Pathophysiology of ctDNA Release into the Circulation and Its Characteristics: What Is Important for Clinical Applications
The clinical implications of being able to accurately detect tumor-derived DNA in the circulation, termed circulating tumor DNA (ctDNA), could be enormous. Already, a plethora of clinical applications is under validation that include detection of minimal residual disease and predicting recurrence, monitoring response and resistance to treatment, identifying targets for therapies, and early detection. ctDNA is only a fraction of the total cell-free DNA (cfDNA) which confounds its detection and sometimes conceals its properties. To use ctDNA as a cancer biomarker with confidence, we need to understand its nature. Its characteristics, including size, half-life, and amount, are critical for the development of tests for its detection and discrimination from the rest of the cfDNA. Technological advances have enabled the detection and quantification of individual fragments of cfDNA, which is pivotal for clinical applications. Understanding the causes, the source of and the mechanisms of release of ctDNA are important for the interpretation of test results. Despite the many advances in understanding the nature and biology of ctDNA, we do not yet have a clear appreciation of the processes that govern its presence and levels in the circulation. ctDNA is not detectable in the blood of every cancer patient, and there is not a directly proportional relationship to tumor type, size, or stage. It is not clear if the lack of correlation with these specific clinical parameters is strictly due to technical or biological challenges. Better understanding of the pathophysiology of ctDNA is therefore important for the improvement of clinical applications and interpretation of their results.
- Bettegowda C, Sausen M, Leary RJ et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:ra224Google Scholar
- Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A (2013) Liquid biopsy: monitoring cancer-genetics in the blood Nature Reviews. Clin Oncol 10:472–484Google Scholar
- Jahr S, Hentze H, Englisch S et al (2001) DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61:1659–1665Google Scholar
- Tie J, Wang Y, Tomasetti C et al (2016) Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 8:346ra92Google Scholar
- Wang Y, Springe S, Mulvey CL et al (2015a) Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med 7:293ra104Google Scholar
- Wang Y, Springer S, Zhang M, McMahon KW, Kinde I, Dobbyn L, Ptak J, Brem H, Chaichana K, Gallia GL et al (2015b) Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad Sci U S A 112:9704–9709PubMedPubMedCentralCrossRefGoogle Scholar