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 Journal Article
| Authors: | Yang, S. R.; Gedvilaite, E.; Ptashkin, R.; Chang, J.; Ziegler, J.; Mata, D. A.; Villafania, L. B.; Nafa, K.; Hechtman, J. F.; Benayed, R.; Zehir, A.; Benhamida, J.; Arcila, M. E.; Mandelker, D.; Rudin, C. M.; Paik, P. K.; Drilon, A.; Schoenfeld, A. J.; Ladanyi, M. |
| Article Title: | 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 |
| 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 5171 patients with NSCLC and 315 patients with SCLC was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines. Results: MSI-H and MMR-D were identified in 21 patients with NSCLC (0.41%) and six patients with SCLC (1.9%). Notably, all patients with NSCLC had a positive smoking history, including 11 adenocarcinomas. Compared with microsatellite stable cases, MSI-H was associated with exceptionally high tumor mutational burden (37.4 versus 8.5 muts/Mb, p < 0.0001), MMR mutational signatures (43% versus 0%, p < 0.0001), and somatic biallelic alterations in MLH1 (52% versus 0%, p < 0.0001). Loss of MLH1 and PMS2 expression by immunohistochemistry was found in MLH1 altered and wild-type cases. Similarly, the majority of patients with MSI-H SCLC had evidence of MLH1 inactivation, including two with MLH1 promoter hypermethylation. A single patient with NSCLC with a somatic MSH2 mutation had Lynch syndrome as confirmed by the presence of a germline MSH2 mutation. Among patients with advanced MSI-H lung cancers treated with ICIs, durable clinical benefit was observed in three of eight patients with NSCLC and two of two patients with SCLC. In NSCLC, STK11, KEAP1, and JAK1 were mutated in nonresponders but wild type in responders. Conclusions: We present a comprehensive clinicogenomic landscape of MSI-H lung cancers and reveal that MSI-H defines a rare subset of lung cancers associated with smoking, high tumor mutational burden, and MLH1 inactivation. Although durable clinical benefit to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes. © 2023 International Association for the Study of Lung Cancer |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; protein expression; aged; major clinical study; promoter region; somatic mutation; smoking; wild type; history; mismatch repair; microsatellite instability; cancer tissue; tumor gene; lynch syndrome; mismatch repair protein; mismatch repair protein pms2; small cell lung cancer; non small cell lung cancer; germline mutation; mlh1; immune checkpoint inhibitor; high throughput sequencing; keap1 gene; human; male; female; article; stk11 gene; whole exome sequencing; non–small cell lung cancer; mutl protein homolog 1; tumor mutational burden; jak1 gene |
| Journal Title: | Journal of Thoracic Oncology |
| Volume: | 19 |
| Issue: | 3 |
| ISSN: | 1556-0864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2024-03-01 |
| Start Page: | 409 |
| End Page: | 424 |
| Language: | English |
| DOI: | 10.1016/j.jtho.2023.10.004 |
| PUBMED: | 37838086 |
| PROVIDER: | scopus |
| PMCID: | PMC10939956 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Soo-Ryum Yang -- Source: Scopus |
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