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Microsatellite Instability in Colorectal Cancer Liquid Biopsy—Current Updates on Its Potential in Non-Invasive Detection, Prognosis and As a Predictive Marker

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Microsatellite Instability in Colorectal Cancer Liquid Biopsy—Current Updates on Its Potential in Non-Invasive Detection, Prognosis and As a Predictive Marker diagnostics Review Microsatellite Instability in Colorectal Cancer Liquid Biopsy—Current Updates on Its Potential in Non-Invasive Detection, Prognosis and as a Predictive Marker Francis Yew Fu Tieng 1 , Nadiah Abu 1, Learn-Han Lee 2,* and Nurul-Syakima Ab Mutalib 1,2,3,* 1 UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; [email protected] (F.Y.F.T.); [email protected] (N.A.) 2 Novel Bacteria and Drug Discovery Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor 47500, Malaysia 3 Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia * Correspondence: [email protected] (L.-H.L.); [email protected] (N.-S.A.M.); Tel.: +60-391459073 (N.-S.A.M.) Abstract: Colorectal cancer (CRC) is the third most commonly-diagnosed cancer in the world and ranked second for cancer-related mortality in humans. Microsatellite instability (MSI) is an indicator for Lynch syndrome (LS), an inherited cancer predisposition, and a prognostic marker which predicts the response to immunotherapy. A recent trend in immunotherapy has transformed cancer treatment to provide medical alternatives that have not existed before. It is believed that MSI-high (MSI-H) CRC patients would benefit from immunotherapy due to their increased immune infiltration and higher neo-antigenic loads. MSI testing such as immunohistochemistry (IHC) and PCR MSI assay Citation: Tieng, F.Y.F.; Abu, N.; Lee, has historically been a tissue-based procedure that involves the testing of adequate tissue with a high L.-H.; Ab Mutalib, N.-S. Microsatellite Instability in Colorectal Cancer concentration of cancer cells, in addition to the requirement for paired normal tissues. The invasive Liquid Biopsy—Current Updates on nature and specific prerequisite of such tests might hinder its application when surgery is not an Its Potential in Non-Invasive option or when the tissues are insufficient. The application of next-generation sequencing, which Detection, Prognosis and as a is highly sensitive, in combination with liquid biopsy, therefore, presents an interesting possibility Predictive Marker. Diagnostics 2021, worth exploring. This review aimed to discuss the current body of evidence supporting the potential 11, 544. https://doi.org/10.3390/ of liquid biopsy as a tool for MSI testing in CRC. diagnostics11030544 Keywords: circulating tumor cells; circulating tumor DNA; cell-free DNA; microsatellite instability; Academic Editor: Rita Zamarchi colorectal cancer; non-invasive; liquid biopsy Received: 16 February 2021 Accepted: 17 March 2021 Published: 18 March 2021 1. Introduction Publisher’s Note: MDPI stays neutral Over the years, colorectal cancer (CRC) displayed a steady increase of incidence and with regard to jurisdictional claims in mortality rates [1–4]. It was one of the top three causes of cancer besides ranking third for all published maps and institutional affil- cancer-related deaths in 2018 [1]. Despite the advancement in the management of resected iations. CRC as well as the introduction of more effective cancer detection tools and treatment options, approximately 30 to 50% of the patients recovered will experience a recurrence in the form of regional lymph node or distant metastasis [5,6]. This data suggested the presence of potential metastatic cells, which had been overlooked by currently available diagnostic tools, limiting the identification of patients in need of adjuvant therapy. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. The rare metastatic cells which released from primary or metastatic cancers into This article is an open access article the blood circulation were reported as circulating tumor cells (CTCs) [7,8]. Previously, distributed under the terms and detection, isolation and molecular characterization of CTCs had been largely hindered conditions of the Creative Commons due to their unknown frequency in metastatic CRC (mCRC) patients, low concentrations 7 9 Attribution (CC BY) license (https:// (one CTC per 10 to 10 hematological cells per mL) and technical limitations such as low creativecommons.org/licenses/by/ separation efficiency and low recovery [9–14]. In recent years, advances in microfluidics 4.0/). and immunoaffinity enrichment technologies along with sequencing platforms, permit Diagnostics 2021, 11, 544. https://doi.org/10.3390/diagnostics11030544 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, x FOR PEER REVIEW 2 of 17 (one CTC per 107 to 109 hematological cells per mL) and technical limitations such as low separation efficiency and low recovery [9–14]. In recent years, advances in microfluidics and immunoaffinity enrichment technologies along with sequencing platforms, permit Diagnostics 2021, 11, 544 2 of 17 robust reproducible detection and isolation of CTCs from the whole blood, leading towards comprehensive interrogation of CTCs [10,15]. For instance, in 2017, Li et al., proposed a detection method using quantum dots and gold nanoparticles as signal probes [16],robust whereas reproducible Chiu detectionet al., introduced and isolation an ofoptically-induced-dielectrophoresis CTCs from the whole blood, leading (ODEP)- towards basedcomprehensive microfluidic interrogation device capable of CTCs of isolating [10,15]. Forhigh-purity instance, and in 2017, integral Li et CTC al., proposedclusters in a 2018detection [17]. methodIn response using to quantum the increasing dots and popularity gold nanoparticles in CTCs, asvarious signal studies probes [were16], whereas carried outChiu to et characterize al., introduced CTCs an optically-induced-dielectrophoresisbased on their distinctive molecular (ODEP)-based and clinicopathological microfluidic featuresdevice capable [9,17–19]. of isolating high-purity and integral CTC clusters in 2018 [17]. In response to theThe increasing revolutionary popularity success in CTCs, of checkpoint various studies inhibitors were carried in mismatch out to characterize repair-deficient CTCs (MMR-D)based ontheir mCRC distinctive [20] also molecular resulted andin a clinicopathological new therapeutic featuresscenario, [ 9where,17–19 ].biomarkers includingThe revolutionary microsatellite success instability of checkpoint (MSI) status inhibitors have been inmismatch validated repair-deficientfor clinical use of (MMR- CRC [21–25].D) mCRC Today, [20] alsopost-diagnosis resulted in MSI a new testing therapeutic is recommended scenario, for where both biomarkers hereditary syndrome including screeningmicrosatellite as well instability as prognosis (MSI) and status treatment have been implications validated forin CRC clinical patients use of [26,27]. CRC [21 In– 25the]. future,Today, post-diagnosisMSI status obtained MSI testing from CTCs is recommended could act as for a bothguide hereditary in early detection, syndrome prediction screening andas well prognosis, as prognosis as well and as treatment facilitating implications therapeutic in CRCtarget patients selection [26 ,27and]. Inmonitoring the future, CRC MSI treatmentstatus obtained response. from CTCs could act as a guide in early detection, prediction and prognosis, as well as facilitating therapeutic target selection and monitoring CRC treatment response. 2. Pros and Cons of Current Tissue Biopsy-Based MSI Testing 2. Pros and Cons of Current Tissue Biopsy-Based MSI Testing Microsatellite instability (MSI) is the manifestation of defective mismatch repair Microsatellite instability (MSI) is the manifestation of defective mismatch repair (MMR), which results in high frameshift mutation frequency in microsatellite DNA, (MMR), which results in high frameshift mutation frequency in microsatellite DNA, in- including gain and/or loss of nucleotides within repeating motifs known as microsatellite cluding gain and/or loss of nucleotides within repeating motifs known as microsatellite tractstracts (Figure (Figure1 1))[ [28,29].28,29]. It It is is mainly mainly de dependentpendent on MLH1 MLH1 (MutL homolog 1), MSH2 (MutS homolog 2), MSH6 MSH6 (MutS (MutS homolog homolog 6), 6), and and PMS2 PMS2 (postmeiotic (postmeiotic segregation segregation 2) 2) proteins proteins [30]. [30]. There areare 33 typestypes of of MSI MSI based based on on its its frequency: frequenc highy: high microsatellite microsatellite instability instability (MSI-H), (MSI-H), low lowmicrosatellite microsatellite instability instability (MSI-L) and(MSI-L) microsatellite and microsatellite stable (MSS) stable [31,32 ]. Approximately(MSS) [31,32]. Approximately12 to 20% of CRCs 12 to are 20% explained of CRCs byare MSI-H explained due by to MSI-H MMR-D, due with to MMR-D, a higher with incidence a higher in incidencethe early stagesin the early (about stages 20% (about in stage 20% I and in st II,age and I and 12% II, in and stage 12% III) in and stage a lower III) and incidence a lower incidencein the metastatic in the metastatic setting (4 tosetting 5%) [ 21(4, 33to, 345%].) Today,[21,33,34]. MSS-L Today, and MSSMSS-L are and still MSS classified are still as classifiedone kind, as thereone kind, is no as distinct there phenotypes/genotypesis no distinct phenotypes/genotypes linked with MSI-L linked determined with MSI-L by determinedmicrosatellite by markers microsat [35ellite,36]. markers [35,36]. Figure 1. (A–C) Functioning mismatch repair system (MMR) capable of repairing DNA mismatch error, whereas (b,c) DefectiveFigure 1. ( mismatchA–C) Functioning
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