DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
03
06
2020
revised:
23
09
2020
accepted:
15
12
2020
pubmed:
24
12
2020
medline:
29
1
2022
entrez:
23
12
2020
Statut:
ppublish
Résumé
Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.
Identifiants
pubmed: 33355208
pii: 2159-8290.CD-20-0790
doi: 10.1158/2159-8290.CD-20-0790
pmc: PMC8223607
mid: NIHMS1656860
doi:
Substances chimiques
DNA-Directed DNA Polymerase
EC 2.7.7.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1176-1191Subventions
Organisme : NIEHS NIH HHS
ID : R01 ES028271
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Organisme : Canadian Institutes for Health Research
ID : PJT-156006
Organisme : CIHR
ID : 108188
Pays : Canada
Informations de copyright
©2020 American Association for Cancer Research.
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