H3K27me3: Definition

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H3K27me3 is a chemical tag found on histones, the proteins that DNA wraps around inside the nucleus of every cell. The tag helps keep certain genes switched off. Pathologists test for H3K27me3 to help diagnose some tumors of the nerves, brain, and spinal cord. In these tumors, the tag is often missing, and pathologists call this “loss” of H3K27me3.

H3K27me3 is a test result, not a diagnosis. It is one of the stains a pathologist uses to work out what type of tumor is present and, in some cases, how it is likely to behave. This article explains what H3K27me3 is, why pathologists test for it, and what a “retained” or “lost” result means in your pathology report.

What is H3K27me3?

The DNA inside each cell is very long. To fit inside the nucleus, it is wound around small proteins called histones. Cells attach small chemical tags to histones to control which genes are switched on and which are switched off. These changes, which affect how genes are used without changing the genes themselves, are called epigenetic changes.

The name H3K27me3 describes one of these tags. “H3” is a type of histone called histone 3. “K27” is a particular building block on that histone, at position 27. “me3” means three small chemical groups, called methyl groups, are attached at that spot. When this tag is present, nearby genes are kept switched off.

A group of proteins called PRC2 adds the H3K27me3 tag. In some tumors, a gene change disables PRC2 or blocks it from working. The tag is then lost, and genes that should stay off are switched on. This can help a tumor grow.

How do pathologists test for H3K27me3?

Pathologists test for H3K27me3 using immunohistochemistry (IHC). In this test, a thin slice of tissue on a glass slide is treated with an antibody that sticks to the H3K27me3 tag. A chemical reaction then colors the nucleus of any cell containing the tag brown so that it can be seen under the microscope.

Almost all normal cells contain H3K27me3. Normal cells in the same sample, such as the endothelial cells lining blood vessels and immune cells, therefore stain brown. These cells act as a built-in check that the test worked properly.

Why do pathologists test for H3K27me3?

Loss of H3K27me3 is seen in a small number of specific tumors. Pathologists test for it in the following situations:

Malignant peripheral nerve sheath tumor. Many malignant peripheral nerve sheath tumors (MPNST), a type of sarcoma that starts from the cells around nerves, show loss of H3K27me3. Loss is less common in MPNSTs that develop in people with neurofibromatosis type 1. Noncancerous nerve tumors, such as neurofibroma and schwannoma, keep the tag. This helps the pathologist separate a cancer from a noncancerous nerve tumor.
Diffuse midline glioma. Diffuse midline glioma, H3 K27-altered, is a brain tumor that usually develops in the brainstem, thalamus, or spinal cord. The tumor cells show loss of H3K27me3. This loss is caused by a change in a histone gene or in a related protein, and it is part of how this tumor is defined.
Posterior fossa ependymoma. Posterior fossa ependymomas are divided into two groups. Group A tumors, which usually occur in young children, show loss of H3K27me3. Group B tumors keep the tag. Group A tumors tend to have a less favorable outcome than Group B tumors.
Meningioma. In a meningioma, loss of H3K27me3 has been linked to a higher chance of the tumor coming back after surgery, especially in grade 2 tumors. It is not used to assign the grade in the World Health Organization classification of brain tumors published in 2021, but some reports include it as additional information.

What does a retained H3K27me3 result mean?

A retained result means the tumor cells still contain the H3K27me3 tag. Your report may describe the result as “retained,” “intact,” or “positive.” This is the normal pattern, and it is seen in most tumors.

The meaning depends on the question. For example, in a nerve sheath tumor, a retained result is expected in a neurofibroma or schwannoma, but it does not rule out an MPNST. In a posterior fossa ependymoma, a retained result supports group B.

What does a loss of H3K27me3 result mean?

A loss result means the tumor cells no longer contain the H3K27me3 tag, while normal cells in the same sample still do. Your report may describe the result as “lost,” “loss of expression,” “deficient,” or “negative.” Some reports describe the loss as “complete” or “partial.” Complete loss in all tumor cells is the most reliable result.

In a nerve sheath tumor, complete loss supports a diagnosis of MPNST. In a brain tumor, loss supports a diagnosis of diffuse midline glioma or a group A posterior fossa ependymoma, depending on where the tumor is and how it looks. In a meningioma, loss suggests a higher chance that the tumor will come back. In every case, the pathologist interprets the result together with the tumor’s appearance and other test results.

Questions to ask your doctor

Why was H3K27me3 tested on my tumor?
Did my tumor retain or lose H3K27me3?
Was the loss complete or partial?
What other stains or molecular tests were done along with H3K27me3?
Does the H3K27me3 result change my diagnosis?
Does the H3K27me3 result affect the chance that my tumor will come back?
Does the result change my treatment or follow-up plan?