- In normal cells, the DNA mismatch repair (MMR) system recognizes and repairs genetic mismatches generated
during DNA replication.1,4
- A deficient MMR (dMMR) system results in the persistence of DNA mismatches in microsatellites that may then be
incorporated into the genetic code as mutations.1,4
- A dMMR system can be hereditary or sporadic in nature.1
- Tumors that have a dMMR system can develop MSI, which is the expansion or reduction in the length of repetitive sequences in tumor DNA compared with normal DNA.1
- Tumors that have MSI due to a dMMR system can exhibit the MSI‑high (MSI‑H) phenotype.1,4
- Tumors with a dMMR/MSI‑H system harbor hundreds to thousands of mutations, which stimulates the
immune system.2,3
- MSI-H tumors contain high levels of lymphocyte infiltrates and strong expression of immune checkpoints,
including PD-1 and PD-L1.3
- In colorectal MSI‑H cancers, the dominant source of PD-L1 may be macrophages or other tumor-infiltrating lymphocytes and myeloid cells, rather than tumor cells.3
PD-L1 = programmed death ligand 1; PD-1 = programmed death receptor-1.
Mismatch repair deficiency across 12,019 tumors.
The proportion of mismatch repair–deficient
tumors in each cancer subtype is expressed as
a percentage. Mismatch repair–deficient tumors
were identified in 24 of 32 tumor subtypes tested,
more often in early-stage disease (defined as
stage <IV).
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Republished with permission of American Association for the Advancement of Science, from Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Le, 357, 2017; permission conveyed through Copyright Clearance Center, Inc.
EGJ = esophagogastric junction; NSCLC = non–small cell lung cancer.