Circulating Virus–Host Chimera DNAs in the Clinical Monitoring of Virus-Related Cancers.

Simple Summary: Cell-free tumor DNA (ctDNA), the DNA released into circulation from tumors, is a promising tumor marker with versatile applications. The associations of the amount, somatic mutation frequency, and epigenetic modifications of ctDNA with the tumor burden, tumor behavior, and prognosis have been widely investigated in different types of tumors. However, there are still some challenging issues to be resolved before ctDNA can complement or even replace current serum tumor markers. We propose employing exogenous viral DNA integration that produces unique virus–host chimera DNA (vh-DNA) at junction sites. Cell-free vh-DNA may become a new biomarker because it overcomes background interference detection problems, takes advantage of virus tropism to localize the tumor, and acts as a universal marker for monitoring clonal expansion or tumor loads in tumors related to oncogenic viruses. The idea of using tumor-specific cell-free DNA (ctDNA) as a tumor biomarker has been widely tested and validated in various types of human cancers and different clinical settings. ctDNA can reflect the presence or size of tumors in a real-time manner and can enable longitudinal monitoring with minimal invasiveness, allowing it to be applied in treatment response assessment and recurrence monitoring for cancer therapies. However, tumor detection by ctDNA remains a great challenge due to the difficulty in enriching ctDNA from a large amount of homologous non-tumor cell-free DNA (cfDNA). Only ctDNA with nonhuman sequences (or rearrangements) can be selected from the background of cfDNA from nontumor DNAs. This is possible for several virus-related cancers, such as hepatitis B virus (HBV)-related HCC or human papillomavirus (HPV)-related cervical or head and neck cancers, which frequently harbor randomly integrated viral DNA. The junction fragments of the integrations, namely virus–host chimera DNA (vh-DNA), can represent the signatures of individual tumors and are released into the blood. Such ctDNA can be enriched by capture with virus-specific probes and therefore exploited as a circulating biomarker to track virus-related cancers in clinical settings. Here, we review virus integrations in virus-related cancers to evaluate the feasibility of vh-DNA as a cell-free tumor marker and update studies on the development of detection and applications. vh-DNA may be a solution to the development of specific markers to manage virus-related cancers in the future. [ABSTRACT FROM AUTHOR]