RAS refers to a group of genes (KRAS, NRAS, HRAS) that act like on/off switches for cell growth. They are very important in making sure that the cells in our body grow in a controlled way.
If an alteration – also called a variant - occurs in one of the RAS genes, the control system becomes faulty, and the switch gets stuck in the ‘on’ position. When this happens, cells keep growing uncontrollably – a process that causes cancer.
Our bodies are made up of trillions of cells. Almost every cell has a nucleus containing a complete set of our genetic material - our DNA.
DNA is tightly wound into structures called chromosomes, which are stored in the nucleus of nearly every cell. Genes are short sections of DNA. Genes tell the body how to grow, work, and react to its surroundings. Genes do this by giving instructions to make proteins. Proteins are the molecules that do the work in cells.
Our cells have a lifespan – they get old and die off. Some cells last only a few hours or days, yet others last for months or years or even a lifetime.
Cells are constantly being renewed, and to do this they divide and replicate to grow more cells. Each time a cell divides, it copies its DNA and sometimes, small copying mistakes can occur. These alterations are known as variants.
Most variants are harmless, and some are repaired automatically by our cells but as we age our DNA repair mechanisms weaken. This means that some abnormal cells survive and multiply.
When DNA is damaged, it can change the instructions. Cancer forms when accumulated DNA damage disables the mechanisms that normally control cell growth, repair and death, allowing cells to grow and spread uncontrollably.
Hormones called growth factors circulate in your body and stimulate your cells to grow. These growth factors do this by attaching (binding) to receptors on the surface of the cells.
Receptors receive these chemical signals and transmit them to the nucleus at the centre of the cell, telling the cell to make more copies of itself. It does this through a signalling pathway. A signalling pathway is a type of chemical chain reaction that allows the inside of a cell to react to things happening on the outside of the cell. The pathway relays growth signals from the receptor on the outside of the cell to the cell's nucleus, telling the cell to copy itself and make new cells.
Each RAS gene makes a RAS protein—a small molecule that sits just inside the cell’s outer surface which relays messages along a signalling pathway.
Normally, the RAS genes turn on briefly when stimulated then switches off again.
When the RAS genes develop some variants, a faulty protein is made which keeps the signalling molecule stuck in the “on” position, sending continuous ‘grow’ signals to the cell. Cells keep dividing and multiplying creating a tumour.
RAS testing It is not a general screening test. It is ordered when doctors are managing specific cancers, where having a RAS variant will help decide on the best treatment or provide information that will help assess how a cancer will behave.
RAS testing is predominantly used when managing colorectal (bowel) cancer and non-small cell lung cancer (NSCLC). More rarely, it is used as a supporting test in melanoma. The two main types of RAS genes that are tested are:
Almost all RAS alterations are termed somatic. This means they occur during the normal course of life. They are not inherited - you were not born with them, and you cannot pass them on to your children. They occur in only the abnormal tumour cells.
Very rarely, a fault in the RAS gene is inherited - you were born with it, and it was passed to you from one of your parents. When a RAS gene variant is inherited, it affects all cells rather than just the tumour cells, and it can cause a group of conditions known as RASopathies. These are present from birth and can affect many parts of the body, including the heart, growth and development. RASopathies include conditions such as Noonan syndrome and it is thought, may be associated with the development of some types of cancer.
Sample
RAS gene testing is typically carried out on a sample of tumour tissue to analyse cancer cells.
Any preparation?
No
KRAS and NRAS testing in bowel (colorectal) cancer
RAS testing plays a critical role in guiding treatment targeted to the specific genetic underpinnings of the tumour. If you have bowel cancer which has spread to other parts of the body, a type of treatment called anti-EGFR therapy is usually very effective.
These are drugs that target the cancer cells to stop them growing. However, they do not work well if your bowel cancer has a variant in one of the RAS genes (KRAS or NRAS). Testing is used to see whether you will or will not benefit from these anti-EGFR drugs.
Anti-EGFR drugs are used in bowel cancer because many of these tumours depend on the EGFR signalling pathway to grow and survive.
Growth factors are proteins that act like messages telling cells to grow. Cells receive these messages through receptors on their surface.
EGFR is one of these receptors. It sits on the outside of many cells. EGFR stands for Epidermal Growth Factor Receptor.
Epidermal growth factor receptors on the surface of cells receive signals and transmit them to the nucleus at the centre of the cell, stimulating the cell to grow and make more copies of itself.
KRAS, NRAS and another gene called BRAF are part of the same signalling pathway:
Anti-EGFR drugs work by binding to EGFR on the surface of tumour cells and blocking the signals that tell the cells to grow and divide. However, if a RAS or BRAF gene is mutated and permanently switched on, it can keep sending growth signals without needing EGFR to trigger them. This means the cancer cells can continue to grow despite anti-EGFR treatment.
It is important to note that currently, targeted treatments are available for only a small number of RAS gene variants. Sotorasib is one of these, designed specifically for cancers with the KRAS G12C variant. This variant only occurs in a small percentage of RAS alterations. It is seen mainly in non-small cell lung cancer (NSCLC) and less commonly in colorectal cancer.
Most KRAS and NRAS variants do not have targeted therapies.
A RAS gene variant can affect your prognosis – the assessment of how the cancer is likely to behave over time. RAS testing it gives your medical team a fuller picture to help plan your care.
If your cancer has a RAS variation (KRAS or NRAS), the treatment approach shifts away from anti-EGFR drugs and focuses on other more effective options. Testing is Medicare-funded when it is used to guide treatment decisions.
Lung cancer (non-small cell lung cancer, NSCLC)
RAS testing in lung cancer is used differently than in bowel cancer. Here, it is not about excluding a therapy like anti-EGFR drugs but about identifying the gene variant so that specific treatment can be used.
Everyone newly diagnosed with non-small cell lung cancer (NSCLC) which includes adenocarcinoma and SCC, will have a KRAS test. Testing focuses on KRAS to see if you can benefit from KRAS-specific therapy. KRAS testing can also be done with advanced disease.
KRAS is not a stand-alone test but is part of a broader multi-gene testing pane that includes, at a minimum, EGFR, BRAF, KRAS, and MET exon 14 and fusion status of ALK, ROS1, RET, NTRK1, NTRK2, and NTRK3. This is because treatment choice is based on which of the gene variations is present.
Testing can show which KRAS variant is present. If you have NSCLC, and test positive for the KRAS G12C variant, you could benefit from a drug that stops cancer growth by binding to KRAS G12C, locking it in the ‘off’ position.
Knowing your KRAS variant status gives your specialist important information about your prognosis. KRAS variants can be associated with a more aggressive cancer. However, some KRAS variations are linked with a better response to immunotherapy, which is another reason why identifying the exact subtype is important.
Testing is Medicare-funded when it is part of a lung cancer panel.
Melanoma
NRAS variants occur in some melanomas, and NRAS testing is occasionally used in managing advanced metastatic melanoma. Some treatments are available for NRAS positive melanomas.
NRAS is usually performed as part of a broader genetic panel that includes BRAF. In melanoma, RAS testing is not routinely Medicare funded and BRAF remains the key funded test.
What may be on your report
A positive test result means a genetic variant has been identified in the genes tested. The variants identified may be called oncogenic or disease-causing variants. Variant is another name for mutation. The variants of strong or potential clinical significance are highlighted, and the results will help your doctors select the most appropriate treatment for the variants identified.
Genetic testing reports are highly complex. They typically present the most important and relevant information first followed by supplementary information.