Gene-specific features (MLH1, MSH2, MSH6, PMS2) of mismatch repair (MMR) protein expression and somatic mutations, microsatellite instability (MSI), and tumor mutational burden (TMB) in MSI-H and MMR-mutated tumor genomic profiles


Michael J Hall, J. Nicholas Bodor, Joanne Xiu, Rebecca Feldman, Elizabeth A Handorf, Axel Grothey, Richard M Goldberg, William M Worrilow, Jimmy Hwang, Edward Kim, Heinz-Josef Lenz, Derek Raghavan, Anthony Shields, W Michael Korn, John L Marshall, Mohamed E Salem


MSI-H is a tumor phenotype associated with increased tumor mutational burden (TMBH) and response to anti-PD1/PD-L1 immune checkpoint inhibition (ICI).

Loss of expression of the mismatch repair (MMR) heterodimers including the MutL homolog 1 (MLH1/PMS2) and MutS homolog 2 (MSH2/MSH6) is characteristic of many MSI-H tumors and is commonly assayed through immunohistochemistry (IHC).

Somatic mutations of the individual MMR genes are less clearly associated with MSI-H, TMB-H, PD-L1 expression, and response to ICI. These relationships are critical in understanding why immune therapies are effective and how resistance develops.


The results from clinical somatic tumor profiles conducted by Caris Life Sciences were examined in two samples of histologically diverse tumors undergoing somatic tumor profiling: 1) all MSI-H tumors or 2) all tumors with somatic MMR mutations. The datasets overlap among tumors with somatic MMR mutations that are also MSI-H (~ 60-70% of tumors with somatic MMR mutations).

The relationship of relevant biomarkers of ICI to TMB-H, PD-L1 expression, IHC loss of expression of the MMR proteins were examined. Associations with the recurrent MSH6 F1088fs mutation, POLE, and HRD somatic mutations (e.g. BRCA1/2, ATM, PALB2, etc.) were also explored.


Heterogeneity of testing conducted was present in both sample groups: e.g., not all tumors had IHC for the MMR proteins conducted, particularly non-CRC non-EC.

Germ-line matched DNA samples were not collected, limiting the ability to distinguish rare germline variants from somatic mutations. Family history data were also uncollected.


MSI-H, TMB-H, and PD-L1 expression are related but non-identical phenotypes that are associated with response to ICI.

MMR gene- and histology-specific variability in MSI-H, TMB-H, and PD-L1 expression suggest that the underlying causes of increased tumor mutation and checkpoint evasion may be relevant to treatment efficacy and resistance.

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