Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance
| Autor: | Rona Yaeger, Jinru Shia, Henry Walch, Diane Reidy-Lagunes, Agata A. Bielska, Nikolaus Schultz, Zsofia K. Stadler, Walid K. Chatila |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mutation rate congenital hereditary and neonatal diseases and abnormalities medicine.medical_treatment DNA Mismatch Repair Article Cancer syndrome 03 medical and health sciences 0302 clinical medicine Germline mutation Neoplastic Syndromes Hereditary Medicine Neoplasm Humans business.industry Brain Neoplasms Microsatellite instability Immunotherapy medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis Lynch syndrome 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research DNA mismatch repair Microsatellite Instability business Colorectal Neoplasms |
| Zdroj: | J Natl Compr Canc Netw |
| ISSN: | 1540-1413 |
| Popis: | Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors. |
| Databáze: | OpenAIRE |
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