Knudson’s Two-Hit Hypothesis of Tumor Formation

00:01 There's a few genetic principles that I'd like for you to know about both NF1, NF2, and tuberous sclerosis.

00:07 And the first is Knudson's Two-hit hypothesis.

00:12 And this is an important hypothesis for understanding why tumors develop in tumor suppressor syndromes? When we think about a tumor, there are two ways to develop a tumor, an oncogene or a tumor suppressor gene.

00:25 The oncogene is like putting your foot on the gas.

00:28 One mutation in one oncogene is sufficient to cause a tumor to grow.

00:32 Tumor suppressor genes are like feet on the brakes, and you have two feet on the brake.

00:39 Mutation in one gene is insufficient to cause a tumor to grow, you really need that second hit.

00:44 And this is going to be a diagram that discusses and details, how that to hit occurs? As we know, we contain genes from both our mom and our dad.

00:55 Alleles from mom and dad for each gene in our body.

00:58 And you can see here at the top, this individual, this parent at the top has two alleles at the NF1 locus.

01:05 A normal allele that's a plus and an abnormal allele or a mutated of allele, that's represented by the minus.

01:14 That parent will give those alleles to offspring.

01:17 And so we can see one offspring has an NF+/+, they've inherited the normal allele from mom and dad.

01:24 And the other offspring has NF -/+, they've inherited that abnormal copy.

01:29 So we see here, the abnormal copy from one parent, the normal copy from the other parent, and this patient has acquired neurofibromatosis or an abnormality in the NF1 gene.

01:42 And this accounts for about 50% of cases of NF1.

01:46 The patient inherits the abnormal copy of NF1 from a parent.

01:51 And that's both at a genetic condition and an inherited condition.

01:55 But that's not the only way patients develop NF1, and NF2.

02:00 Sometimes the parent has both normal copies of NF1.

02:04 Both allele's are normal.

02:05 There is no mutated copy of NF1 in the parent, and yet the child still develops neurofibromatosis.

02:13 And that results from a mutation in this gene that's acquired at the time of conception.

02:17 When that gamete is formed, as a result of DNA replication, there is a mutation in the NF1 gene.

02:26 The NF1 gene is one of the largest genes in the body.

02:28 So it's really common that we see sporadic or spontaneous mutations.

02:32 And it turns out that de novo mutations in NF1 account for about 50% of patients with neurofibromatosis.

02:39 So while all NF patients have a genetic condition, about half are acquired from a parent and are inherited, and half are sporadic or de novo.

02:49 That's an important principle that I want you to know.

02:53 And one key principle in genetics that we think about with NF 1 and 2 is complete penetrance.

02:59 What is complete penetrance? Well, this is a genetic condition in which all patients who have the disease causing mutation will show a sign of the disease.

03:08 So if those cells, if the germline contains a mutation in NF1, there will be clinical signs or symptoms.

03:15 That's an important genetic principle to take away from these conditions.

03:20 We talked about the first hit. What's the second hit? All the cells in the body as we can see here depicted have a normal NF1 copy and an abnormal NF1 copy.

03:32 Those cells we call heterozygous.

03:34 They're heterozygous at the NF1 allele.

03:37 And heterozygosity is not sufficient to cause tumor growth, but is sufficient to cause a number of symptoms.

03:43 And we'll talk about some of the minor symptoms in NF that can develop as a result of this haploinsufficiency having one normal copy, and one abnormal copy.

03:51 As a result of life and acquired mutations in living, some cells will acquire a second hit.

03:58 A mutation in that one remaining normal NF1 copy that one foot that is on the brake and preventing tumor growth, and we call that loss of heterozygosity.

04:08 There's no longer a heterozygous allele at the NF1 locus, and that cell is NF1 -/- and this is sufficient for tumor growth.

04:18 So NF1 patients have symptoms that both result from haploinsufficiency, things like learning disabilities, scoliosis, short stature, and these things called UBO's, or Focal Areas of Signal Intensity that we'll talk about.

04:32 And tumors.

04:34 In the tumors are a result of that second hit.

04:36 Loss of the second break, on tumor growth or cell growth.

04:40 And that's why we see things like neurofibromas, optic pathway, gliomas, sphenoid wing dysplasia, and tibial pseudarthrosis.

04:49 We also see in this a concept that's called variable expressivity.

04:54 This is another important genetic principle.

04:57 What is variable expressivity? Well, this is the degree to which a phenotype, a clinical phenotype is expressed by individuals that have a particular genotype.

05:08 Those are a lot of words. What is that mean? Well, in other words, patients with the same genetic mutation may have different severity of disease.

05:16 A mom and a daughter may both have the same NF1 mutation, but one may have severe disease and one may not.

05:23 A brother and sister, both may have the same mutation in the NF1 gene, and one may have more severe or less severe disease.

05:31 And this is because of that second hit, the loss of heterozygosity.

05:35 The acquired mutation that occurs for no other reason than chance.

05:40 The environment gives it to us, and that results in variable expression of these conditions.

05:46 So important genetic principles that I want you to be able to take away from this lecture.