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Non-Blood Sources of Cell-Free DNA for Cancer Molecular Profiling In Critical Reviews in Oncology / Hematology 141 (2019) 36–42 Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc Non-blood sources of cell-free DNA for cancer molecular profiling in clinical pathology and oncology T Giovanni Pontia, Marco Manfredinib, Aldo Tomasia a Department of Surgical, Medical, Dental & Morphological Sciences with Interest Transplant, Oncological & Regenerative Medicine, Division of Clinical Pathology, University of Modena & Reggio Emilia, Modena, Italy b Department of Surgical, Medical, Dental & Morphological Sciences with Interest Transplant, Oncological & Regenerative Medicine, Dermatology Unit, University of Modena & Reggio Emilia, Modena, Italy ARTICLE INFO ABSTRACT Keywords: Liquid biopsy can quantify and qualify cell-free (cfDNA) and tumour-derived (ctDNA) DNA fragments in the Cell-free DNA bloodstream. CfDNA quantification and mutation analysis can be applied to diagnosis, follow-up and therapeutic Non blood cfDNA management as novel oncologic biomarkers. However, some tumor-types release a low amount of DNA into the Liquid biopsy bloodstream, hampering diagnosis through standard liquid biopsy procedures. Several tumors, as such as brain, Biomarkers kidney, prostate, and thyroid cancer, are in direct contact with other body fluids and may be alternative sources Cancer diagnosis for cfDNA and ctDNA. Non-blood sources of cfDNA/ctDNA useful as novel oncologic biomarkers include cere- Cancer management brospinal fluids, urine, sputum, saliva, pleural effusion, stool and seminal fluid. Seminal plasma cfDNA, which can be analyzed with cost-effective procedures, may provide powerful information capable to revolutionize prostate cancer (PCa) patient diagnosis and management. In the near future, cfDNA analysis from non-blood biological liquids will become routine clinical practice for cancer patient diagnosis and management. 1. Introduction humoral balance for that individual. The most extensively studied body fluids are blood and urine, but many other liquids, such as cere- Over recent decades there has been a rapid expansion of knowledge brospinal fluid, saliva and seminal fluids have been analyzed in order to in the field of molecular biology and biochemistry, leading to the de- determine their diagnostic and prognostic potential. velopment of precision medicine and tailored therapies.(Lu and Liang, An example of a routinely applied liquid biopsy for patient man- 2016) The understanding of oncogenic pathways and neoplastic genetic agement is the dosage of prostate specific antigen (PSA) in the blood- signatures shed the conceptual basis for the development of liquid stream. However, the PSA protein is present both in healthy and in biopsy procedures and oncological-targeted therapies. Today, im- neoplastic prostate cells and therefore has a low sensitivity and speci- munohistochemical and biochemical tumor characterization are part of ficity for prostate cancer (PCa) diagnosis. In contrast, tumor-derived the routine process to define patient diagnosis and prognosis.(Ponti cell-free DNA (ctDNA) based techniques are more specific and can be et al., 2016; Hofman et al., 2018; Ponti et al., 2018d) applied to many body fluids in order to identify novel oncologic bio- The identification of new diagnostic and prognostic markers from markers for diagnosis, prognosis and monitoring of tumor therapeutic non-tumoral biological samples is an interesting field in continuous response. evolution. Liquid biopsy procedures have been developed to identify The presence of DNA within the non-cellular fraction of peripheral oncologic biomarkers in several body fluids such as blood, plasma, blood, termed cell-free DNA (cfDNA), was initially identified more than cerebrospinal liquid, seminal fluid, saliva and urine.(Ulrich and 50 years ago.(Ulrich and Paweletz, 2018; Stewart et al., 2018; Burgener Paweletz, 2018; Stewart et al., 2018; Burgener et al., 2017) The concept et al., 2017) Decades passed before cfDNA levels were found to be that body fluids may reveal the presence of several systemic diseases elevated within the serum of cancer patients, with at least a portion of dates back to ancient Greek and Indian history. The development of the cfDNA being tumor-derived (ctDNA). The advantage of ctDNA humoral theory was attributed to Hippocrates (ca. 460–370 BCE), and analysis from liquids other than blood is the collection of targeted in- its concepts were the base of Western medicine from antiquity through formation from a body fluid directly in contact with the tumor source to the 19th century. “Humoral” derives from the word “humor,” which (eg. cerebrospinal fluid for central nervous system neoplasm). Fur- in ancient greek means “fluid”, and health was defined as the proper thermore, contrary to what occurs with ctDNA in the bloodstream, E-mail address: [email protected] (G. Ponti). https://doi.org/10.1016/j.critrevonc.2019.06.005 Received 24 July 2018; Received in revised form 19 September 2018; Accepted 4 June 2019 1040-8428/ © 2019 Elsevier B.V. All rights reserved. G. Ponti, et al. Critical Reviews in Oncology / Hematology 141 (2019) 36–42 ctDNA in other bodily fluids are not diluted and higher concentrations complexes. of ctDNA are derived from active secretion and/or necrotic phenomena. In cancer, a portion of cfDNA originates from tumor cells, referred ctDNA harbors cancer-specific genetic and epigenetic alterations to as circulating-tumor DNA (ctDNA), and can harbor specific muta- that allow its detection and quantification using a variety of emerging tions corresponding to the patient's tumor. ctDNA profiling has recently techniques. The promise of convenient non-invasive access to the become an area of increasing clinical relevance in oncology, in parti- complex and dynamic molecular features of cancer through peripheral cular due to advances in the sensitivity of sequencing technologies, blood has galvanized translational researchers around this topic with allowing a reliable identification of cancer mutations. Several studies compelling routes to clinical implementation, particularly in the post showed high concordance between individual mutations found in -treatment surveillance setting. (Ulrich and Paweletz, 2018; Stewart ctDNA samples and tumor tissue.(Bettegowda et al., 2014) Cancer pa- et al., 2018; Burgener et al., 2017) Although analysis methods must tients have much higher cfDNA concentrations (0 to > 1000 mg/mL) contend with small quantities of ctDNA present in most patients and the than healthy individuals (0–100 ng/mL) and the total amount varies relative over-abundance of background cfDNA derived from normal among patients with comparable cancer type and stage.(Bettegowda tissues, recent technical innovations have led to dramatic improve- et al., 2014) Direct correlations between ctDNA level and tumor ments in the sensitivity of ctDNA detection. The collection of biologic burden, stage, vascularity and therapy response have been described for samples to isolate cfDNA is often repeatable, allowing for real-time and several cancers. dynamic monitoring of molecular changes.(Zeng et al., 2018) As a re- cfDNA can be found in plasma as well as other body fluids such as sult, ever more studies are investigating the clinical utility of ctDNA for urine, cerebral spinal fluid (CSF), pleural fluid, and saliva, among applications in treatment response assessment,(Dawson et al., 2013) others.(Stewart and Tsui, 2018) Depending on tumor type, different identification of emerging resistance mechanisms,(Mok et al., 2015; rates of cfDNA/ctDNA have been reported in blood samples. CtDNA was Tabernero et al., 2015) and minimal residual disease detection.(Guo detected in over 75% of patients with advanced pancreatic, ovarian, et al., 2016) In addition, ctDNA is released from multiple tumor regions, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocel- and may thereby represent the whole molecular picture of a patient's lular, and head and neck cancers. However, levels below 50% were malignancy, potentially solving the problem of intra-tumor hetero- found in primary brain tumors, in kidney, prostate, and thyroid cancers, geneity,(L De Mattos-Arruda et al., 2014; Leticia De Mattos-Arruda (Bettegowda et al., 2014) and may be due to the influence other factors, et al., 2015; Jamal-Hanjani et al., 2016) which may lead to false-ne- such as blood-brain barrier restriction mechanisms, inflammatory or gative results and suboptimal therapy selection, and characterization of autoimmune processes that increase non-tumor cfDNA fraction, effec- clonal heterogeneity and selection. (Ulrich and Paweletz, 2018; Stewart tively diluting the ctDNA amount. The identification of ctDNA from et al., 2018; Burgener et al., 2017). biologic fluids other than blood, enables prompt diagnosis and a reli- In this review we explore the application of non-blood derived able genetic identification of cancer types, characterized by shedding ctDNA and cfDNA in the discovery of novel oncological biomarkers, low concentrations of ctDNA into the blood stream. These tumors are describing the existing evidence and focusing on the recent develop- often in direct contact with other body fluids, such as urine, saliva, ment of seminal plasma analysis. cerebrospinal fluid, pleural effusion or seminal liquid, releasing a considerable amount of ctDNA and creating a privileged source for non- 2. Biology of cell free DNA and cell tumoral DNA invasive ctDNA quantification and characterization. Cell-free DNA
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