Diagnostic and Therapeutic Potential of Circulating-Free DNA and Cell-Free RNA in Cancer Management

Abstract

Over time, molecular biology and genomics techniques have been developed to speed up the early diagnosis and clinical management of cancer. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. Important advances in applying molecular testing involve circulating-free DNA (cfDNA)- and cell-free RNA (cfRNA)-based liquid biopsies for the diagnosis, prognosis, prediction, and treatment of cancer. Both cfDNA and cfRNA are sensitive and specific biomarkers for cancer detection, which have been clinically proven through multiple randomized and prospective trials. These help in cancer management based on the noninvasive evaluation of size, quantity, and point mutations, as well as copy number alterations at the tumor site. Moreover, personalized detection of ctDNA helps in adjuvant therapeutics and predicts the chances of recurrence of cancer and resistance to cancer therapy. Despite the controversial diagnostic values of cfDNA and cfRNA, many clinical trials have been completed, and the Food and Drug Administration has approved many multigene assays to detect genetic alterations in the cfDNA of cancer patients. In this review, we underpin the recent advances in the physiological roles of cfDNA and cfRNA, as well as their roles in cancer detection by highlighting recent clinical trials and their roles as prognostic and predictive markers in cancer management.

Keywords: anticancer therapy; biomarkers; cancer; cfDNA; cfRNA; diagnosis; liquid biopsy.

Figure 1

Secretion of cfDNA from tumor cells. Cell death by apoptosis, pyroptosis, or necrosis is one of the most important sources of ctDNA in body fluids; however, even without cell death, cfDNA/ctDNA has been found in the medium. This means that live cells can actively release cfDNA. Due to autophagy and exosome activity, the active secretion of cfDNA through microvesicles has also been observed. Once the cfDNA is released into the body fluids, it is detected by various methods, based on its size, concentration, frequency of repeats, or presence of mutations.

Figure 2

Sources of cfRNA. Similar to ctDNA, it is secreted into the body fluids through cell death events or by attaching itself to the nuclear proteins. The presence of cfRNA plasma can reflect the phenotypic alterations of localized sites of cancer as well as a systemic host response.

Figure 3

For cell-free DNA or RNA screening, the blood sample is taken from the patient and analyzed through techniques, such as qPCR, NGS WGS, etc. The non-invasiveness of a liquid biopsy makes it suitable for a myriad of applications, including cancer diagnoses, tumor burden analyses, and therapeutic analyses.