The clinical and genomic characteristics of MSI-h/dMMR lung cancer.

Abstract

e21142 Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) have been confirmed to be positively predictive biomarkers for immune checkpoint inhibitors (ICIs), especially in colorectal cancer and endometrial cancer. Numerous studies about molecular characteristic or clinical trails of MSI-H/dMMR have been achieved or ongoing. However, there are few researches of MSI-H/dMMR in lung cancer which has the highest morbidity in malignant tumors. Here, we explored clinical and genomic characteristics of MSI-H/dMMR lung cancer. Methods: We retrospectively analyzed 4996 lung cancer patients with available tissue NGS data. Microsatellite status was decided by MSI score which was tested by NGS combined with bioinformatics algorithms (MSI score < 0.05: MSS; MSI score > 0.15: MSI-H). In the absence of MMR IHC, dMMR was alternatively defined that DNA mismatch repair genes, including MLH2, PMS2, MSH2 and MSH6, had pathogenic or likely pathogenic mutations based on the American College of Medical Genetics and Genomics (ACMG) guidelines. RNA data of 552 lung cancer patients from The Cancer Genome Atlas (TCGA) was obtained to analyze immune microenvironment. Results: Of 4996 lung cancer patients, 58 (1.16%) patients were identified to be MSI-H/dMMR with a median age of 65.5 years old, of which 2.80% (9/322) patients were squamous carcinoma, significantly higher than adenocarcinoma 1.06% (30/2839) (p < 0.05). In MSI-H/dMMR, 8 (13.89%) patients were MSI-H, 41 (70.69%) patients were dMMR and 9 patients were both MSI-H and dMMR (15.52%). Compared with MSS patients, MSI-H/dMMR patients had more frame shift mutations. Moreover, it more often happened in dMMR than MSI-H that there were multiple mutations in one gene, which was indicated by Multi-Hit. Further exploration found that MSI-H/dMMR tumors had higher tumor mutation burden (TMB) than MSS (p < 0.05). RNA data revealed that enhanced anti-tumor immunity was observed in MSI-H/dMMR tumors. Activated CD4 memory T cell and CD8 T cell were more abundant in MSI-H/dMMR tumors. Conclusions: We analyzed clinical and genomic characteristics of MSI-H/dMMR lung cancer for the first time. Our data showed that MSI-H/dMMR was found in 1.16% lung cancer patients and more likely to occur in squamous cell lung carcinoma. MSI-H/dMMR in lung cancer was associated with higher TMB and may well enhance anti-tumor immunity.