Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches

Abstract

Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.

Keywords: Adjuvant chemotherapy; Gastric cancer; Immune-checkpoint inhibitors; Microsatellite instability; Molecular stratification; Predictive and prognostic value.

Fig. 1

Different immune microenvironment in microsatellite instability-high (MSI) hypermutated tumours and in microsatellite stable (MSS) tumours with low-mutational rate. a In the presence of deficient mismatch repair (MMR), DNA replications errors go undetected and unrepaired, leading to a tumour with high mutational burden. Hyper-mutated cancer cells produce several neo-antigens, which stimulate T-cell activation and tumour infiltration by immune cells. To counteract this vigorous immune response, tumour cell exposes checkpoint molecules, e.g., PD-L1, to inhibit anti-tumour activity. b In the presence of functional MMR system, replication errors occur rarely with lower mutational rate and, as a consequence, limited production of neo-antigens. For this reason, in MSS tumour, the amount of T-cell infiltration and checkpoint molecules exhibition is low. The peculiar immune microenvironment of MSI tumours is thought to explain why they are ideal target for therapy with immune-checkpoint inhibitors. MHC major histocompatibility complex, TCR T-cell receptor

Fig. 2

Representative capillary electrophoresis (pherogram) of the Promega MSI Analysis System generated using GeneMapper 3.7 Analysis Software. The upper part of the figure shows microsatellite stability (MSS) in normal tissue, without shifted alleles. The lower part is representative of tumour microsatellite instability-high (MSI) in all loci, with evident alleles shifting. Green: peaks of mononucleotides NR-21, BAT-25, and MONO-27. Blue: peak of BAT-26. Black: peak of NR-24