ATRX

ATRX stands for alpha-thalassemia/mental retardation X-linked. The ATRX gene provides instructions for producing the ATRX protein, which plays a crucial role in the packaging and repair of DNA within our cells. This protein helps control which genes are turned on or off, supports DNA repair, and maintains the ends of chromosomes, known as telomeres.

ATRX is classified as a tumor suppressor gene, which means it normally helps prevent the development of cancer by regulating cell growth and division in a controlled manner.

What does ATRX do?

The ATRX protein has many important jobs inside the cell:

• Chromatin remodeling: DNA is packaged around proteins called histones to form a structure called chromatin. ATRX helps rearrange this structure so that genes can be turned on or off at the right time.
• DNA repair: ATRX aids in repairing broken DNA and facilitates cell recovery when DNA is damaged.
• Telomere maintenance: ATRX helps protect telomeres, the caps at the ends of chromosomes that maintain the stability of our genetic material.
• Control of gene expression: ATRX influences which genes are active or silent in different types of cells.

ATRX works closely with another protein called DAXX, and together they help place a special version of histone protein (H3.3) in specific areas of the DNA, especially in regions that are repetitive or tightly packed.

What types of normal cells express ATRX?

ATRX is found in nearly all the cells of the body. It is especially active in cells that divide rapidly or have complex DNA packaging, such as brain cells and early developing cells in embryos. In the brain, it plays a major role in normal development.

How do pathologists test for ATRX?

Pathologists usually test for ATRX using a method called immunohistochemistry. This test uses special antibodies that attach to the ATRX protein in a tissue sample. When viewed under a microscope, cells with normal ATRX expression will exhibit dark brown staining in the nucleus. This is referred to as a positive result, indicating that the ATRX protein is present.

If the ATRX protein is missing due to a mutation in the ATRX gene, there will be no staining in the tumor cell nucleus. This is referred to as a negative result, suggesting that a mutation or other alteration is affecting the ATRX gene. Importantly, pathologists will look for positive staining in surrounding normal (non-tumor) cells as a built-in control to ensure the test worked properly.

In some cases, particularly for inherited conditions or research studies, a genetic test may be used to directly examine the DNA sequence of the ATRX gene. This is often done using next-generation sequencing (NGS), which reads the gene’s code and can detect mutations, deletions, or other changes.

What types of tumors show changes in ATRX?

ATRX is commonly altered in several types of tumors. These changes are usually the result of a mutation that causes the loss of ATRX protein in tumor cells.

• Gliomas – Many adult and pediatric high-grade gliomas (tumors in the brain and spinal cord) show loss of ATRX expression. This is especially common in astrocytomas and other gliomas with mutations in the IDH gene.
• Pancreatic neuroendocrine tumors – Loss of ATRX is seen in some pancreatic neuroendocrine tumors and is associated with chromosomal instability and worse survival outcomes.
• Uterine smooth muscle tumors – ATRX loss has been identified in certain types of leiomyosarcomas, a rare cancer of the uterus.
• Acquired alpha-thalassemia myelodysplastic syndrome (ATMDS) – This is a rare condition that develops in people with myelodysplastic syndromes (a group of bone marrow disorders). In ATMDS, somatic mutations in ATRX can lead to the development of alpha-thalassemia, a blood disorder affecting hemoglobin production.
• Pheochromocytoma and paraganglioma – Loss of ATRX is seen in some of these rare tumors, which arise from cells of the adrenal gland or nearby nerves.
• Other cancers – ATRX mutations have also been reported in a small number of tumors in the lung, prostate, pancreas, and sarcomas. The significance of ATRX loss in these tumors remains to be studied.

Why is ATRX important in a pathology report?

Pathologists use loss of ATRX expression to help diagnose and classify certain tumors, particularly brain tumors such as astrocytomas and glioblastomas. If ATRX is absent in a tumor, this may suggest the presence of a genetic mutation in the ATRX gene.

In gliomas, loss of ATRX is often combined with other test results, such as IDH mutation status and 1p/19q codeletion, to help confirm the tumor type and guide treatment decisions.

In neuroblastoma and pancreatic neuroendocrine tumors, ATRX mutations may influence prognosis and open the door to targeted therapies that exploit the cancer cells’ impaired ability to repair DNA.

Questions to ask your doctor

• Was ATRX tested in my tumor?
• What do the results of the ATRX test mean for my diagnosis or treatment?
• Does the presence or absence of ATRX affect my prognosis?
• Could ATRX testing suggest a genetic condition in my family?
• Should I or my family members consider genetic counseling or further testing?