SeminarCirculating free tumor DNA and colorectal cancerADN libre circulant d’origine tumorale et cancer colorectal
Introduction
A number of alterations occurring in cells and biological molecules during the course of neoplastic processes can be considered markers of cancer, and advances in genomics and proteomics now make it possible to identify such markers in plasma and serum, as well as in other bodily fluids such as urine, pancreatic juice, fecal matter and saliva. This makes these biological media highly useful for screening and making the diagnosis, and for determining the patient's prognosis and therapeutic assessment. In patients with solid tumors, management decisions are made on the basis of clinical, histological and, more rarely, molecular factors, yet the overall picture—given the heterogeneous nature of tumorigenesis—remains imperfect, making it difficult to determine the most appropriate diagnostic or therapeutic strategy. However, one of the characteristic features of cancer cells is the presence of genetic anomalies (amplifications, deletions, point mutations, chromosomal translocations, microsatellite instability [MSI]) and/or epigenetic alterations (promoter gene hypermethylation, acetylation) that perturb the expression of the genes controlling critical cell processes, such as proliferation, differentiation, the cell cycle, apoptosis and angiogenesis [1].
Thus, an improved knowledge of the molecular biology of cancer can be expected to open the way for new perspectives not only in fundamental research (better understanding of carcinogenesis), but also in drug development (for example, the currently rapidly developing ‘target-therapy’ approach) and clinical management (use of biomarkers to establish the diagnosis or prognosis, or to predict response to treatment). Previous research has demonstrated that either plasma or serum can contain a small quantity of free (non-cell-bound) circulating DNA. Concentrations of this free circulating DNA, in the order of a few nanograms per milliliter (ng/mL), increase significantly in patients with cancer compared with healthy subjects [2]. Also, there is clear evidence that, in cancer patients, a fraction of this DNA is tumor-derived, as the genetic and/or epigenetic molecular alterations characteristic of the tumor are found in the free DNA circulating in the plasma or serum. In fact, molecular alterations characteristic of the majority of solid tumors have been detected in the serum or plasma of cancer patients [3]. However, most of the research into the detection of free tumor-derived DNA in blood samples, and in other biological samples such as fecal matter, urine or pancreatic juice, is still in the preliminary stage. Nevertheless, this molecular approach to the detection of free circulating tumor-associated DNA in non-tumor biological samples introduces exciting new perspectives for the diagnosis and follow-up of patients with cancer.
Section snippets
Free cirulating DNA in plasma and serum
Free circulating DNA was first reported in serum from patients with systemic lupus erythematosus, rheumathoid arthitis and glomerulonephritis [4], [5], [6], [7], [8]. Leon et al. [2] were the first to report that cancer patients presented with higher levels of such non-cell-bound circulating DNA in their blood than did patients with non-cancerous diseases. These findings were later confirmed in a series of patients with gastrointestinal cancer [9]. The mean concentration of free DNA circulating
Molecular alterations of plasma or serum free circulating DNA in colorectal cancer
When precisely characterized, genetic or epigenetic molecular alterations of cancer-cell DNA should offer a means of identifying the presence of cancer-cell DNA in biological samples. PCR has enabled the development of sensitive, specific and reproducible molecular-biology techniques that can demonstrate the presence of one altered gene copy in 10,000 to 100,000 normal copies. Such diagnostic techniques have been used for years to detect residual disease in bone-marrow samples from patients
Free tumor-derived circulating DNA in plasma or serum: a biomarker with prognostic value and/or predictive of treatment effect in colorectal cancer
In light of the growing complexity of management strategies for colorectal cancer, it is essential to validate any new prognostic factors that could be used to identify subgroups of patients who may be expected to benefit from the various therapeutic strategies. For a given type of cancer at a given stage, the expected beneficial effect of a particular therapeutic strategy is never observed in all patients. The reason is undoubtedly related to the biological heterogeneity of most solid tumors.
Conclusion
The identification of new markers of colorectal cancer responds to the need for new sensitive and specific biological tests to enable earlier diagnosis, more accurate evaluation of the prognosis and earlier detection of recurrent disease, while also offering new directions towards the development of other diagnostic and/or therapeutic strategies to improve the prognosis. Cell-free circulating tumor-associated DNA, easily detectable in blood and possibly urine, is a potentially attractive
Conflict of interest statement
None.
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Cited by (45)
The clinical role of circulating free tumor DNA in gastrointestinal malignancy
2017, Translational ResearchCitation Excerpt :A small study found 16 of 27 (59%) patients who had CRC tumors with confirmed microsatellite instability also had detectable markers of microsatellite instability in ctDNA.92 However, detection artifacts and high false positive rates for detection in ctDNA are likely to limit its utility as a diagnostic marker of CRC.1 To summarize, these studies collectively demonstrate utility of both ctDNA levels and gene mutations for the diagnosis of CRC compared with the healthy state.
Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility?: A report of the association for molecular pathology
2015, Journal of Molecular DiagnosticsCitation Excerpt :The analysis of cfDNA for specific gene mutations, such as those in KRAS and TP53, is desirable because these genes have a high mutation frequency in many tumor types and contribute to tumor progression. The overall detection rate of KRAS mutations in serum or plasma of patients with colorectal cancer ranges from 25% to 30% up to 50% in different studies when considering only tumors harboring these same genetic alterations.126 KRAS mutations in ctDNA have been detected in different stages of colorectal carcinoma and in premalignant disease, with the highest level found in the more advanced stage.97
Assessment of DNA Integrity, Applications for Cancer Research
2015, Advances in Clinical ChemistryComparison of KRAS mutation analysis of primary tumors and matched circulating cell-free DNA in plasmas of patients with colorectal cancer
2014, Clinica Chimica ActaCitation Excerpt :Circulating cfDNA as a starting material for tumor biomarker analysis is less invasive than tumor biopsies or resection specimens and can be significantly specific if cancer-specific DNA alterations are tested [23–26]. In addition, analysis of cfDNA also provides a better representation of the cancer patient as a whole, as it has the potential to yield information about all cell subpopulations of the primary tumor as well as distant metastatic tumor [22,27]. The major technical challenge of using plasma cfDNA as the initial source for the detection of somatic mutations is that clinical samples frequently contain only trace amounts of the mutant allele.