Relationship between MLH1 , PMS2 , MSH2 and MSH6 gene‐specific alterations and tumor mutational burden in 1057 microsatellite instability‐high solid tumors
| Autor: | Mohamed E. Salem, Heinz-Josef Lenz, Michael J. Hall, John L. Marshall, Alberto Puccini, Richard M. Goldberg, William M Worrilow, Anthony F. Shields, J. Nicholas Bodor, Edward S. Kim, Joanne Xiu, W. Michael Korn, Axel Grothey |
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| Rok vydání: | 2020 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Cancer Research nutritional and metabolic diseases Microsatellite instability Gene mutation Biology medicine.disease MLH1 digestive system diseases MSH6 03 medical and health sciences 0302 clinical medicine Oncology MSH2 030220 oncology & carcinogenesis medicine PMS2 Cancer research Immunohistochemistry Missense mutation neoplasms |
| Zdroj: | International Journal of Cancer. 147:2948-2956 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/ijc.33115 |
| Popis: | Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI. |
| Databáze: | OpenAIRE |
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