The current status of cell‐free human papillomavirus DNA as a biomarker in cervical cancer and other HPV‐associated tumors: A review

Abstract

Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA), allowing for analysis of tumor DNA in a simple blood test, that is, liquid biopsy. Cervical cancer is one of the most common malignancies among women worldwide and high-risk human papillomavirus (HR-HPV) is the cause of the majority of cases. HR-HPV integrates into the host genome and is often present in multiple copies per cell and should thus also be released as ctDNA. Such ctHPV DNA is therefore a possible biomarker in cervical cancer. In this review, we first give a background on ctDNA in general and then a comprehensive review of studies on ctHPV DNA in cervical cancer and pre-malignant lesions that may develop in cervical cancer. Furthermore, studies on ctHPV DNA in other HPV related malignancies (eg, head-and-neck and anogenital cancers) are briefly reviewed. We conclude that detection of ctHPV DNA in plasma from patients with cervical cancer is feasible, although optimized protocols and ultra-sensitive techniques are required for sufficient sensitivity. Results from retrospective studies in both cervical cancer and other HPV-related malignancies suggests that ctHPV DNA is a promising prognostic biomarker, for example, for detecting relapses early. This paves the way for larger, preferably prospective studies investigating the clinical value of ctHPV DNA as a biomarker in cervical cancer. However, there are conflicting results whether ctHPV DNA can be found in blood from patients with pre-malignant lesions and further studies are needed to fully elucidate this question.

Study on the efficacy and prognostic value of minimal residual disease in locally advanced cervical cancer based on plasma HPV-ctDNA protocol

“…This is a prospective, safety and feasibility trial that will include a total of 30 subjects according to the relevant study [18,19] and will not be subject to formal sample size measurement.…”

“…With the rapid development of liquid biopsy technology, HPV-ctDNA-based assessment of MRD status (hereinafter referred to as HPV/MRD) can become an ideal biomarker for the treatment and prognosis of malignant tumors. The feasibility of detecting ctHPV DNA in the plasma of cervical cancer patients has been a rmed by Prof. Sivars L's team in Gynecologic Oncology and the International Journal of Cancer [18,19], although optimized protocols and ultra-sensitive techniques are needed to obtain su cient sensitivity, ctHPV DNA is a potential prognostic biomarker for cervical cancer patients. A prospective study by Sivars et al [20] similarly concluded that follow-up plasma ctHPV DNA is a promising prognostic biomarker for LACC patients and that monitoring of plasma ctHPV DNA concentrations in patients with follow-up can help analyze their response to treatment and early detection of LACC recurrence.…”

Circular RNAs in gynecologic cancers: mechanisms and implications for chemotherapy resistance

“…Among these CC is primarily caused by persistent human papillomavirus (HPV) infection, with HPV types 16 and 18 responsible for 71% of cases worldwide ( Choi et al, 2023 ; Reich and Regauer, 2023 ). Prevention and treatment of high-risk HPV cervical infections remain the main approach in combating CC, with the introduction of CC vaccines being a major development in recent years, together with screening technologies ( Rahangdale et al, 2022 ; Rimel et al, 2022 ; Sivars et al, 2022 ; Sun et al, 2022 ; Sabeena, 2023 ). OC, as the seventh most commonly diagnosed female cancer worldwide, poses as the fifth leading cause of cancer-related deaths in women and the most lethal of all gynecological malignancies ( Chen et al, 2023 ; Ye et al, 2023 ).…”

The Clinical Utility of Circulating HPV DNA Biomarker in Oropharyngeal, Cervical, Anal, and Skin HPV-Related Cancers: A Review

“…These biomarkers could be used in early cancer detection, in the follow-up of detected diseases, and in the evaluation of responses and resistance to therapy [ 12 ]. These biomarkers have the advantage of being relatively non-invasive for patients [ 13 ].…”