.

01:13 When we talk about pathology and other settings, we'll get into more detail here.

01:17 But basically, it's going to be the upregulation and increased activity of these proteins that will allow us to interact and make Rb go away.

01:29 Rb normally sits, so the RB gene that kind of read lips normally sits on top of elongation factor and like a big sumo wrestler says "Nope, you're not going to do your job.

01:40 I'm going to keep you in an inactive form." Well, if we want the cell to go through cell cycle, we have to convince the sumo wrestler to step away from elongation factor 2.

01:51 So in order to do that, what we do is cyclin E and cdk2, they work together to phosphorylate the retinoblastoma gene, and when it does that, that hyperphosphorylation means it goes away.

02:02 It is released from elongation factor 2.

02:05 And now, E2F, elongation factor 2 can allow the synthesis of the DNA.

02:13 We will get past that block the G1 to S block.

02:16 Okay, that's what normally Rb does.

02:19 It sits like a break on the system and says, "Nope, you're not going anywhere." And it's not until we've specifically activated by phosphorylation, that it releases E2F to do its job.

02:31 So what goes on in retinoblastoma when there's mutations? Well, in that setting, the sumo wrestler has been convinced to never bind the elongation factor 2.

02:42 It's just going to go, you know, I don't care anymore, and it's an abnormal form of protein.

02:47 So E2F is free to do its thing all the time.

02:50 We've taken away the brake on the cell cycle.

02:54 And so, by having that mutant form, we constantly drive cells through the cell cycle.

03:01 The familial form of retinoblastoma actually makes a lot of sense when we think about genetic mutations and how things are passed down.

03:12 The familial form means that either mom or dad has one bad copy of the gene.

03:16 That's indicated here in blue.

03:18 Normal, is indicated as red.

03:21 So the normal retinoblastoma gene on chromosome 13 is going to be red.

03:26 Dad, in this case, it could be mom, but dad, in this case is the carrier.

03:30 He doesn't have any disease necessarily.

03:34 But half of his sperm will carry that mutant form of retinoblastoma.

03:40 Now, when he and mom get together and make a zygote, every gene or every cell in this new zygote will have one bad copy.

03:51 So all the somatic cells of the child will have this.

03:56 Now, all it takes is a second hit.

03:58 So, with just one bad when there is just one bad copy, that means there's one good copy of the sumo wrestler that can sit on E2F and keep it from doing its job.

04:11 So with one bad copy were good, but if every cell in the body has one bad copy, all it takes is an additional hit of the normal chromosome, a mutation of the Rb of the normal one, and now we have no sumo wrestler.

04:29 We have no ability to turn off E2F, no ability to regulate cellular proliferation.

04:35 So, this frequently the second mutation of a somatic cell will occur in retinal cells.

04:41 The exact reason for this is not exactly no because every cell in the body has got one bad gene.

04:51 Why is the retina so prone? Well, do you remember that I told you that you are kids with the art the familial form, the hereditary form of Rb, a retinoblastoma are also more prone to glioblastoma, to other tumors such as sarcomas.

05:09 So, okay, that kind of makes sense.

05:11 But why is this hidden in the retina? And part of the reason is that we think that the retina, because of light going in through the pupil is more susceptible to secondary UV damage.

05:26 This is a little hand wavy, okay.

05:28 And when I waved my hands furiously, that means we're not exactly sure.

05:32 This is an example where we're not exactly sure.

05:35 But nevertheless, these kids will get a second hit at a certain frequency, and now developed loss of the regulation of the cell cycle.

05:47 And then the consequence is we get retinoblastoma.

05:51 So the familial form of retinoblastoma.

05:54 This hereditary form constitutes about 40% of the cases of retinoblastoma.

05:59 So one in 15,000 kids, 40% of those will be due to this.

06:04 And it tends to as you would imagine, because we carry that mutation in every somatic cell in the kid's body, it will tend to be bilateral or multi-focal, okay.

06:15 There are sporadic forms.

06:16 The sporadic forms are a little bit harder to achieve, because it requires mutations, multiple mutations in the same cell.

06:26 So, both parents are all red in their chromosome 13 RB gene.

06:33 And so all of the germ cells are going to be normal.

06:35 They're all going to be red, all the way through.

06:38 The zygote is going to be red-red.

06:40 All the somatic cells of the child completely normal.

06:43 But somewhere along the line, one of the cells in the retina gets a mutation in Rb.

06:50 So one cell out of that entire population gets that mutation.

06:56 And then we have to get a second hit.

06:58 In the sec, in that same cell that has already lost the original wild type Rb, in order to get retinoblastoma.

07:07 In yet it happens.

07:08 In about 60% of the cases of retinoblastoma, overall, are due to this sporadic double mutation in a single cell.

07:17 Tends to be unilateral, and, you know, it's just incredibly bad luck.

07:21 And so it tends to be unifocal and unilateral because only very few cells ever get the double mutation in their RB gene.