Circulating Tumor DNA for Early Cancer Detection

Abstract

Background Cancer cells release circulating tumor DNA (ctDNA) into the bloodstream, which can now be quantified and examined using novel high-throughput sequencing technologies. This has led to the emergence of the “liquid biopsy,” which proposes to analyze this genetic material and extract information on a patient's cancer using a simple blood draw. Content ctDNA has been detected in many advanced cancers. It has also been proven to be a highly sensitive indicator of relapse and prognosis. Sequencing the genetic material has also led to the discovery of mutations targetable by existing therapies. Although ctDNA screening is more expensive, it is showing promise against circulating tumor cells and traditional cancer biomarkers. ctDNA has also been detected in other bodily fluids, including cerebrospinal fluid, urine, saliva, and stool. The utility of ctDNA for early cancer detection is being studied. However, a blood test for cancer faces heavy obstacles, such as extremely low ctDNA concentrations in early-stage disease and benign mutations caused by clonal hematopoiesis, causing both sensitivity and specificity concerns. Nonetheless, companies and academic laboratories are highly active in developing such a test. Conclusion Currently, ctDNA is unlikely to perform at the high level of sensitivity and specificity required for early diagnosis and population screening. However, ctDNA in blood and other fluids has important clinical applications for cancer monitoring, prognosis, and selection of therapy that require further investigation.

Engineered immune cells as highly sensitive cancer diagnostics

“…In cfDNA, for example, mutation allele frequency decreases with disease burden, leading to an increasing probability that there will not exist a single copy of a mutation in a 10 mL blood draw 36 . It is estimated 35,37 that tumors must reach volumes greater than 1,000 mm 3 (corresponding to allele frequencies of 0.01 %) for there to exist even one genome equivalent of tumor DNA in 4 mL of plasma. Our studies mirror these findings as the macrophage sensor could detect tumors up to 50-fold smaller in volume than possible with cfDNA mutation detection.…”

Can Grail find the trail to early cancer detection?

“…We have previously correlated ctDNA abundance with cancer volume based on published empirical data. The minimum percent mutant allele fraction of circulating DNA needs to be around 0.01% in order for any method to detect ctDNA fragments with a 10 mL blood draw [4,5]. Below this fraction, there will be less than one tumor DNA genome equivalent in a 10 mL blood draw.…”

“…For more details see Refs. [4] and [5]. Currently, imaging technologies can readily detect 6 mm diameter tumors [11].…”

“…As we explained in previous publications [4,5], the ratio of tumor DNA to normal DNA (generally expressed as a percentage) is an important parameter for this test. For example, a 0.1% mutant allele fraction means that one out of every 1000 DNA molecules in the circulation, originates from the tumor and the other 999 DNA molecules originate from healthy cells.…”

The paradox of cancer genes in non-malignant conditions: implications for precision medicine

“…Numerous studies have reported the utility of ctDNA in advanced cancer [194][195][196][197]. In particular, ctDNA assays can capture a more global portrait of tumor heterogeneity than that provided by tissue DNA (which reflects the small piece of tissue that is biopsied rather than DNA shed from both primary and multiple metastatic sites [198]); therefore, ctDNA can be exploited to monitor tumor response and resistance.…”