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Salem ME, Bodor JN, Puccini A, Xiu J, Goldberg RM, Grothey A, Korn WM, Shields AF, Worrilow WM, Kim ES, Lenz HJ, Marshall JL, Hall MJ
Relationship between MLH1, PMS2, MSH2, and MSH6 gene specific alterations and tumor mutational burden (TMB) in 1,057 microsatellite instability-high solid tumors
Int J Cancer (2020) In process.
Abstract
Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs), but 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 and hypothesized differences would be identified by protein/gene affected/mutated and the tumor histology/primary site. Overall 1,057 MSI-H tumors were identified from 32,932 tested. MSI was examined by NGS using 7,000+ 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 versus 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<0.0001), and was associated with lower mean TMB [(MLH1/PMS2: 25.03 mut/Mb versus MSH2/MSH6 46.83 mut/Mb)](p<0.0001). 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<0.0001). 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. This article is protected by copyright. All rights reserved.
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Publication Date: 2020-05-24.
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Last updated on Sunday, July 05, 2020