Genetic changes and cancer risk

Cancers are caused by a change in, or damage to, one or more genes. Most changes in a gene are because of a gene mutation. Mutations can stop genes from working properly. Genes that have mutations that are linked to cancer are sometimes called cancer genes.

Gene mutations happen when:

• We are born with a mutated gene that is either inherited from a parent or that develops in an embryo.
• We are exposed to something around us that damages our genes, like cigarette smoke.
• Genes wear out as we get older.

It takes more than one gene mutation for a cell to become cancerous. Researchers have been able to link some types of cancer to certain gene mutations. But there are also cancers where we don’t know which gene mutations cause them. Researchers are also trying to find out if gene mutations that are already linked to some types of cancer may also cause other types to develop.

There are 3 main types of cancer genes that control cell growth and can cause cancer to develop.

Oncogenes are mutated genes that cause cells to grow out of control and can lead to cancer. Proto-oncogenes are normal genes that control cell growth but if they become mutated they can turn into oncogenes. Proto-oncogenes and oncogenes act like on/off switches. A proto-oncogene is usually switched off. When a proto-oncogene is switched on, it is telling a cell to grow or divide. But oncogenes are always switched on – so its cells grow out of control.

Tumour suppressor genes are normal genes that slow cell growth and division, repair mistakes in DNA and tell cells when to die (a normal process called apoptosis or programmed cell death). They help protect us against cancer. Tumour suppressor genes are working properly when they are switched on. They prevent cells from dividing too quickly. But when these genes are mutated, they are turned off. This causes cells to grow out of control which can lead to cancer.

DNA repair genes fix mistakes in other genes that can happen when DNA is copied. When DNA repair genes are mutated, they can’t fix mistakes in oncogenes and tumour suppressor genes, and this can lead to cancer.

Scientists have learned a great deal about how changes in our genes can affect our health and increase the risk of cancer. They have linked the following genetic changes to cancer.

The BRCA genes are tumour suppressor genes that normally help to prevent cancer. They control cell growth and division and help repair damage to DNA. But mutated BRCA genes can increase the risk of developing certain types of cancer. There are 2 BRCA gene mutations that are known to cause cancer – BRCA1 and BRCA2. These gene mutations increase the risk of a woman developing breast cancer and ovarian cancer. BRCA2 gene mutations are also linked to a higher risk of male breast cancer and prostate cancer. BRCA2 gene mutations also give both men and women a slightly higher risk of developing pancreatic cancer.

TP53 is a tumour suppressor gene that controls cell growth and division. TP53 also sends signals to other genes to help repair damaged DNA. If the DNA damage can’t be repaired, TP53 prevents the cell from dividing and tells the cell to die. When the TP53 gene is mutated, it causes cells with damaged DNA to grow and divide out of control. TP53 gene mutations are common and happen in more than 50% of all cancers.

MLH1, MSH2, MSH6 and PMS2 are DNA mismatch repair (MMR) genes that prevent errors in DNA when it is copied as cells divide. Researchers have found mutations in these genes in people with Lynch syndrome. Mutations in an MMR gene increase a person’s risk of developing colorectal and uterine (endometrial) cancers. These mutations also slightly increase the risk of stomach, kidney, bladder and ovarian cancers.

Adenomatous polyposis coli (APC) is a tumour suppressor gene that controls cell growth. Researchers have found mutations in this gene in people with familial adenomatous polyposis (FAP). APC mutations increase a person’s risk of developing colorectal, small intestine and pancreatic cancers.

The HER2 gene is also known as the ERBB2 gene or HER2/neu gene. HER2 stands for human epidermal growth factor receptor 2. HER2 is an oncogene and protein on the surface of cells that causes a cell to grow. When a cancer has extra HER2 protein, it’s called HER2 overexpression or a HER2-positive cancer. Some types of cancer have a mutated HER2 gene that makes extra HER2 proteins and causes the cancer to grow.

Some breast, esophageal and stomach cancers are HER2-positive. These cancers can be treated with trastuzumab (Herceptin). Trastuzumab is a targeted therapy drug that attaches to the extra HER2 proteins and helps to stop the cancer from growing. Researchers are also trying to find out how well trastuzumab works to treat other cancers that are HER2-positive. Find out more about HER2.

The BCR-ABL fusion gene (also called the Philadelphia chromosome) is formed when pieces of chromosomes 9 and 22 break off and trade places. This gene makes an enzyme called a tyrosine kinase that causes blood cells in the bone marrow to grow abnormally. This can lead to chronic myelogenous leukemia (CML). Testing for this gene may help doctors diagnose some types of leukemia. About 95% of people with CML and about 25% of adults with acute lymphocytic leukemia (ALL) have the BCR-ABL fusion gene.

People with certain types of leukemia who test positive for the BCR-ABL fusion gene may benefit from targeted therapy. Imatinib (Gleevec), dasatinib (Sprycel) and nilotinib (Tasigna) are tyrosine kinase inhibitors that target the enzyme made by the BCR-ABL gene.

Some people with colorectal cancer have a KRAS gene mutation. Doctors test for a KRAS gene mutation so they know which patients with metastatic colorectal cancer will benefit from treatment with the targeted therapy drugs cetuximab (Erbitux) and panitumumab (Vectibix). These drugs are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) on cancer cells. The EGFR sends signals that promote the growth and survival of cancer cells. Cetuximab and panitumumab block these receptors, which cuts off the signal pathway and causes the cells to die. Cetuximab and panitumumab don’t work in people who have KRAS gene mutations. So only people who test negative for KRAS gene mutations may benefit from cetuximab or panitumumab.

Some people with non–small cell lung cancer have epidermal growth factor receptor (EGFR) gene mutations. Testing for an EGFR gene mutation can identify which people with non–small cell lung cancer would likely benefit from treatment with certain tyrosine kinase inhibitors (TKIs). TKIs block proteins called tyrosine kinases. These proteins are part of the signalling process within cells that happens after a growth factor binds to its receptor. When this process is blocked, the cell stops growing and dividing. Gefitinib (Iressa) and erlotinib (Tarceva) are TKIs that target EGFR.

The anaplastic lymphoma kinase (ALK) gene sends signals to proteins that make cells grow and divide. About 5% of non–small cell lung cancers (usually adenocarcinomas) have a mutation in the ALK gene. These cancers are called ALK-positive. When a cancer is ALK-positive, drugs called ALK inhibitors can be used to treat it. ALK inhibitors block the signals that tell the cancer cells to divide, so the cancer stops growing.

Only non–small cell lung cancers that test positive for the ALK gene are treated with ALK inhibitors such as crizotinib (Xalkori). Crizotinib is used to treat people who have ALK-positive advanced or metastatic non–small cell lung cancer.

About half of all melanomas have mutations in the BRAF gene. These mutations make abnormal proteins that cause melanoma cells to grow and divide. Vemurafenib (Zelboraf) targets the BRAF gene. Vemurafenib may be used to treat people with advanced or metastatic melanoma. Researchers have found that people with metastatic melanoma who take vemurafenib live longer than people who don’t take the drug.

The neurotrophic tyrosine receptor kinase (NTRK) gene tells nerve cells to make a protein that helps the cells send information about sensations like pain, temperature and touch. When a piece of the NTRK gene breaks off and joins with another gene, it is called a NTRK gene fusion. This change causes abnormal proteins called TRK fusion proteins, which may cause cancer cells to grow. NTRK gene fusions are found in some types of cancer such as thyroid, colon, lung and primary brain tumours. A new drug called larotrectinib (Vitrakvi) has been approved in Canada to treat tumours that have a NTRK gene fusion.

Genes can be mutated in a number of different ways. The simplest type of mutation is a change in the DNA that makes up the gene. DNA is made up of 4 different bases, which are arranged in a specific order. A mutation happens when a base is changed or the order of the bases is changed.

Other types of gene mutations include:

• An insertion is when an extra piece of DNA is added to a gene.
• A duplication is when part of a gene’s DNA or part of a chromosome is copied one or more times. A duplication can be large enough that a person has extra copies of a gene or part of a chromosome.
• A deletion is when a piece of DNA is removed from a gene, when an entire gene is missing or when a chromosome breaks and some genetic material is lost.
• A translocation is when a piece of one chromosome breaks off and attaches to another chromosome.
• An inversion happens when a chromosome breaks in 2 places and a piece of DNA flips upside down and reinserts back into the chromosome.

Sometimes gene mutations can also change the structure of an entire chromosome.