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Circulating Tumour DNA: a Minimally Invasive Biomarker for Tumour Detection and Stratification

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      Abstract

      Genetic and epigenetic alterations significantly contribute to development of human cancer. Genotyping tumour tissue in search for these actionable genetic and epigenetic changes has become routine practice in oncology. However, sampling tumour tissue has significant inherent limitations. It provides only a single snapshot in time, prone to selection bias due to intra-tumour heterogeneity, and cannot always be performed owing to its invasive nature. Circulating tumour DNA (ctDNA) based liquid biopsy provides an effective alternative to invasive tissue sampling and have emerged as a minimally invasive, real-time biomarker. Recent advancements in DNA sequencing technologies have revealed enormous potential of ctDNA to improve tumour detection and stratification. In this review, we critically appraise the role of ctDNA as a liquid biopsy for cancer and evaluate the role of circulating tumour DNA as a diagnostic, prognostic and predictive biomarker. We also highlight some technical challenges and constraints associated with circulating DNA analysis.

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      Most cited references 132

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      Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.

      Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).
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        Cell-free nucleic acids as biomarkers in cancer patients.

        DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.
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          Detection of circulating tumor DNA in early- and late-stage human malignancies.

          The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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            Author and article information

            Affiliations
            [a ]Centre for Skin Sciences
            [b ]School of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
            Author notes
            *Corresponding author. Tel.: +(01274) 234732 E-mail: a.a.surani@ 123456bradford.ac.uk
            Journal
            BJPharm
            British Journal of Pharmacy
            University of Huddersfield Press
            2058-8356
            14 November 2016
            : 1
            : 1
            : 3-18
            10.5920/bjpharm.2016.07
            © 2016, Arif Surani, Krzysztof Poterlowicz

            This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0 https://creativecommons.org/licenses/by/4.0/.

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