Abstract
Microsatellite instability (MSI) is the landmark feature of DNA mismatch repair deficiency, which can be found in 15–20% of all colorectal cancers (CRC). This specific set of tumors has been initially perceived as a niche for geneticists or gastroenterologists focused on inherited predispositions. However, over the years, MSI has established itself as a key biomarker for the diagnosis, then extending to forecasting the disease behavior and prognostication, including the prediction of responsiveness to immunotherapy and eventually to kinase inhibitors, and possibly even to specific biological drugs. Thanks to the contribution of the characterization of MSI tumors, researchers have first acknowledged that a strong lymphocytic reaction is associated with a good prognosis. This understanding supported the prognostic implications in terms of the low metastatic potential of MSI-CRC and has led to modifications in the indications for adjuvant treatment. Furthermore, with the emergence of immunotherapy, this strong biomarker of responsiveness has exemplified the capability of re-activating an effective immune control by removing the brakes of immune evasion. Lately, a subset of MSI-CRC emerged as the ideal target for kinase inhibitors. This therapeutic scenario implies a paradox in which appropriate treatments for advanced disease are effective in a set of tumors that seldom evolve towards metastases.
Highlights
Colorectal cancer (CRC) is the third most common malignancy and cause of cancer mortality in Europe and the United States, accounting for nearly 900.000 deaths every year worldwide [1]
This review summarizes the evidence demonstrating the value of microsatellite instability (MSI) as a diagnostic and prognostic tool and eventually a predictive biomarker in the personalized approach to CRC
In a study on patients included in a randomized trial on adjuvant 5-FU plus Oxaliplatin and folinic acid (FOLFOX) after resection of stage III CRC, Sinicrope et al found that KRAS and BRAF mutations had a negative prognostic effect on disease-free survival, while MSI was not prognostic in all patients but significantly interacted with the tumor site and nodal status [78]
Summary
Colorectal cancer (CRC) is the third most common malignancy and cause of cancer mortality in Europe and the United States, accounting for nearly 900.000 deaths every year worldwide [1]. Among the newly diagnosed CRC, approximately 20% of patients still present with a metastatic disease, and a further 25% of those with an initially localized disease will eventually develop distant metastases [2,3]. It is known that a small subset of CRCs, approximately 15% of the cases, demonstrate microsatellite instability (MSI). Due to an impaired DNA mismatch repair (MMR) system, though the vast majority of CRCs belong to the microsatellite stable (MSS) biomarker list [4]. The MSI status defines the largest group of inherited predispositions to gastrointestinal cancers and impacts the prognosis of CRC, giving better stage-adjusted survival rates compared to MSS tumors [6,7]. Discovery of MSI, Its Relevance in Lynch Syndrome and Understanding the Different Molecular Pathogenesis of CRC
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