2023 World Conference on Lung Cancer (Posters)-P1.21. Microsatellite Instability Defines a Subset of Lung Cancers with Smoking Exposure, High Tumor Mutational Burden and MLH1 Inactivation.<b></b>

P1.21. Microsatellite Instability Defines a Subset of Lung Cancers with Smoking Exposure, High Tumor Mutational Burden and MLH1 Inactivation. - PDF(Slides)

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A study conducted at the Memorial Sloan Kettering Cancer Center has identified a subset of lung cancers characterized by microsatellite instability (MSI) and mismatch repair deficiency (MMR-D). This subset of lung cancers is associated with smoking exposure, high tumor mutational burden, and inactivation of MLH1 gene. The study analyzed the MSI status of 5,171 patients with non-small cell lung cancer (NSCLC) and 315 patients with small cell lung cancer (SCLC) using next-generation sequencing data. MSI-H/MMR-D was observed in 0.41% of NSCLC cases and 1.9% of SCLC cases. Among NSCLC cases, MSI-H/MMR-D was associated with higher tumor mutational burden, dominant MMR mutational signatures, and somatic biallelic alterations in MLH1 gene. In SCLC cases with MSI-H/MMR-D, there was a significant enrichment of combined histology with large cell neuroendocrine carcinoma. The study also found that somatic truncating MSH2 mutations were seen in MLH1 wild type cases. A single patient with MSI-H/MMR-D NSCLC and a somatic MSH2 mutation had Lynch syndrome, a hereditary cancer predisposition syndrome. Among patients with MSI-H/MMR-D lung cancers treated with immune-checkpoint inhibitors (ICIs), durable clinical benefit was observed in some cases. However, the study also found that the clinical activity of ICIs may be modulated by co-mutational landscapes. Overall, this study provides further understanding of the characteristics of MSI-H/MMR-D lung cancers and the potential for targeted therapies in this subset of patients.

Asset Subtitle

Soo-Ryum Yang

Meta Tag

Speaker Soo-Ryum Yang

Topic Pathology & Biomarkers: Biomarkers for Immuno-oncology

Keywords

lung cancers

microsatellite instability

mismatch repair deficiency

smoking exposure

tumor mutational burden

MLH1 gene

non-small cell lung cancer

next-generation sequencing

large cell neuroendocrine carcinoma

immune-checkpoint inhibitors