National Cohort of Colorectal Cancers With Microsatellite Instability

Colorectal cancers with microsatellite instability The 3 main pathways of colorectal carcinogenesis are chromosomal instability (75% of CRCs), microsatellite instability (15% of CRCs) and CpG island hypermethylation or CIMP (CpG island methylator phenotype) (25% of CRCs).

Microsatellite instability (MSI) or RER+ (replication errors) phenotype is related to an acquired or inherited inactivation of the MMR (mismatch repair) system of DNA mismatch repair. In MSI CRCs associated with Lynch syndrome or HNPCC (hereditary nonpolyposis colorectal cancer) (3% of CRCs), there is a germline mutation in one of the genes of the MMR system, essentially MLH1 or MSH2, more rarely MSH6 or PMS2. In sporadic MSI cancers, frequently observed in the elderly, the loss of function of the MMR system is linked to a biallelic hypermethylation of the CpG islands of the MLH1 gene promoter causing its inactivation. Molecular individualization of CRCs has allowed the identification of tumor subgroups, such as MSI CRCs, that are more homogeneous in terms of their progression pathway, but the impact in terms of prognosis and treatment sensitivity remains to be clarified.

Prognosis and chemosensitivity of colorectal cancers with microsatellite instability MSI CRCs are associated with a better prognosis after curative surgery than CRCs without microsatellite instability (MSS) . In contrast, retrospective analyses of randomized trials indicate that patients with MSI CRC do not appear to benefit from adjuvant 5-FU-based chemotherapy in contrast to patients with MSS CRC. Nevertheless, the benefit of adjuvant chemotherapy with FOLFOX seems to be retained . The identification of prognostic markers in this subgroup of patients is therefore essential to decide on adjuvant chemotherapy, the efficacy of which is currently debated in MSI CRC.

To date, there are very few data concerning metastatic MSI CRC. Metastatic forms are rare (about 5% of metastatic CRCs), but are thought to be associated with chemoresistance and poor prognosis . Nevertheless, data are very sparse and there are no data regarding the use of modern chemotherapies and targeted therapies in metastatic MSI CRC. Thus, it is important to characterize the chemosensitivity of metastatic forms in order to offer the best treatment to patients.

Recent data show significant efficacy of immune checkpoint inhibitors in MSI CRC, including anti-PD1. Indeed, these tumors present a high number of mutations generating immunogenic neo-antigens. Thus, escape from anti-tumor immunity is a major mechanism of progression of MSI CRCs .