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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Although DNA is mostly found within chromatin, fragment cell-free DNA (cfDNA) is found circulating in healthy individuals in the range of 1–10 ng/mL. cfDNA can increase under various physiological and pathological conditions such as exercise, trauma, infections, inflammation, and cancer (e.g., prostate and breast cancer) [324–328]. Genetic material released into the bloodstream by the tumor is identified as circulating tumor DNA (ctDNA) [325, 329]. It was in 1948 that molecules of cfDNA were first discovered in the human circulatory system, and Stroun and colleagues in 1989 confirmed that a portion of that circulating noncellular DNA comes from neoplastic cells within cancer patients [327, 330, 331].
Liquid Biopsies for Pancreatic Cancer: A Step Towards Early Detection
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Joseph Carmicheal, Rahat Jahan, Koelina Ganguly, Ashu Shah, Sukhwinder Kaur
Circulating cell-free DNA (cfDNA) are degraded DNA fragments released into the blood plasma. cfDNA can be used to describe various forms of DNA which are freely circulating in the bloodstream, such as circulating tumor DNA (ctDNA) and cell-free fetal DNA (cffDNA) [3]. Circulating tumor DNA (ctDNA) originates specifically from tumor cells and potentially harbors tumor-associated genetic mutations that inherently provide a marker for disease progression and/or therapeutic response [4]. Many cell death mechanisms including apoptosis, necrosis, oncosis, and phagocytosis release cfDNA/ctDNA into the bloodstream. These molecules can be present in their free form circulating by themselves or in the intravesicular compartment of various cell-derived vesicles [4]. They can also be bound to a DNA binding protein (specific or nonspecific) and the multi-nucleosome complex during vascular transport [4, 5].
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The use of Circulating Tumor DNA (ctDNA) as a biomarker of cancer is another important concept, as it is assumed that free circulating DNA of this type must originate in a primary tumor somewhere in the body. ctDNA typically contains somatic mutations specific to a particular tumor type, and the exact sequence can provide useful information about the molecular state and stage of the disease. Such mutations include epigenetic changes such as DNA hypermethylation and also point mutations, which can all be quantified. As these DNA alterations are disease specific, it is possible to use ctDNA as a biomarker to diagnose and assess the prognosis of patients with cancer. Similarly, exosomes have emerged as a promising biomarker both in cancer diagnostics and treatment monitoring. Compared to CTCs they are abundant in bodily fluids, and the molecular information they carry makes them a potentially useful tool in providing information on the primary tumor. One of the most prominent uses of detecting circulating nucleic acids is in the identification of epigenetic changes, and this is covered in more detail in the section below.
Trends in molecular diagnostics: 12th European Meeting on Molecular Diagnostics, Noordwijk aan Zee, the Netherlands, 12-14 October 2022
Published in Expert Review of Molecular Diagnostics, 2023
Anne J.M. Loonen, Rob Schuurman, Adriaan J.C. van den Brule
The second day of the meeting covered topics in the areas of liquid biopsies, quality management, and automation and the role of molecular diagnostics in preventive medicine. The first session was opened by Ellen Heitzer (Medical University of Graz, Austria) who provided an overview of liquid biopsy diagnostics by focusing on technologies and applications in cancer. An interdisciplinary molecular tumor board was suggested in which specialists from pathology and genetics are combined for therapy decisions. Circulating tumor DNA 1) can serve as a response to therapy marker and 2) a marker to (de)escalate adjuvant treatment, and 3) recurrence is predictive for relapse. Interesting discussion followed with questions from the infectious disease specialists. In sepsis (bloodstream infection) targeted testing to detect microorganisms in blood is very difficult. Why does it work for tumors? Possibly it has a relation to the amount of target DNA present in the liquid sample. Liquid biopsy mutation detection is more successful in higher-stage cancer. Jaap Jan Boelens (Memorial Sloan Kettering Cancer Center, New York, U.S.A) discussed ways toward a predictable optimal immune reconstitution after stem cell transplantation (SCT). One size does not fit all, and results showed that CD4+ T-cell reconstitution is crucial in survival chances. Furthermore, it turned out that pulmonary microbiome (respiratory viruses) can predict outcome after SCT. Microbiome analysis should gain more attention in the clinic.
Chromosome 6p amplification detected in blood cell-free DNA in advanced intraocular retinoblastoma
Published in Ophthalmic Genetics, 2022
Shreya Sirivolu, Liya Xu, Mikako Warren, Rishvanth K. Prabakar, Rachana Shah, Peter Kuhn, James Hicks, Jesse L. Berry
The tumor genomic SCNA profile was reflected in the AH cfDNA, in concordance with prior studies demonstrating that the AH is a rich source of eye-specific tumoral genomic information (10,14,22). This case is the first time a significant 6p gain was detected in the blood. It is not currently known if there are systemic associations with 6p gain, however the higher tumor fraction in the blood suggests the potential for metastatic cancer. Studies from Memorial Sloan Kettering Cancer Center (MSKCC) suggest that higher tumor fraction of circulating tumor DNA in the blood has been associated with development of metastatic disease (11,12); however, there has been no objective validation of when there is increased risk based on tumor fraction alone. For this patient, MRI results showed no signs of extraocular spread in the optic nerve or brain at the time of diagnosis; this patient has now been followed clinically for 24 months after diagnosis and there is no evidence of metastatic disease. Thus, at this time, we do not know the risk to the patient with circulating tumor DNA in the blood. Further, despite no evidence in the patient’s MRI, it also remains to be seen if 6p gain in the blood also relates to increased risk of a new primary cancer such as pineoblastoma, which may also have a 6p gain (23).
Genetic testing for the clinician in prostate cancer
Published in Expert Review of Molecular Diagnostics, 2020
Fernando López-Campos, Estefanía Linares-Espinós, Xavier Maldonado Pijoan, Gemma Sancho Pardo, Todd Mathew Morgan, Claudio Martínez-Ballesteros, Juan Martínez-Salamanca, Felipe Couñago
Molecular analysis of plasma DNA has gained prominence in recent years due to the noninvasive nature of this technique, which provides a dynamic image of molecular changes taking place in the tumor. The potential clinical applications for circulating tumor DNA (ctDNA) analysis are numerous, including risk stratification, determination of possible causes of treatment resistance, and selection of the most appropriate treatment, among other applications. Different platforms can also be used for ctDNA detection, including BEAMing, ddPCR, and next-generation sequencing (NGS), with excellent concordance between platforms [108], highlighting the potential value of ddPCR, a recently developed technology that utilizes Taq polymerase in a standard PCR reaction to amplify a target DNA fragment from a complex sample using pre-validated primer or primer/probe assays. In turn, the PCR reaction can be partitioned into thousands of individual reaction vessels prior to amplification and data acquisition at the reaction end point [109].