Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients

Abstract

Qualitative and quantitative analysis of circulating cell-free DNA (cfDNA) is an emerging non-invasive blood biomarker utilized to assess tumor progression and to evaluate prognosis, diagnosis and response to treatment. There is a need to develop cfDNA biomarkers to avoid complex risk-prone biopsy procedures for primary or metastatic tumors. Given the challenges associated with inter- and intra-tumor heterogeneity, the implementation of genome-wide cfDNA analysis will become an important avenue to understand tumor progression and therapeutic settings, not only for predominant, but also for under-represented tumor subclones with specific genomic aberrations. We summarize the latest publications in cfDNA analysis, including a metric analysis of clinical trials and new high-throughput technology applied to cfDNA analysis in clinical oncology.

Keywords::

• biomarkers
• cancer
• circulating cell-free DNA
• diagnostic
• epigenomics
• genomics
• metastasis
• mutation
• prognostic
• serum and plasma DNA

Financial & competing interests disclosure

This work was supported by National Institute of Health; National Cancer Institute grant number PO1 CA029605 Project II and Core C to DSB Hoon; Ruth and Martin H. Weil Foundation (DSB Hoon); and the Leslie and Susan Gonda (Goldschmied) Foundation (Los Angeles, CA, USA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • cfDNA has become increasingly used as a non-invasive diagnostic and prognostic liquid biopsy for cancer patients.

• • cfDNA has been detected in plasma and serum of cancer patients as well as other pathological processes. It has been established that the level of cfDNA is generally higher in cancer patients than in healthy controls.

• • In solid tumors, cfDNA is mainly released from non-programmed cell death such as necrosis. This process can be distinguished from apoptotic processes by assessing and comparing the length of the produced cfDNA fragments (DNA integrity index).

• • Recently, the application of next generation sequencing to cfDNA analysis has provided a new alternative to profile tumor genomic alterations. This strategy allows the identification of under-represented tumor clones and inaccessible primary or metastatic tumors. The high cost and sensitivity of NGS remains a major challenge for its wide spread application.

• • Detection of tumor-associated DNAm changes in cfDNA is a highly informative approach for both tumor biology and clinical application. It is imperative that this field expand to whole-genome approaches to elucidate more comprehensive DNAm landscapes.

• • There is a need to evaluate cfDNA markers in large clinical trials. Currently, a small number of trials are focused on cfDNA, some of which include a large number of patients. However, to effectively evaluate the clinical utility of classical and NGS, an analysis of cfDNA is needed in the context of more and larger multicenter clinical trials.