All these techniques have led to the discovery of various therapeutic molecules for cancer treatment, and the optimization of drug therapy. No doubt molecular diagnosis will lead to significant improvements in care for cancer patients in the not-too-distant future. Anand, P. September , Cancer is a preventable disease that requires major lifestyle changes. Retrieved 11 May Kinzler, Kenneth W.
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Journal of Clinical Investigation, , — Stem Cell Rev. National Human Genome Research Institute Retrieved Concepts of genetics 10th ed. San Francisco: Pearson Education. ISBN Staudt, L. May , Molecular Diagnosis of the Hematologic Cancers. N Engl J Med , Chen, Kevin; Rajewsky, Nikolaus The evolution of gene regulation by transcription factors and microRNAs Reviews Genetics 8 2 , 93— MicroRNA biogenesis, functionality and cancer relevance.
Lewis B. Cell 1 , 15— Genome Res. Molecular Cancer, 6, Cell Research, Dawn C. Miller J. B 3, The B. Proteomics , 3, 56— Emanuel F. Current Opinion in Biotechnology, 15, 24— The Breast Volume 14, Issue 4, Pages BMC Cancer, 5, Ferrari M. Volume 5. Pg no. Write to us at publications. Figure 2: Molecular diagnostics of cancer A. The establishing of the tumor cell lines is not a practical approach at the moment: only a minor part of naturally occurring tumors can be converted to viable cell cultures, and the properties of the obtained cell clones do not necessarily reflect the biological features of the original tumors Kreahling and Altiok, ; Izumchenko et al.
Transplantation of the tumors to immune-deficient mice could be advantageous in terms of the success rate and mimicking the native physiological conditions for cancer growth. Patient-derived xenografts PDXs are being increasingly utilized in drug trials as well as in patient management undertaken in advanced cancer centers Evans et al.
Clinical studies demonstrate that mouse PDXs mirror therapeutic responses observed in patients with a remarkable level of accuracy Izumchenko et al. While murine experiments are expensive and time-consuming, there are efforts to establish short-term PDXs in zebrafish models Fior et al.
Lack of proper immune context and absence of human tissue environment are considered as critical limitations of PDX-based assays Cassidy et al. Further, although PDXs are characterized by relatively good preservation of original tumor molecular portraits Izumchenko et al. Animal experiments demonstrate that topical intratumoral microinjection of cancer drugs followed by microscopic analysis of drug-exposed tumor areas may be a promising predictive test Jonas et al. It is essential to recognize that all current predictive tests ignore the issue of intratumoral heterogeneity.
Multiple evidences suggest that tumors consist of distinct populations of transformed cells, which are characterized by substantial subclonal genetic diversity and epigenetic plasticity. Even if the treatment is apparently effective and results in the shrinkage of the gross tumor mass, it is unlikely to eliminate all cancer cells and may even promote the expansion of drug-resistant clones Amirouchene-Angelozzi et al.
The development of cancer drugs and corresponding predictive markers currently focuses mainly on tumor molecular portraits. A thorough consideration of other relevant factors may provide some unexpected opportunities. For example, cancers arising in visceral organs were long considered to be sterile, similarly to normal tissues.
Recent data indicate that some tumors may be colonized by specific microorganisms, and these bacteria may participate in drug metabolism and contribute to the treatment response Bullman et al.
For example, pancreatic carcinomas often contain viable Gammaproteobacteria , which are capable to metabolize gemcitabine into an inactive compound Geller et al. There are convincing evidences demonstrating that composition of gut microbiome influences the interaction between tumor and systemic therapy.
For example, the intestinal microbe Akkermansia muciniphila was shown to mediate the efficacy of immune checkpoint modulators Routy et al. The outcome of immune therapy may also critically depend on the patient age and HLA genotype Champiat et al. Surgical intervention may trigger the growth of dormant cancer cells by inducing the systemic inflammatory response and therefore significantly affect the probability of cancer relapse Krall et al.
Tumors almost always shed some amount of their fragments into peritumoral space. These fragments may be represented by single malignant cells or their clusters as well as by various proteins, nucleic acids, small molecules, etc. Consequently, these entities can be collected in various body fluids serum, saliva, urine, etc. Serum protein markers are the most established tools for cancer diagnosis Duffy, For example, PSA prostate-specific antigen , CA cancer antigen and CEA carcinoembryonic antigen are widely used for the diagnosis and management of prostate, ovarian and gastrointestinal cancers, respectively.
Measurement of serum antigens allows to discriminate between various types of malignancies at the first suspicion for cancer disease and thus guide imaging analysis, endoscopic examination and other diagnostic procedures. Monitoring of the level of tumor-specific protein markers in patients with the established diagnosis of cancer permits the disease monitoring, e. PSA is used in some countries for prostate cancer screening. Protein markers, being the only type of liquid biopsy widely incorporated in routine clinical practice, have significant limitations in terms of sensitivity and specificity.
It is expected that the revolution in molecular genetic research will dramatically improve the performance of fluid-based assays. Indeed, DNA markers may have significant advantages as compared to proteins. Several methods of genetic analysis, particularly PCR and NGS, are potentially capable to detect a single molecule of tumor-specific DNA even in the presence of an excess of normal nucleic acids.
Furthermore, while the majority of known protein markers are not truly tumor-specific but rather tissue-specific, DNA tests usually rely on cancer-driving mutations and therefore are less prone to false-positive results.
Modern methods of liquid biopsy are not limited to the analysis of tumor-free DNA. For example, some experimental approaches utilize the detection of circulating microRNAs owing to their relatively good stability in body fluids. In addition, a number of investigational diagnostic procedures rely on the isolation and analysis of circulating tumor cells Antonarakis et al. While discussing the perspectives for the liquid biopsy, it is critically important to recognize that its actual relevance may significantly depend on particular clinical context.
For example, virtually all current diagnostic standards for cancer patients require mandatory biopsy of the tumor lump followed by morphological validation of the presence of malignant disease.
Therefore, if one considers cancer patients at the initial stage of their treatment, virtually all of them have primary tumor tissue available for detailed investigation. For the time being, all methods of liquid biopsy are based on the analysis of residual amounts of tumor fragments in body fluids. Therefore, it is hard to expect, that this indirect and potentially error-prone examination of single tumor cells or circulating tumor-specific molecules will indeed replace the direct tissue analysis in the near future.
It is also essential to acknowledge, that the majority of actionable mutations demonstrate limited intratumoral heterogeneity; therefore, the analysis of a single tumor lump is usually sufficient for the choice of treatment and liquid biopsy is unlikely to have a high added value for the initial selection of optimal drugs Jamal-Hanjani et al.
The situation becomes entirely different when the liquid biopsy is utilized during the treatment course. First of all, tumor response to the treatment cannot be always reliably assessed by the visualization of tumor lumps, especially given the fact that not all tumors are manifested by measurable tumor lesions. Marker response is an exceptionally valuable end-point for the evaluation of treatment efficacy.
As already mentioned above, PSA and CA are routine tools utilized in the management of prostate and ovarian cancer patients, respectively Kobayashi et al. While informative serum markers are available for the minority of human tumors, the use of blood-based mutation tests for the immediate assessment of treatment efficacy can potentially be applied to every cancer patient, as all malignant neoplasms contain a spectrum of somatic mutations.
The utility of circulating tumor DNA for the control of surgical tumor eradication as well as the response to systemic treatment has already been exemplified in a number of studies Tie et al. A similar approach can be applied for the early detection of tumor relapse.
The situation is getting more demanding while considering patients, whose tumors progressed after treatment. The phenotype of drug-resistant tumors may significantly evolve over time, and the choice of the right treatment strongly depends on the spectrum of newly acquired targets. For example, a novel lung cancer drug, osimertinib, has been intentionally developed to target non-small cell lung cancers, which progress after TKI therapy via acquisition of TM mutation in EGFR gene Lamb and Scott, The analysis of treatment-resistant tumors may require repetitive biopsies, which is not feasible if one considers a direct analysis of visceral, bone, or brain metastases.
Liquid biopsy is expected to provide a more integral portrait of molecular events underlying tumor progression as compared to a single tissue-take Gremel et al. There are hundreds of studies demonstrating the potential utility of the analysis of extracellular RNA for diagnosis of cancer disease Xi et al. Nevertheless, RNA is relatively well preserved in various body fluids, as it is secreted as a part of microvesicles or lipoprotein complexes and therefore somehow protected from external hazards.
Although the detection of extracellular RNA and the interpretation of obtained data is less straightforward as compared to mutation-based tests, there are some potential advantages of RNA testing. Some highly expressed extracellular RNA species are significantly more abundant than cell-free DNA, thus decreasing the requirements for the sensitivity of corresponding molecular tests.
While DNA is released to the body fluids mainly due to cell death, the secretion of RNA is a physiological process; this is particularly relevant to some cancer types, e. There are some approaches, which allow to enrich the preparations of RNA by tissue-specific molecules, for example, by antibody-driven selection of particular category of exosomes. Some RNA species are present in increased amounts in body fluids, which are in close contact with the affected organ.
The development of other RNA-based assays is currently underway Xi et al. There is a hope that combined use of an array of DNA- and protein-based markers will result in a breakthrough in early cancer diagnosis and screening. The potential promise of these complex platforms has already been demonstrated in the study of early-stage cancers Cohen et al.
Nevertheless, many modern varieties of liquid biopsy still require proper clinical validation Merker et al. In many instances, the inability to assign the right diagnosis is attributed purely to limitations in tumor visualization techniques.
This is compatible with the recent findings demonstrating that the spread of malignant cells may occur before the formation of the primary tumor lump Harper et al. Furthermore, there are occasional examples of spontaneous regression of neoplastic lesions in the primary tumor site occurring simultaneously with the progression of distant metastases Kamposioras et al.
The diagnostic approach to patients with CUP largely relies on common clinical sense. IHC testing, which utilizes a spectrum of tissue-specific markers, is a gold standard for CUP clinical analysis. IHC has significant limitations. In particular, many expression-based markers are not sufficiently specific for a given tumor type. Some proteins are expressed at low levels and therefore cannot be detected by conventional antibody-based methods.
The spectrum of diagnostic antibodies is restricted to the ones marketed by biotech companies. Finally, interpretation of IHC results is a subject of interlaboratory variations Pavlidis and Fizazi, ; Massard et al. In particular, some mutations are highly characteristic for cancers of a certain type. In contrast to antibody production, the development of personalized PCR diagnostic tests does not require industrial facilities and can be done in any molecular genetic laboratory.
Finally, PCR assays can be performed and interpreted in a semi-automated manner. They include genomics points mutations, copy number variations, single nucleotide polymorphisms , epigenomics genome-wide analysis of DNA modifications, e.
Sometimes these approaches result in the discovery of a single medically relevant marker, e. Many omics-derived classifiers provide an approach for semi-automated discrimination between different conditions, such as healthy status vs. Almost all high-throughput studies deal with datasets, in which the number of considered features significantly exceeds the number of analyzed cases. For example, while the expression microarrays are designed to simultaneously assess over twenty thousand genes, the number of included patients with different disease characteristics is usually limited to at best several hundreds of observations.
In any event, this amount of data cannot be curated manually in a meaningful way, therefore the development of viable hypothesis and data interpretation are largely outsourced to computer intellect. In addition, there are some research initiatives aimed at integration of high-throughput technologies with clinical trials Pauli et al.
We are currently witnessing a revolution in medical research, which is attributed to the invention and rapidly increasing uptake of the next generation sequencing. NGS allows comprehensive description of germ-line DNA, analysis of somatic mutations and RNA profiles in naturally occurring tumors, systematic analysis of microbiomes, etc. There is an ongoing accumulation of data, which results in the identification of novel hereditary syndromes, molecular targets for cancer therapy, tumor-specific diagnostic markers, etc.
It is difficult to foresee, how practical medicine will manage an overwhelming flow of novel candidate markers, given that they are represented by a multitude of rare and diverse molecular events and therefore cannot be clinically validated on the individual basis.
These advances may need to be considered while discussing the standards of clinical research, data dissemination and interaction between clinical and laboratory specialists. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the Russian Science Foundation grant number National Center for Biotechnology Information , U. Journal List Front Mol Biosci v. Front Mol Biosci. Published online Aug Anna P. Petersburg, Russia Find articles by Anna P. Evgeny N. Petersburg, Russia 3 Department of Oncology, I. Petersburg, Russia 4 Department of Oncology, St. Petersburg State University, St. Petersburg, Russia Find articles by Evgeny N. Author information Article notes Copyright and License information Disclaimer.
Edited by: Anton A. Buzdin, I. Sokolenko ur. Imyanitov ur. This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal Frontiers in Molecular Biosciences.
Received May 30; Accepted Jul The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract There are multiple applications of molecular tests in clinical oncology. Keywords: carcinoma of unknown primary site, hereditary cancer syndromes, liquid biopsy, molecular diagnostics, predictive markers, review. Introduction Molecular diagnostics is a part of laboratory medicine, which relies on the detection of individual biologic molecules.
Open in a separate window. Figure 1. Hereditary cancer syndromes Hereditary cancer syndromes compose a group of genetic defects, which render highly significant elevation of cancer risk; importantly, this risk is more or less organ-specific, which allows to arrange meaningful diagnostic and preventive interventions for germ-line mutation carriers.
Table 1 Hereditary cancer syndromes: selected examples. Molecular markers for the choice of cancer therapy First examples of the use of predictive markers in oncology were related to breast cancer research Engelsman, ; Jensen, NPJ Breast Cancer.
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