title: Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks.
abstract: DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and whole-exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, indicating that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the 'DNA double-strand break repair by homologous recombination' pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dose-dependent sensitivity of MMR-deficient tumor cultures to DSB inducers.
authors.affiliation: VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Bernard
authors.identifier: http://orcid.org/0000-0002-8772-6845
authors.initials: B
authors.lastname: Thienpont
authors.affiliation: VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Betül Tuba
authors.initials: BT
authors.lastname: Yesilyurt
authors.affiliation: VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Matthieu
authors.identifier: http://orcid.org/0000-0001-8880-9311
authors.initials: M
authors.lastname: Moisse
authors.affiliation: VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Reumers
authors.affiliation: Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Coenegrachts
authors.affiliation: Division of Pathology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.affiliation: Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schrauwen
authors.affiliation: VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Dominiek
authors.initials: D
authors.lastname: Smeets
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Stein
authors.initials: S
authors.lastname: Aerts
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.affiliation: Division of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Metcalf
authors.affiliation: Division of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Spurdle
authors.affiliation: Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Amant
authors.affiliation: VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium diether.lambrechts@vib-kuleuven.be.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
mesh_terms: D020137:Base Pair Mismatch; D014408:Biomarkers, Tumor / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D016172:DNA Fingerprinting; D053843:DNA Mismatch Repair; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D059765:Homologous Recombination; D006801:Humans; D054643:INDEL Mutation; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor
keywords: DNA double-strand breaks; DSB inducers; MSI; mismatch repair deficiency; mutation pattern; whole-genome sequencing
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