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

Meike Kohlruss, Shounak Chakraborty, Alexander Hapfelmeier, Moritz Jesinghaus, Julia Slotta-Huspenina, Alexander Novotny, Leila Sisic, Matthias M. Gaida, Katja Ott, Wilko Weichert, Nicole Pfarr, Gisela Keller

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)17727-17737
Number of pages11
JournalJournal of Cancer Research and Clinical Oncology
Volume149
Issue number20
DOIs
StatePublished - Dec 2023
Externally publishedYes

Keywords

  • Adenocarcinoma
  • Gastric
  • Microsatellite instability
  • Neoadjuvant chemotherapy
  • Tumor mutation burden

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