Skip to 0 minutes and 14 seconds Hello, and welcome to the next video in this course. I know that you’ve already heard about how cancer development involves multiple steps and involves several cancer genes. Genes are, in fact, hugely important in cancer. They are crucial to our understanding of how cancers arise and why some people are far more likely to develop cancer than others. Cancer genes and their alterations have also become extremely important for the use of new moleculary-targeted treatments and the development of personalised medicine. In this video, I’ll tell you more about the different types of cancer genes and the fascinating ways in which they work. And you’ll also see some of the molecular and clinical consequences that result when these genes are altered or mutated.
Skip to 1 minute and 3 seconds The two main types of cancer genes are known as oncogenes and tumour suppressor genes. Oncogenes encode or make proteins that, in most cases, normally help to promote cell division when it is required. For example, these proteins may normally become active if you accidentally cut your skin. The proteins would help to make your skin cells divide and multiply to repair the damage with multiple rounds of the cell cycle. You can think of these genes as acting on the pedals of a bicycle, pushing it forwards and also pushing the cell cycle forwards. Technically, oncogenes are actually known as proto-oncogenes when they are unaltered in their normal form and are known as oncogenes when they are mutated.
Skip to 1 minute and 51 seconds At the molecular level, the equivalent of the bicycle pedals are growth factor signalling pathways like the one shown here. An important point to remember is that the cancer-causing mutations that occur in these oncogenes will generally cause the proteins that they make to become overactive or to gain a new function. Amazingly, over 380 different oncogenes have now been identified in humans. These oncogenes can be activated in different ways. For example, they can be activated by point mutations, such as those we can detect in the KRAS gene in colon cancer. In fact, mutations in this gene can now help predict treatment effectiveness.
Skip to 2 minutes and 38 seconds For example, with specific new drugs, such as the EGFR inhibitors, the activation may instead be due to an increase in the number of copies of the gene. This is called gene amplification, and is seen with the NMYC oncogene in approximately 25% of the childhood tumours called neuroblastomas, and also in some small-cell carcinomas of the lung. Activation of oncogenes can also occur by a chromosome rearrangement or translocation that changes the extent to which oncogenes are switched on. For example, this is the mechanism by which the ABL1 oncogene is activated in chronic myeloid leukaemia. And it’s one of the ways in which the MYC oncogene is activated in Burkitt’s lymphoma.
Skip to 3 minutes and 29 seconds As you have heard, the other main class of cancer-causing genes is known as the tumour suppressor genes. There are at least 105 of these, and they are different from the proto-oncogenes or oncogenes in at least two important ways. Firstly, the proteins that they make or encode are typically involved in preventing the growth of tumours. They do this by inhibiting cell cycle progression and cell proliferation, rather like acting on the brakes of a bicycle. Alternatively, these proteins can cause the cells to die by programmed cell death or apoptosis. A second crucial difference is that unlike with proto-oncogenes, both copies of the gene usually need to be inactivated before the tumour- causing effects result.
Skip to 4 minutes and 23 seconds As you’ve heard previously, this is known as Knudson’s two-hit hypothesis. Oncogenes require just one hit because their mutations cause a gain of function not a loss of function. There are several mechanisms by which tumour suppressor genes can be inactivated. They can be altered by a point mutation, which often causes protein shortening or truncation, for example, if it is a premature stop codon. Alternatively, there may be a deletion of the whole gene, for example, as can happen with the NF1 gene, which is associated with neurofibromatosis type one. You can see that condition here in this picture of an affected lady’s back. A deletion can also affect the MLH1 or MSH2 genes, which are associated with colorectal cancer.
Skip to 5 minutes and 19 seconds Or there may be gene silencing by methylation of the tumour suppressor genes promoter or control region. And this can often switch off the transcription of genes, such as MLHL or BRCA1, particularly, as a second hit. A very well known example of a tumour suppressor gene is the retinoblastoma or RB1 gene that you have already heard about it. Children who inherit a mutation in that gene usually have a very high risk of developing a retinoblastoma tumour at the back of at least one of their eyes. As well as that, their own children– when they have them– will, unfortunately, each have a 50% chance of inheriting the gene mutation. Another well-known example of a tumour suppressor gene is the BRCA1 gene.
Skip to 6 minutes and 12 seconds Mutations in that gene can cause breast and ovarian cancer. It is actually a type of tumour suppressor gene that is called a stability gene or DNA repair gene, as it makes a protein that helps to prevent DNA damage to other genes and chromosomes. One of the many functions of the large BRCA1 protein is to assist in the repair of so-called double-strand breaks in chromosomes. This is an important function as the broken ends of chromosomes, if not repaired properly by BRCA1, can join up in ways that can lead to the malfunction of other genes, and these can, of course, include other cancer genes.
Skip to 6 minutes and 55 seconds Other important stability genes that you should know about include BRCA2 and the so-called mismatch repair genes, MLH1 and MSH2. These mismatch repair genes encode proteins that can bind to DNA and repair errors that sometimes occur during DNA replication in the S-phase of the cell cycle that you’ve already heard about. Much more information about the many different cancer genes, proteins, and cancer syndromes is accessible from the accompanying website that I have created at essentialmedgen.com. The website is free to use. It provides a guide to 70 different online resources and databases, and it also summarises some of the very latest exciting advances relating to this topic. You will hear more about cancer genes throughout the rest of the course.
Skip to 7 minutes and 48 seconds And I hope that the important principles that you’ve learned from this video will be helpful to you.
Oncogenes and tumour suppressor genes
Professor Ed Tobias introduces oncogenes and tumour suppressor genes
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