Oncogenes and Tumour Suppressor Genes

How can proto-oncogenes become oncogenes?

1. A mutation 2. Overexpression of a normal proto-oncogene makes it effectively an oncogene

How does knowing about all these genes that cause cancer useful for medicine in terms of innovating treatment options?

1. Gene therapy - inject correct gene 2. Pre implantation screening - select a healthy embryo without the susceptibility gene

How does Herceptin work?

1. HER2 (human epidermal growth factor 2) causes proliferation in breast cells 2. In breast cancer, HER2 receptor is overexpressed -> too much proliferation 3. Herceptin is a monoclonal antibody to the HER2 receptor 4. Binds to and inhibits these receptors = normal proliferation again

How do our genes get damaged/get mutated?

1. Mutagens - toxins, diet, smoking, UV etc. 2. By chance during replication 3. It's inherited

What are the two types of oncogenes?

1. Viral oncogenes (v-onc) - viruses inject an oncogene, causing cancer 2. Cellular oncogenes (c-onc) - from human or other higher organisms

What is retinoblastoma?

A childhood eye tumour that is, 40% of the time, from a germ-line mutation (every cell affected - not a spontaneous mutation)

What is a polyp?

A growth in the colon that may or may not become cancerous

What is LGR-5?

A marker that if seen proves presence of stem cells in the small intestine

What is an oncogene?

An abnormal gene that can push a cell towards transforming into a cancer. They're mutant versions of proto-oncogenes (hence the name)

What happens when one of them is mutated?

Because it's a balancing act, if you get a mutation in either you could potentially cause neoplasms and cancer

How can retinoblastoma have an autosomal dominant inheritance pattern yet TSG inheritance is recessive?

Because when we say TSG inheritance is recessive, we mean that people need both chromosomes to be 'hit' with a mutation in order for there to be disease. When you inherit the first 'hit', you become 100,000x more likely to develop the second hit and develop retinoblastoma, so effectively you only need one of your chromosomes to be affected in order to pretty much guarantee that you'll get retinoblastoma, and hence the inheritance pattern is autosomal dominant

What's the difference between proto-oncogenes and tumour suppressor genes?

Both are part of normal cell control. Proto-oncogenes are normal genes that stimulate growth in a controlled way, by pushing the cell through the R point/G1-S checkpoint. Tumour suppressor genes are normal genes that suppress growth in a controlled way, by arresting the cell in the G1-S checkpoint.

What is sporadic colon cancer?

Colon cancer due to two 'hits' of somatic mutation. They don't have a germline mutation but just got really unlucky and developed 2 mutations in both of the APC genes

How do you treat a mutated tumour suppressor gene or proto-oncogene?

Either with a drug or with gene therapy

Tumour Suppressor Gene: p53 - guardian of the genome

If the p53 gene is damaged, tumor suppression is severely compromised. P53 normally induces apoptosis before DNA replication if the DNA is highly damaged. People who inherit only one functional copy of the p53 gene will most likely develop tumors in early adulthood (once other copy is mutated too), a disorder known as Li-Fraumeni syndrome.

Tumour Suppressor Gene: TGF β

Inhibits growth in epithelial cells (but also in a lot more places). Makes cells that rise up from the crypts in the gut epithelium stop growing.

What is Familial adenomatous polyposis, FAP?

It's a hereditary form of colorectal cancer. Sufferers inherit a single mutation in the Adenomatous polyposis coli (APC) tumour suppressor gene. They then have almost 100% chance of getting the 'second hit' and developing a mutation in the other APC tumour suppressor gene = cancer in their 40s. FAP sufferers have one APC mutated and one normal APC in every cell in the body.

What is c-ras and what happens when it's mutated?

It's a proto-oncogene that is mutated into an oncogene in 50% of colon cancers. Ras is involved in cell signalling in response to the binding of growth factor: o Normally ras becomes active only when the growth factor is present, and it then sends growth signals to the cell, which proliferates o When its mutated, it doesn't need the growth factor and sends the proliferating signal anyways = uncontrolled growth that doesn't need a growth signal

Surely a mutation wouldn't affect the cell because it has another identical chromosome with the unmutated proto-oncogene?

No, because mutations of protooncogenes are dominant, so the oncogene will overpower the proto-oncogene = tumour growth

Tumour Suppressor Gene: Retinoblastoma protein

Note that the TSG is retinoblastoma protein, which is named after the cancer it causes, retinoblastoma

What was the first oncogene to be discovered?

SRC, which was a v-onc found in chickens

How do cells know to stop dividing as they rise up the villus?

TGF-β is expressed at the top of the crypts, which arrests cell growth.

Tumour Suppressor Gene:Adenomatous polyposis coli (APC)

TSG in colon cancer

What goes wrong in colorectal cancer - why don't they also stop growing?

They become resistant to TGF-β, as the receptors are mutated. Also, Bcl-2 is overexpressed in cancer cells, protecting it from apoptosis.

How do we think v-oncs came into existence?

They infected a cell that had an oncogene and integrated it into its genome by recombination.

What is Knudson's 2 hit theory?

Unlike with proto-oncogenes, you can survive with no effect if only one of your chromosomes has a mutation in the tumour suppressor gene. Mutations in tumour suppressor genes are recessive. It's when both are mutated (or one is mutated and one is lost) - the two hits - that you get cancer. In hereditary tumours, the first 'hit' is genetic, so you only need one more hit before cancer, so you're at a much higher risk.

Will FAP patients only have the one cancer?

Usually, patients develop many benign polyps first due to the first mutation in the APC, but they stay benign. Then eventually the other APC gets mutated/other tumour suppressor genes or proto-oncogenes mutate, promoting uncontrolled growth, and that polyp becomes a malignant cancer.

Can you treat colonic cancer cells with a mutated p53 with gene therapy?

Yes, you can insert a chromosome 17, which has the normal p53 on it.

Epidermal growth factor (EGF)

o Proto-oncogene o Stimulates growth in digestive system

Platelet derived growth factor (PDGF)

o Proto-oncogene o Stimulates growth, particularly in new blood vessels -> angiogenesis

Transforming growth factor β (TGFβ)

o Tumour suppressor gene o Inhibits growth in epithelial cells (but also in a lot more places)