p53

p53 is a protein made by a gene called TP53, which plays a critical role in protecting the body from cancer. Because of this, p53 is known as a tumor suppressor. The TP53 gene is located on chromosome 17 and provides instructions for making the p53 protein, which works like a quality control inspector inside cells. Its job is to stop damaged cells from dividing and to help repair them—or, if the damage is too severe, to trigger cell death. This process helps prevent abnormal cells from turning into cancer.

What does p53 do?

p53 acts as a guardian of the cell’s genetic material. When a cell’s DNA becomes damaged, p53 steps in to either stop the cell from dividing or to initiate repair. If the damage cannot be fixed, p53 tells the cell to self-destruct, preventing it from becoming cancerous. p53 works by controlling other proteins and pathways that regulate the cell cycle, DNA repair, and programmed cell death (apoptosis). Under normal conditions, p53 is kept at very low levels in cells, but when DNA damage or stress occurs, its levels rise quickly.

Where is p53 normally found or active?

In healthy tissues, p53 is found in the nucleus of the cell, where it monitors DNA integrity. Most normal cells show low and scattered nuclear staining for p53 when tested with immunohistochemistry. This pattern is considered “wildtype,” or normal. In contrast, mutations in the TP53 gene may cause the p53 protein to build up abnormally or be completely lost in tumor cells—patterns that can be detected in pathology tests.

Why is p53 important in disease?

Mutations in the TP53 gene are among the most common genetic changes found in human cancers. When p53 is mutated, it often loses its ability to stop cell division or trigger cell death, allowing abnormal cells to grow unchecked. These mutations are common in many cancers, including:

• High-grade serous ovarian carcinoma.

• Endometrial carcinoma.

• Pancreatic, stomach, and colorectal cancers.

• Bladder cancer.

• Urothelial carcinoma in situ.

• Brain tumors (glioma, medulloblastoma).

• Certain types of breast cancer.

• HPV-independent vulvar cancer.

People with inherited mutations in the TP53 gene have a condition called Li-Fraumeni syndrome, which greatly increases their risk of developing multiple types of cancer, often at a young age.

How do pathologists test for p53?

Pathologists use immunohistochemistry (IHC) to test for p53 in tissue samples. The test uses special antibodies that bind to the p53 protein, allowing pathologists to see how it appears under the microscope. The staining pattern helps pathologists understand whether the TP53 gene is normal or mutated:

• Wildtype (normal): p53 is present in scattered cells with mild to moderate nuclear staining.

• Mutated (aberrant): p53 is either:

  • Strong and diffuse in almost all tumor cells (suggesting a mutation that stabilizes the protein), or

  • Completely absent (suggesting a mutation that stops the protein from being made).

These abnormal patterns are often used as a surrogate marker for TP53 mutations, which can have important implications for diagnosis, classification, and prognosis.

What types of tumours express abnormal p53?

p53 testing is useful in many types of cancer to help determine how aggressive the tumor might be and whether specific genetic mutations are present. Abnormal p53 expression is commonly seen in:

• High-grade intraepithelial neoplasia and carcinoma of the esophagus, stomach, colon, pancreas, and bladder.

• High-grade serous carcinomas of the ovary and endometrium.

• Urothelial carcinoma in situ.

• Pancreatic adenocarcinoma.

• Gliomas and medulloblastomas.

• Subtypes of endometrial and vulvar carcinoma not linked to HPV.

p53 is also used to help distinguish high-grade lesions from low-grade ones in organs such as the gastrointestinal tract and urinary bladder. In these settings, abnormal p53 expression suggests that a tumour is more likely to behave aggressively.

Why is p53 important in a pathology report?

p53 is important because it provides valuable information about the behavior and aggressiveness of a tumor. For example:

• In ovarian and endometrial cancers, abnormal p53 expression is linked to more aggressive disease.

• In bladder and esophageal tissue, p53 helps distinguish between high-grade precancerous changes and reactive or benign ones.

• In brain tumors, p53 mutations help identify subtypes and predict prognosis.

• In Li-Fraumeni syndrome, detecting a p53 mutation may lead to genetic counseling and cancer screening for affected families.

Overall, p53 testing helps pathologists accurately classify tumours, estimate how aggressive they might be, and support treatment planning.

Questions to ask your doctor

• What does the p53 result in my pathology report mean?

• Does the p53 result suggest that my tumour is more or less aggressive?

• Could my p53 result indicate a genetic condition like Li-Fraumeni syndrome?

• Will the p53 result affect my treatment plan or follow-up?

• Are additional tests, such as genetic testing for TP53 mutations, recommended?