Low microsatellite instability: A distinct instability type in gastric cancer?

Abstract

Purpose We recently showed that low microsatellite instability (MSI-L) is associated with a good response to platinum/5-fluorouracil (5-FU) neoadjuvant chemotherapy (CTx) in gastric cancer. The purpose of this study was to characterize the instability pattern and to investigate an association of MSI-L tumors with mutations in genes of DNA repair pathways and with total tumor mutation burden (TMB). Methods MSI patterns were compared between 67 MSI high (-H) and 35 MSI-L tumors. Whole-exome sequencing was performed in 34 microsatellite stable (MSS) and 20 MSI-L tumors after or without neoadjuvant CTx. Results Of the 35 MSI-L tumors, 33 tumors had instability at a dinucleotide repeat marker. In the homologous recombination (HR) pathway, 10 of the 34 (29%) MSS and 10 of the 20 (50%) MSI-L tumors showed variants (p = 0.154). In the DNA damage tolerance pathway, 6 of the 34 (18%) MSS and 7 of the 20 (35%) MSI-L tumors had variants (p = 0.194). The HR deficiency score was similar in both tumor groups. TMB was significantly higher in MSI-L compared to MSS tumors after CTx (p = 0.046). In the MSS and MSI-L tumors without CTx no difference was observed (p = 1.00). Conclusion MSI-L due to instability at dinucleotide repeat markers was associated with increased TMB after neoadjuvant CTx treatment, indicating sensitivity to platinum/5-FU CTx. If confirmed in further studies, this could contribute to refined chemotherapeutic options including immune-based strategies for GC patients with MSI-L tumors.

Clinical features and oncological outcomes of bladder cancer microsatellite instability

“…The implication of higher TMB in MSI-L tumors may account for a higher risk of intravesical recurrence with intravesical BCG by more aggressive phenotype in tumors with high TMB while MSI-L tumors may be more sensitive to intravesical chemotherapeutic agents as supported by previous study. 28 Consistently, it was reported that MSI-H was associated with high intravesical recurrence. 29 These findings imply that MSI-L/H status may be a predictive marker of intravesical BCG therapy.…”

“…Interestingly, Kohlruss et al have recently shown that tumors with MSI-L demonstrated higher susceptibility to the chemotherapeutic agents, and TMB was higher in tumors with MSI-L compared to tumors with MSS after chemotherapy for gastric cancer. 28 This finding suggests that the MSI-L phenotype reflects higher mutability by chemotherapeutic agents, implying that the tumors with MSI-L were associated with higher TMB in carcinogeninduced bladder cancer.…”