High microsatellite instability (MSI-H) colorectal carcinoma: a brief review of predictive biomarkers in the era of personalized medicine

Abstract

Approximately 15 % of colorectal carcinomas (CRC) display high level microsatellite instability (MSI-H) due to either a germline mutation in one of the genes responsible for DNA mismatch repair (Lynch syndrome, 3 %) or somatic inactivation of the same pathway, most commonly through hypermethylation of the MLH1 gene (sporadic MSI-H, 12 %). Although heterogeneous, MSI-H colorectal carcinomas as a group show some distinct biologic characteristics when compared to CRC with stable or low level microsatellite instability. In the present review we will highlight therapeutically relevant characteristics of MSI-H tumors which could lead to specific responses to some conventional chemotherapy or novel targeted therapy agents.

Keywords: Biomarkers; Colorectal cancer; Conventional chemotherapy; Lynch syndrome; Microsatellite instability; Targeted therapy.

Fig. 1

A colorectal carcinoma from a case of Lynch syndrome caused by an MLH1 gene mutation: A hematoxylin and eosin (H&E) stained slide, B immunohistochemistry (IHC) showing concurrent loss of PMS2 in tumor cells, C tumor cells were diffusely positive (90–100 %) for topoisomerase 1 and D strongly positive (3+) for thymidylate synthase

Fig. 2

A poorly differentiated (signet ring) colorectal carcinoma with microsatellite instability-high status caused by the loss of MLH1: A H&E-stained slide, B loss of MLH1 in tumor cells by IHC, C concurrent loss of PMS2 in tumor cells by IHC; note retained expression of both MLH1 and PMS2 proteins in adjacent tumor-infiltrating lymphocytes, D IHC showing that the tumor also harbored the BRAF V600E mutation, E the tumor cells exhibited 2+ PD-L1 expression in ~85 % of the tumor cells (anti-PD-L1 clone SP142) and F while tumor infiltrating lymphocytes were positive for PD-1 protein

Fig. 3

The case from Fig. 2: A showing loss of MGMT protein expression by IHC and B pyrosequencing results showing hypermethylation of the MGMT promoter (57–66 % methylation at five different sites)