Summary

• An ALK gene rearrangement test is mainly performed when someone has non-small cell lung cancer (NSCLC), especially if they have a type called adenocarcinoma which is the most common form of lung cancer.
• Unlike most lung cancers, which are strongly linked to smoking, ALK-positive lung cancer has a different pattern. ALK-positive cancers are often diagnosed in people who are considered at low risk – nonsmokers, women and people of Asian descent.
• If you have an ALK gene rearrangement you may benefit from an ALK-targeted treatment.
• An ALK gene rearrangement test can also be used if you are having ALK-targeted treatment to check for drug resistance.

What is an ALK gene rearrangement?

ALK stands for the anaplastic lymphoma receptor tyrosine kinase gene. It is a gene that acts like an on/off switches for cell growth. It very important in making sure that the cells in our body grow in a controlled way.

An ALK gene rearrangement is a specific genetic change that can occur during the normal course of life. If this happens the control system becomes faulty and the switch gets stuck in the ‘on’ position, cells keep growing uncontrollably – a process that causes cancer.

Genetic mutations and 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.

Inside the nucleus are structures called chromosomes. Tightly packaged up inside chromosomes is our DNA. 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 actually do the work in cells. Genes give the instructions and proteins are the building materials made from those instructions. About two per cent of our DNA carries the instructions to make all the proteins our body needs to function. About two per cent of our DNA carries the instructions to make all the proteins our body needs to function, while the remaining DNA helps control how our genes work.

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. The cells in our bodies continuously divide to grow. Each time a cell divides, it copies its DNA and sometimes, small copying mistakes can occur, called mutations.

Most mutations are harmless, and some are repaired automatically by our cells. Normally, our immune system gets rid of these mutated or altered cells but as we age our DNA repair mechanisms weaken and our immune system becomes less good at this. This means that some abnormal cells survive and multiply.

When DNA is damaged, it can change the instructions. Some mutations allow a cell to make too many copies of itself while others stop it from dying and yet others stop repairs from being made.

Cancer forms when accumulated DNA damage disables the mechanisms that normally control cell growth, repair and death, allowing cells to grow and spread uncontrollably.

These changes occur only in the affected group of cells, which is why cancer can often be cured when detected early and removed before it spreads.

Cancer that spreads - metastatic cancer

All cancers begin in a single organ or tissue but over time, cancer cells can break off and travel to other parts of the body. Many of these cancer cells will die, but some will settle in a new location and begin to form new cancers. When cancer spreads in this way, it is called metastasis.

Cancer cells that travel do not change. Breast cancer cells that move to the liver remain breast cancer cells. Doctors will treat metastatic cancer based on the type of cancer cells, not the location of the metastatic tumour.

What happens in an ALK gene rearrangement?

An ALK gene rearrangement usually happens during cell division, when DNA strands break and are incorrectly rejoined.

The ALK gene latches on to (fuses with) another gene by mistake. This is usually a gene called EML4. There are different types of EML4-ALK fusions depending on exactly where ALK is fused with the gene. The fusion of these two genes results in a faulty protein being made called the EML4-ALK fusion protein. Less commonly, the ALK gene can fuse together with other genes such as TFG or KIF5B.

The other gene’s promoter (on switch) is often very active. It becomes attached to the active part of the ALK gene. The ALK gene is now controlled by the wrong switch. That switch keeps telling it to stay on all the time. This causes uncontrolled growth of cells which results in a tumour being formed.

ALK gene rearrangements cause a type of lung cancer called non-small cell lung cancer (NSCLC).

The ALK gene sits in a region of chromosome 2. For more on chromosomes see Chromosome studies (karyotyping). The rearrangement causes what is called an inversion on chromosome 2.

Most cancer is caused by somatic mutations

ALK mutations are termed somatic. This means they occur during life. They are not inherited - you were not born with them, and you cannot pass them on to your children. Only abnormal tumour cells carry the cancer-causing DNA mutations.

Why get tested?

ALK gene rearrangement testing may be offered if you have a cancer that can be caused by an ALK mutation, such as NSCLC. Not all cancers are likely to have an ALK mutation. ALK testing is performed on a sample of your tumour to see if you have an ALK mutation and will benefit from a targeted therapy.

If you have a positive result, you will be able to be treated with a drug that is designed to target cancer specifically caused by ALK mutations. If you do not have an ALK mutation, you will be treated with a different type of drug.

Knowing exactly where in the gene and what type of rearrangement is there will help decide which targeted therapy will be most effective and your treatment options

There are several targeted therapies in use in Australia for NSCLC. The specific therapy depends on the type of ALK mutation and whether the cancer is early-stage or metastatic. The choice of therapy also often depends on a person’s overall health, and the potential for serious complications.

The targeted therapies used for the ALK gene rearrangement are called tyrosine kinase inhibitors (TKIs). This treatment works by blocking the ALK signal telling the cell to grow. They act on the signalling pathways inside the cell.

ALK and EGFR

EGFR is another type of gene mutation that causes cancer. EGFR stands for Epidermal Growth Factor Receptor. It works in a similar way in managing cell growth. ALK and EGFR are different genes, but both can drive cancer by permanently switching on growth signals.

Tumours almost never have both EGFR and ALK mutations at the same time – so they almost never occur together in a cancer. Usually, you will be tested for EGFR first. If EGFR mutation testing is negative, then a test for ALK gene rearrangement is performed.

Treatment resistance
Even though EGFR and ALK inhibitors can work very well at first, many people eventually develop drug resistance. This means the cancer finds a way around the blockade. Cancer cells can develop resistance, so repeat testing may be necessary if the treatment stops working.

Your doctor may repeat the ALK rearrangement testing on a blood sample to check for cancer’s resistance to ALK targeted treatment. The tumour leaves DNA fragments in the blood stream which can be collected and tested.

ALK gene rearrangements can also cause other types of cancers

ALK gene arrangement can lead to various cancers such as anaplastic large cell lymphoma (ALCL), neuroblastoma and inflammatory myofibroblastic tumours (IMT). These are treated with a range of different therapies.

However, having ALK-positive NSCLC does not increase your risk of developing other, unrelated cancers in the way that some inherited cancer syndromes do.

Having the test

Sample
Most ALK testing involves taking a sample of tumour tissue using a fine needle aspiration, needle biopsy or surgical biopsy. When used to monitor treatment a blood sample is used.

Any preparation?
None.

Your results

Two types of tests
There are two main ways to test ALK gene rearrangement in cancer tissue. These are IHC and FISH. IHC measures the amount of ALK protein present. FISH looks for the ALK gene rearrangement.

The way your results are shown on your report will depend on which type of test has been used.

IHC test
IHC stands for immunohistochemistry. A sample of your tissue is dissected and stained so that the cells can be seen under a microscope. In this way, a pathologist can see how much ALK protein is present.

FISH test
FISH stands for fluorescence in situ hybridisation. This test detects the actual ALK gene rearrangement in your tissue sample.

What may be on your report

A positive test result means a genetic mutation has been identified in the genes tested. The mutations identified may be called pathogenic 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 mutations identified.

Genetic testing reports are highly complex. They typically present the most important and relevant information first followed by supplementary information.

Questions to ask your doctor

The choice of tests your doctor makes will be based on your medical history and symptoms. It is important that you tell them everything you think might help.

You play a central role in making sure your test results are accurate. Do everything you can to make sure the information you provide is correct and follow instructions closely.

Talk to your doctor about any medications you are taking. Find out if you need to fast or stop any particular foods or supplements. These may affect your results. Ask:

• Why does this test need to be done?
• Do I need to prepare (such as fast or avoid medications) for the sample collection?
• Will an abnormal result mean I need further tests?
• How could it change the course of my care?
• What will happen next, after the test?

More information

Pathology and diagnostic imaging reports can be added to your My Health Record. You and your healthcare provider can now access your results whenever and wherever needed.
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