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.

The evolving role of microsatellite instability in colorectal cancer: A review / Gelsomino, Fabio; Barbolini, Monica; Spallanzani, Andrea; Pugliese, Giuseppe; Cascinu, Stefano. - In: CANCER TREATMENT REVIEWS. - ISSN 0305-7372. - 51:(2016), pp. 19-26. [10.1016/j.ctrv.2016.10.005]

The evolving role of microsatellite instability in colorectal cancer: A review

Gelsomino, Fabio;Barbolini, Monica;Spallanzani, Andrea;Pugliese, Giuseppe;Cascinu, Stefano
2016

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.
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The evolving role of microsatellite instability in colorectal cancer: A review / Gelsomino, Fabio; Barbolini, Monica; Spallanzani, Andrea; Pugliese, Giuseppe; Cascinu, Stefano. - In: CANCER TREATMENT REVIEWS. - ISSN 0305-7372. - 51:(2016), pp. 19-26. [10.1016/j.ctrv.2016.10.005]
Gelsomino, Fabio; Barbolini, Monica; Spallanzani, Andrea; Pugliese, Giuseppe; Cascinu, Stefano
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1157144
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