Abstract 181P
Background
Among Microsatellite instability-high (MSI-H) solid tumors, a subgroup demonstrates detectable mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations (MSI-H/MMR+), while the other subgroup lacks these mutations (MSI-H/MMR-). It is crucial to investigate potential distinctions among these two groups of patients.
Methods
A total of 9781 patients with pan-solid tumors were enrolled in the study, and their tissue samples were subjected to genetic testing by Next Generation Sequencing (NGS). Additionally, Multiplex immunofluorescence (mIF) staining was performed to investigate tumor immune microenvironment in 12 patients with MSI-H.
Results
A total of 311 (3.2%) patients were identified as MSI-H by NGS. A majority of MSI-H patients (94.5%, 294/311) exhibited detectable MMR gene mutations, while a minority (5.5%, 17/311) lacked MMR gene mutations. There was no significant difference in the distribution of cancer types between patients in the MSI-H/MMR+ and MSI-MMR- groups. The top three cancer types were colorectal, gastric and endometrial cancer. Comparison revealed MSI-H/MMR+ patients exhibiting a higher prevalence of male patients (49.3% vs. 17.6%, p=0.01), elevated tumor mutational burdens (median: 56.13 vs. 13.51 Muts/Mb, p=0.003), and increased mutation rates in POLE (45.2% vs. 17.6%, p=0.02) and POLD1 (73.5% vs. 35.3%, p=0.0007). Additionally, the frequency of NTRK gene fusion was higher in MSI-H patients compared to microsatellite stable (MSS) patients (1.6% vs. 0.2%, p<0.001). Interestingly, MSI-H/MMR+ patients exhibited a higher incidence of NTRK gene fusion than MSI-H/MMR- patients (1.7% vs. 0%, p=0.6). 12 patients with available mIF data revealed that MSI-H/MMR+ patients (n=7) exhibited a significantly higher infiltration of M1 macrophages within the tumors than MSI-H/MMR- patients (median: 308.0 vs. 48.1 cells/mm2, p=0.03).
Conclusions
The study supports the concept that MSI-H patients with or without MMR gene mutations comprise two distinct molecular subgroups. We propose that MSI-H patients with MMR gene mutations may be more amenable to immunotherapy, although additional validation is warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
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