The Genetics of Cancer

This section has been reviewed and approved by the Cancer.Net Editorial Board, 3/2012 All cancer cells occur because of gene mutations. A mutation is a change or error that occurs in the deoxyribonucleic acid (DNA; the complex set of instructions that tells every cell in a person's body how to function). Genes are the basic biologic units passed from parent to child that provide information about a person's physical characteristics, such as eye color or risk of getting a certain disease. Genes are located on chromosomes (strands of DNA). Each cell in a person's body contains about 20,000 to 25,000 genes. They are located on 46 chromosomes, which are arranged in two sets of 23 chromosomes one set inherited from the mother and one set inherited from the father. One chromosome in each set of 23 determines whether a person is female or male (these are called the X and Y chromosomes). The other 22 chromosome pairs, called autosomes, determine other physical characteristics. About genetic mutations There are two basic types of genetic mutations: germline and acquired. If the mutation is passed directly from a parent to a child, it is called a germline mutation. This means that the mutation is present in every cell of an individual's body, including the reproductive sperm cells (in a boy's body) and egg cells (in a girl's body). Because the mutation affects reproductive cells, it is passed from generation to generation. Cancer caused by germline mutations is called inherited cancer, which accounts for 5% to 10% of all cancer cases. Acquired mutations occur during a person's life, and they are not passed from parent to child. Factors such as tobacco, ultraviolet (UV) radiation, viruses, and age cause these mutations. Cancer that occurs because of acquired mutations is called sporadic cancer and is much more common than familial cancer. Mutations and cancer Mutations happen often, and the human body has processes in place to correct most of these changes. Depending on where in the gene the change occurs, a mutation may be beneficial, harmful, or make no difference at all. Therefore, the likelihood of one mutation leading to cancer is small. Usually, it takes multiple mutations over a lifetime to cause cancer. This is why cancer occurs more often in older people, for whom there have been more opportunities for mutations to build up. Types of genes linked to cancer Many of the genes that contribute to the development of cancer fall into broad categories: Tumor suppressor genes are protective genes. Normally, they suppress (limit) cell growth by monitoring the rate at which cells divide into new cells, repairing mismatched DNA (a cause of mutations), and controlling cell death. When a tumor suppressor gene is mutated (due to heredity or environmental factors), cells grow uncontrollably and may eventually form a mass called a tumor.BRCA1, BRCA2, and p53 are examples of tumor suppressor genes. Germline mutations in BRCA1 orBRCA2 genes increase a woman's risk of developing hereditary breast or ovarian cancers. The most commonly mutated gene in people who have cancer is p53. In fact, more than 50% of all cancers

involve a missing or damaged p53 gene. Most p53 gene mutations are acquired mutations. Germlinep53 mutations are exceptionally rare. Oncogenes turn a healthy cell into a cancerous one. HER2 (a specialized protein that controls cancer growth and spread, found on some cancer cells, such as breast and ovarian cancer cells) and the rasfamily of genes (genes that make proteins involved in cell communication pathways, cell growth, and cell death) are common oncogenes. Mutations in these genes are acquired (not germline or inherited). DNA repair genes fix mistakes made when DNA is replicated (copied). If a person has a mutation in a DNA repair gene, these mistakes are not corrected. Mistakes that aren't fixed become mutations, which may eventually lead to cancer (especially if the mutation occurs in a tumor suppressor gene or oncogene). Mutations in DNA repair genes can be inherited in the germline (in Lynch syndrome, for example) or acquired. Despite all we know about the different ways cancer genes work, many cancers cannot be tied to a specific gene. It is likely that multiple different genes are involved in the development of cancer. Learn more aboutcancer risk. In the future, doctors hope to learn more about the role of genetic changes in the development of cancer, which may lead to improved cancer treatment and prevention strategies. How do our genes affect our risk of cancer? What are genes and DNA? Each of our cells contains DNA, a molecular manual for building our bodies and keeping them in good working order. DNA is packaged into units called genes, which each instruct different aspects of our cells behaviour. Cancer is caused by faults in certain genes, resulting in cells multiplyingout of control. These gene faults accumulate over our lifetimes, and our cells build up many of them before they become cancerous. Inheriting faulty genes While we cannot inherit cancer itself, some people are born one or more steps closer to cancer because they inherit faulty genes from their parents. This doesnt mean that they will definitely develop cancer. But it does mean that they need to accumulate less DNA damage for this to happen. They are statistically more likely to get cancer and doctors say that they have a genetic predisposition to the disease. Only around 5-10 per cent of cancers are thought to be caused by faulty inherited genes. Worried about family history If you are worried about a family history of cancer, you should visit your GP. They will either reassure you that you are not at particularly high risk, or refer you to a clinical genetics centre. If the centre thinks you are at a high risk of cancer, they will discuss this with you and help you examine your options. These can include genetic testing, increased screening and cancer prevention advice.

Different types of genes Most of the inherited cancer genes that we know about are high-risk genes - they greatly increase the risk of cancer, but are relatively rare. Many scientists are now focusing on finding subtle genetic variations that have weaker effects but are more common. Together, these low-risk variants could be very important in determining overall cancer risk. How do I know if I am at risk? There is a possibility that cancer may run in your family if on one side of the family: there are several cancers of the same type there are several cases of rare cancers members developed cancer before the age of 50 members developed multiple cancer tumours (for example in both breasts) Clinical genetics centres In the UK there are 26 NHS clinical genetics centres, most with an associated family cancer clinic. If your doctor refers you to a clinical genetics centre they will asses your risk based on the details of your family history. The clinic will be able to tell many people that they are not at high risk of cancer at this stage. If the clinic thinks you are at a high risk of cancer, they will discuss this with you and help you examine your options. Options may include genetic testing, increased screening and cancer prevention advice. Can we do anything about things that are in our genes? Absolutely - our genes interact with our environment and lifestyle to affect our risk of cancer. This means that people who inherit faulty genes that predispose them to cancer can sometimes take steps to reduce their risk of the disease. For example, CDKN2A is a high-risk gene for melanoma, a type of skin cancer. People with faulty copies of CDKN2A are five times less likely to develop melanoma in the UK than in Australia, a sunnier country. So in this case, sun exposure clearly makes a crucial difference. How do genes and lifestyle choices interact? Our genes can alter our risk of cancer by changing the effects of our lifestyle choices. Some genes neutralise toxic chemicals. Faulty versions of these could make people more vulnerable to the poisons in tobacco smoke and increase their risk of lung, bladder and other cancers. Other genes control how we process chemicals in our food and could influence how our diet affects our cancer risk. Genes could even make us more likely to adopt less healthy lifestyles that eventually increase our risk of cancer. For example, genes that make people sensitive to bitter tastes could affect how often they eat vegetables. And genes that make people respond more strongly to the taste, smell or sight of food could lead them to eat more and put on weight. Your Immune System and Cancer

Breast cancer cells start out as normal body cells, but they begin to grow out of control because of an abnormal gene. The immune system plays a major role in limiting the development of these abnormalities, often before cancer has a chance to grow. This gets rid of many cancerous cells before they can do any harm. Damaged, pre-cancerous cells may be a constant presence, but an ever-alert immune system takes them out and protects us from many assaults of cancer that never get beyond the very earliest stage. When the immune system fails Occasionally, though, even though cells are changing from normal to abnormal, they may still appear to be normal. Their outer appearance (proteins and other molecules on their surface) may look unchanged, even though profound changes may be happening on the inside. In this way, these abnormal cells manage to escape attack by the immune system and grow and multiply without triggering an immune response. This is how it's possible for a tumor to form, even when your immune system is working normally. Eventually, however, the tumor becomes so altered and threatening that it can no longer hide its malignant character. The immune system is no longer fooled into recognizing these cells as normal, and launches its attack. The attack may succeed, or it may come too late: the tumor may be beyond the power of the immune system by itself. The immune system may need helpbold measures such as:

immune growth factorsmedicines that stimulate the production of new immune cells; antibody medicationsspecial antibodies made in a laboratory, designed to target a specific antigen on a cancer cell; vaccinesagents that stimulate your immune system to fight back, giving it a wake-up call to action; and non-immune-system intervention, such as:
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surgical removal of the harmful growth; chemotherapy; and radiation.