Liquid Biopsy of Circulating Tumor HPV DNA

Reading time: 4 minutes

Sabarish Srinivasan

Introduction to Human Papillomavirus

Human papillomavirus (HPV) is a small, circular double-stranded DNA virus, of which there are several strains. HPV infection is the most common sexually transmitted infection (STI) in the US. Unfortunately, this infection is difficult to identify, as it is asymptomatic in the majority of cases, and, if symptoms do manifest, the only prevalent symptom is genital warts.

The role of HPV has been well-documented by the scientific community. Fortunately, in around 90% of HPV cases, the body naturally eliminates the virus, and there are no lasting effects. However, there are around 200 strains of HPV, and 14 are considered to be high-risk. A significant risk of cervical, vaginal, penile, anal, and oropharyngeal cancer is linked with these 14 forms of HPV.

The HPV genome contains the E6 and E7 oncogenes, which inactivate tumor suppressor proteins by binding to them. Expression of E6 inactivates the p53 protein while expression of E7 inactivates the retinoblastoma protein (Rb). This degradation leads to a loss of cell cycle regulation, cellular proliferation, and chromosomal instability, resulting in HPV-associated (+) cancer.

Screening of HPV-associated Cancer

HPV+ cancers encompass 4.5% of all cancers globally, and the two most prevalent types are HPV+ cervical cancer and HPV+ oropharyngeal squamous cell carcinoma.

HPV+ cervical cancer is well-known and preventable due to available screening protocols, namely the Papanicolaou, or Pap, smear. 

Unlike cervical cancer, however, there are no generally approved screening tests for other HPV+ cancers, demonstrating a substantial public health concern. Recently, HPV+ oropharyngeal cancer has surpassed HPV+ cervical cancer, becoming the #1 HPV+ cancer in the US in terms of incidence. 

Even though forms of HPV+ cancer are widespread in the US, there are no effective options for screening most subtypes, with the exception of HPV+ cervical cancer. This predicament raises a crucial question. If there is no way of screening patients, how can physicians monitor the disease and identify any recurrence of the malignancy? Moreover, how can they catch cancer at an earlier stage for a better prognosis?

The Role of Liquid Biopsy

Liquid biopsy, a breakthrough in precision medicine, could be the solution. A liquid biopsy is an inexpensive test on patient blood samples that eliminates the need for tumor tissue biopsy to obtain information about malignancy. As Sara and Beth discussed in previous articles, a simple blood test opens up a wide range of possibilities. 

Fundamentally, liquid biopsy allows researchers to identify cancer cells in the blood that die from natural causes or treatment. In past studies conducted with multiple cancers, it has been observed that the cancer cells in a tumor release fragments of DNA into the bloodstream. This freely circulating tumor DNA found in the blood is called ctDNA and can be detected in liquid biopsy samples.

In HPV+ cancer, the circulating tumor HPV DNA (ctHPVDNA) can be isolated and quantified using polymerase chain reaction (PCR) methods to determine the concentration of ctHPVDNA in the patient’s blood. This quantification then provides physicians with valuable information about disease progression and recurrence because the ctHPVDNA level is connected with these factors.

Recent Advances

In recent years, cancer researchers have directed their attention towards HPV+ cancer, and incredible advances have been made in this field. For instance, Naveris, an emerging company in the field of early cancer detection, seeks to implement liquid biopsy to improve patient outcomes in HPV+ cancer. Their highly sensitive technology, NavDx™, enables examination of ctHPVDNA in blood plasma and is remarkably effective in early screening of patients and their surveillance after chemoradiotherapy.

An especially exciting new prospect is the concept of treatment modification in which the quantity of ctHPVDNA in a patient’s blood can be applied to alter therapy, reducing the toxic effects of chemoradiotherapy. Studies are being conducted to employ liquid biopsy for improving the care of HPV+ cancer patients and scoring treatment efficacy.

The use of liquid biopsy to aid in the treatment and diagnostics of patients with HPV-associated cancer ushers in a new era of precision medicine with a focus on personalized therapy. Emerging advances in this field augment the quality of life for HPV+ cancer patients and improve the outlook of this condition. Liquid biopsy in HPV+ cancer has significant potential and will likely serve as a vital tool for medical professionals and researchers in the near future.

Edited by Sara Musetti

Works Discussed

Maitra, R. (2016). Viruses and Head and Neck Cancers. Head and Neck Cancer Research, 01(01). doi: 10.21767/2572-2107.100003

Chera, B. S., Kumar, S., Beaty, B. T., Marron, D., Jefferys, S., Green, R., … Gupta, G. P. (2019). Rapid Clearance Profile of Plasma Circulating Tumor HPV Type 16 DNA during Chemoradiotherapy Correlates with Disease Control in HPV-Associated Oropharyngeal Cancer. Clinical Cancer Research, 25(15), 4682–4690. doi: 10.1158/1078-0432.ccr-19-0211

Crowley, E., Nicolantonio, F. D., Loupakis, F., & Bardelli, A. (2013). Liquid biopsy: monitoring cancer-genetics in the blood. Nature Reviews Clinical Oncology, 10(8), 472–484. doi: 10.1038/nrclinonc.2013.110

Image Credits

Images Created with BioRender

Cover Image Reprinted with permission from http://www.thewellproject.org. © 2003-2014 The Well Project, Inc. A Not For Profit Corporation. All warranties expressly disclaimed.

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