Editors' ChoiceCancer

Unraveling the mysteries of microsatellite instability

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Science Translational Medicine  06 Jan 2021:
Vol. 13, Issue 575, eabg1757
DOI: 10.1126/scitranslmed.abg1757


DNA polymerase proofreading and mismatch repair deficiency have different microsatellites signatures.

Human cells have developed several enzymatic pathways to repair damaged DNA during DNA replication and recombination, such as DNA mismatch repair (MMR), which recognizes and repairs erroneous insertion, deletion, or misincorporation of bases, and DNA polymerase (encoded by POLE and POLD1), which proofreads each nucleotide and excises mismatched nucleotides. Deficiencies of MMR, caused by somatic hypermethylation of the MLH1 promoter or loss of heterozygosity from the germline allele in any one of the MMR genes, can lead to accumulation of microsatellite insertions and deletions known as microsatellite instability (MSI). MSI has been approved as a biomarker for cancer treatment with immune checkpoint inhibitors. In the clinic, MSI is commonly detected by comparing microsatellite lengths of a limited panel of microsatellites at five loci between germline and tumor DNA. Using this assay, patients with DNA polymerase proofreading–deficient tumors do not exhibit a high MSI phenotype and therefore do not receive treatment with immune checkpoint inhibitors.

Chung et al. conducted exome- and genome-wide microsatellite instability analysis in multiple cancer types and identified five distinct signatures, including specific signatures for MMR and DNA polymerase deficiencies. The MMR deficiency signature is dominated by multi-base losses that are dependent on the initial microsatellite length, whereas polymerase proofreading deficiency leads to accumulation of single-base gains that are also associated with high microsatellite insertions and deletions (MS-indels). Further, the authors show that the signatures can be used as clinical tool for managing screening of individuals with germline MMR deficiency and replication repair–deficient cancers through detection of replication repair deficiency in healthy cells.

The findings of this study answer essential biological questions about how MMR and DNA polymerase can lead to accumulation of insertion or deletions during carcinogenesis. Furthermore, these findings demonstrate that the identified signatures can be used both for diagnosis of replication repair deficiency and as a predictive biomarker for treatment with immune checkpoint inhibitors.

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