What Does HPV p16-Negative or Positive Mean? Understanding HPV mRNA E6/E7 and DNA Tests

The Cause of 5% of All Cancers

Human papillomavirus (HPV) is a common infection worldwide that can cause cancer, particularly in the cervix, head and neck, and anus. HPV has been found to account for approximately 5% of all cancers, causing around 630 thousand cancers worldwide each year.

In the early diagnosis and treatment of HPV-related cancers, p16 and E6/E7 are biomarkers of critical importance. This article explains what p16 and HPV mRNA E6/E7 mean and how HPV-related tests are used to assess cancer risk.

Important Note: The presence of mRNA E6/E7 or p16 in an HPV test does not mean someone has cancer. However, it indicates that the person has a high-risk HPV type that could cause cancer. Further testing, monitoring and treatment may be needed.

In people infected with HPV, the immune system usually clears HPV cells within 1-2 years. If it cannot clear the infection, however, high-risk HPV may cause precancerous cellular changes. Without treatment, these cells may become cancerous over time.

According to a 2022 review, high-risk HPV infection causes the following cancers:

• More than 99% of cervical cancers
• 95% of anal cancers
• 80% of head and neck cancers
• 63% of penile cancers
• 69% of vulvar cancers
• 75% of vaginal cancers

High-risk HPV types include:

High-risk HPV types have the potential to cause cancer. The most common are:

• HPV 16: The most common cause of cervical cancer.
• HPV 18: The second most common high-risk type.
• HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59: Other high-risk types that may cause cancer less frequently.

The Gardasil 9 vaccine protects against nine of these types: HPV 16, 18, 31, 33, 45, 52, 58 and the two low-risk types HPV 6 and HPV 11.

RELATED TOPIC: The HPV Vaccine Protects Against Other Cancers as Well as Cervical Cancer

What Is HPV and How Does It Cause Cancer?

HPV is a virus transmitted through the skin and mucosal surfaces. It usually spreads through sexual contact and has many types. Some are known as high-risk HPV types because they can cause cancer.

The mechanism behind HPV's cancer-causing effect begins by disrupting the function of important proteins regulating the cell cycle:

High-risk HPV types cause the host cell to produce E6 and E7, two oncoproteins. These suppress tumor suppressor proteins that prevent uncontrolled cell proliferation, such as p53 and retinoblastoma (Rb) .

In more detail:

• The E6 protein binds to p53, causing its degradation. This eliminates p53's functions in regulating cell death (apoptosis) and DNA repair.
• The E7 protein inactivates retinoblastoma (Rb), releasing control of the cell cycle and causing cells to divide uncontrollably.

What Is HPV p16? What Does Negative or Positive Mean?

p16 is a tumor suppressor protein that normally regulates the cell cycle and is produced by the CDKN2A gene. p16 controls cell division and protects against abnormal proliferation. During high-risk HPV infection, however, the E7 protein suppresses the Rb gene, causing the p16 protein to accumulate excessively in the cell. This allows p16 to be used as an indicator of cellular changes.

The p16 test measures p16 levels in a cell and is used to assess cancer development. p16 positivity indicates that HPV is active in the cell and carries a risk of causing cancer. Particularly in head and neck and cervical cancers, p16 positivity indicates the presence of an HPV-related cancer.

However, p16 positivity in the tissues of people already diagnosed with cancer is generally associated with a better treatment response and disease outcome.

• p16-Positive: This indicates that high-risk HPV is active in the cell and that cellular changes have the potential to become precancerous or cancerous. Because p16 positivity indicates a risk of cancer development, further investigations and treatment planning are required.

• p16-Negative: A negative p16 result in a cell indicates that the effects of HPV infection are not observed or that the risk of HPV-related cancer is low.

What Does HPV mRNA E6/E7 Mean?

HPV's two main cancer-causing oncoproteins are E6 and E7. These proteins cause uncontrolled cell proliferation, leading to cancer development. The HPV mRNA E6/E7 test directly detects whether HPV has initiated the production of E6 and E7 proteins in cells.

This test directly indicates the virus's cancer-causing potential. If E6 and E7 proteins are detected, HPV infection is active and cells have a high risk of becoming cancerous. The test is used particularly to detect and manage precancerous lesions.

Are p16 and HPV mRNA E6/E7 Tests Different?

Yes, p16 and E6/E7 tests are different, but both are used in diagnosing and managing HPV-related cancers.

• The p16 test is an indirect marker of HPV's cellular effects. During HPV infection, p16 protein levels increase, which is considered an indicator of cellular changes.

• The E6/E7 test directly detects whether HPV is active in the cell and whether E6 and E7 oncoproteins are being produced. It confirms HPV's potential cancer-causing effects.

Both tests help doctors better understand the cellular changes caused by HPV infection and guide treatment planning.

Which Tests Are Used?

1. p16 Test:

   • Immunohistochemistry (IHC): This examines the presence of p16 protein in tissue from a biopsy sample. A positive result indirectly indicates HPV's presence in the cell.

2. E6/E7 Test:

   • mRNA Test: This detects whether HPV is signaling cells to produce E6 and E7 oncoproteins.
   • PCR (Polymerase Chain Reaction): Used to detect HPV's genetic material and identify the HPV type causing the infection.

What Happens if p16 or E6/E7 Is Positive?

• p16-Positive: This indicates cellular changes carrying a cancer risk. Doctors may request additional biopsies to monitor the situation or investigate further. Treatment options may include surgical removal of precancerous lesions, cryoablation, laser treatment or, at more advanced stages, more aggressive procedures such as hysterectomy.

• E6/E7-Positive: This confirms that HPV is active in the cell and is exerting potentially cancer-causing effects. If the test is positive, further investigations are performed, and options such as surgery, radiotherapy or chemotherapy may be used to treat precancerous or cancerous cells.

What Is an HPV DNA Test? Is It Different From p16 and E6/E7 Tests?

The HPV DNA test does not examine p16 or E6/E7 proteins; it is something entirely different. It looks in a person's cells for HPV's genetic material (DNA) and determines which HPV type is present. It is used particularly to detect high-risk HPV types and is an important cervical cancer screening tool.

In summary:

• The HPV DNA test detects whether cells contain HPV's genetic material (DNA). It does not examine p16 or E6/E7 proteins.
• The p16 test is a biomarker test showing HPV infection's cellular effects and is usually performed using immunohistochemistry.
• The E6/E7 test detects whether HPV's potentially cancer-causing oncoproteins are being produced in the cell. It generally detects HPV mRNA and indicates precancerous cellular changes.

The HPV DNA test detects genetic material, while p16 and E6/E7 tests measure HPV's effects within the cell.

What Happens After an HPV Test?

If an HPV test detects HPV mRNA E6/E7, p16 or HPV DNA, healthcare professionals assess the person's risk of developing cervical cellular changes that could lead to cancer. Based on this assessment, the doctor may recommend:

• Repeat testing: The person may wish to have another HPV test within 1-3 years.
• Colposcopy: The doctor applies a vinegar solution to the cervix. This makes abnormal areas visible, allowing the doctor to examine them with an instrument called a colposcope.
• Cervical biopsy: The doctor takes a small tissue sample from the cervix, which is examined under a microscope for abnormal cells.

If these tests reveal high-grade cellular changes, the doctor may recommend treatment.

RELATED TOPIC: Cervical Precancers: What Are CIN1, CIN2 and CIN3? Can Progression to Cancer Be Prevented?

Types of Treatment

Treatment options for HPV-related cellular changes may include:

• Conization: Abnormal tissue is removed with a thin electrical wire loop. Sometimes it may also be removed using a scalpel in cold-knife conization.
• Cryoablation: The doctor freezes and destroys abnormal tissue using cold probes.
• Laser treatment: A laser is used to destroy or remove tissue.
• Total hysterectomy: Surgical removal of the cervix and uterus may be necessary to remove advanced precancerous cells.

When Should HPV Screening Be Performed?

The American Cancer Society recommends HPV testing every 5 years for people aged 25-65. If primary HPV testing is unavailable, combined HPV and Pap testing every 5 years or Pap testing every 3 years is recommended. People with an abnormal Pap result should also have an HPV test.

HPV generally does not cause symptoms, and a person may learn of the infection only through testing. Some HPV-related cancers can cause symptoms such as bleeding, pain and lumps. Consult a doctor if these occur in the genital area, mouth or throat.

Frequently Asked Questions

How Long Does It Take for HPV mRNA E6/E7 to Disappear?

The immune system usually clears HPV infection within 1-2 years. If it cannot clear the infection, the virus may persist, and treatment may be needed to prevent or manage precancerous or cancerous cells.

Is HPV mRNA E6/E7 Sexually Transmitted?

HPV is usually transmitted sexually. High-risk HPV types that lead to E6 and E7 protein production can also be transmitted this way.

Does Detection of HPV mRNA E6/E7 Mean Cancer?

No. Detecting HPV mRNA E6/E7 does not mean someone has cancer. However, the results indicate that the person has a high-risk HPV type that could cause cancer.

Brief Summary

Detecting HPV's cancer-causing effects early can make treatment much more successful. Regular screening and biomarker monitoring are therefore vital.

HPV p16 and HPV mRNA E6/E7 tests play a critical role in understanding HPV's cellular effects and assessing the risk of progression to cancer. p16 positivity indicates that abnormal cellular changes are HPV-related and carry a risk of cancer, while the E6/E7 test directly measures HPV's potentially cancer-causing activity. These tests help doctors diagnose HPV-related cancers early and offer appropriate treatment options.