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

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 has historically been a tissue-based procedure that involves the testing of adequate tissue with a high concentration of cancer cells, in addition to the requirement for paired normal tissues. The invasive nature and specific prerequisite of such tests might hinder its application when surgery is not an option or when the tissues are insufficient. The application of next-generation sequencing, which is highly sensitive, in combination with liquid biopsy, therefore, presents an interesting possibility worth exploring. This review aimed to discuss the current body of evidence supporting the potential of liquid biopsy as a tool for MSI testing in CRC.

MSI Analysis in Solid and Liquid Biopsies of Gastroesophageal Adenocarcinoma Patients: A Molecular Approach

“…Indeed, IHC, which still represent the gold standard for diagnostic typing, is time-consuming and costly and not feasible for longitudinal monitoring of patients. On the other hand, the PCR-based analysis in FFPE samples has demonstrated that it is an optimal alternative to IHC in colorectal cancer [ 26 ]. Moreover, the molecular MSI detection permits one to identify also the cases with a normal expression of dysfunctional MMR proteins, explaining the discordance observed between IHC and molecular tests in the literature [ 10 , 27 ].…”

Detection of Microsatellite Instability in Colorectal Cancer Patients With a Plasma-Based Real-Time PCR Analysis

“…It might also be used as an MSI test in patients with other unresectable tumors such as metastatic endometrial and pancreatic cancer. Studies on the effectiveness of MSI diagnosis using liquid biopsy have been actively reported in MSI tests ( Tieng et al, 2021 ). The study of NGS-based liquid biopsy is still limited to the academic field because it is expensive, takes a long time to analyze, and has limitations in interpreting data used in bioinformatics ( Niu et al, 2014 ; Liu et al, 2019 ).…”

“…During the interpretation process, the assessment of MMR status can be influenced by the pathologist’s subjective interpretation and technical factors. This method requires an invasive procedure to obtain tissue and is limited in the case of patients who cannot provide tissue ( Joosse and Pantel, 2016 ; Tieng et al, 2021 ). Detection of MSI by PCR through fragment analysis, such as endoscopic biopsy, may not be appropriate because samples from both tumor and normal tissues are required.…”

“…Research to find diagnostic markers and prognostic factors of tumors through liquid biopsy is ongoing. In colorectal cancer, research has been conducted to utilize it for blood-based diagnosis and screening, and its usefulness has been reported in some cases ( You et al, 2010 ; Ferreira et al, 2016 ; Habli et al, 2020 ; Tieng et al, 2021 ). Therefore, the MSI molecular test has been suggested for blood samples and many studies are currently being conducted on its efficacy, but further research is still needed on its diagnostic value and clinical utility ( Mokarram et al, 2014 ; Silveira et al, 2020 ).…”

Liquid Biopsy-Based Colorectal Cancer Screening via Surface Markers of Circulating Tumor Cells

“…In short, CTCs are believed to generate valuable information and provide critical insights into the aggressive nature of the tumor and also a better understanding of the underlying biology related to CRC dissemination and metastasis [21,39]. Thus, the application of CTCs as cancer biomarkers offers a more effective alternative to detect, analyze, treat, and monitor CRC therapeutic responses and disease progression [40,41].…”