title: The evolving role of microsatellite instability in colorectal cancer: A review.
abstract: Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs), more frequently in early than late-stage of disease. While in sporadic cases (about two-thirds of MSI-H CRCs) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene, the remainder are associated with Lynch syndrome, that is linked to a germ-line mutation of one of the MMR genes (MLH1, MSH2, MSH6, PMS2). MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations. In early-stage CRC, MSI can select a group of tumors with a better prognosis, while in metastatic disease it seems to confer a negative prognosis. Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors. The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination. Based on these considerations, MSI-H CRCs seem to be particularly responsive to immunotherapy, such as anti-PD-1, opening a new era in the treatment landscape for patients with metastatic CRC.
authors.affiliation: Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy. Electronic address: fabiogelsomino83@yahoo.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Gelsomino
authors.affiliation: Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy. Electronic address: barbolini.monica@gmail.com.
authors.forename: Monica
authors.initials: M
authors.lastname: Barbolini
authors.affiliation: Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy. Electronic address: andrea.spallanzani@gmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallanzani
authors.affiliation: Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy. Electronic address: giuseppe.pugliese.med@gmail.com.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
authors.affiliation: Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy. Electronic address: stefano.cascinu@unimore.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D006801:Humans; D053842:Microsatellite Instability; D011379:Prognosis
keywords: Colorectal cancer; Immunotherapy; Lynch syndrome; Microsatellite instability; Predictive