Microsatellite instability and mismatch repair deficiency define a distinct subset of lung cancers characterized by smoking exposure, high tumor mutational burden and recurrent somatic MLH1 inactivation.
Academic Article
Overview
abstract
INTRODUCTION: Microsatellite instability (MSI) and mismatch repair (MMR) deficiency represent a distinct oncogenic process and predict response to immune-checkpoint inhibitors (ICIs). The clinicopathologic features of MSI-High (MSI-H) and MMR deficiency (MMR-D) in lung cancers remain poorly characterized. METHODS: MSI status from 5,171 patients with non-small cell lung cancer (NSCLC) and 315 patients with small cell lung cancer (SCLC) was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines. RESULTS: MSI-H/MMR-D was identified in 21 (0.41%) NSCLC and 6 (1.9%) SCLC patients. Notably, all patients with NSCLC histology had a positive smoking history, including 11 adenocarcinomas. Compared to microsatellite stable cases, MSI-H/MMR-D was associated with exceptionally high tumor mutational burden (TMB) (37.4 vs. 8.5 muts/Mb, p<0.0001), MMR mutational signatures (43% vs. 0%, p<0.0001), and somatic biallelic alterations in MLH1 (52% vs. 0%, p<0.0001). Loss of MLH1/PMS2 expression by immunohistochemistry was seen in MLH1 altered and wild type cases. Similarly, most patients with MSI-H/MMR-D SCLC showed evidence of MLH1 inactivation, including two with MLH1 promoter hypermethylation. A single NSCLC patient with a somatic MSH2 mutation had Lynch syndrome as confirmed by the presence of a germline MSH2 mutation. Amongst patients with advanced MSI-H/MMR-D lung cancers treated with ICIs, durable clinical benefit (DCB) was seen in 3/8 NSCLC patients and 2/2 SCLC patients. In NSCLC, STK11, KEAP1, and JAK1 were mutated in non-responders but wild type in responders. CONCLUSIONS: We present a comprehensive clinico-genomic landscape of MSI-H/MMR-D lung cancers and demonstrate that MSI-H/MMR-D defines a rare subset of lung cancers associated with smoking, high TMB, and MLH1 inactivation. While DCB to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes.
