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Elife. 2014 Aug 1;3:e02725. doi: 10.7554/eLife.02725.

Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks.

Author information

1
VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium.
2
Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Leuven, Belgium.
3
Division of Pathology, University Hospital Gasthuisberg, Leuven, Belgium.
4
Department of Human Genetics, KU Leuven, Leuven, Belgium.
5
Department of Human Genetics, KU Leuven, Leuven, Belgium VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium.
6
Division of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
7
VIB Vesalius Research Center, KU Leuven, Leuven, Belgium Department of Oncology, KU Leuven, Leuven, Belgium diether.lambrechts@vib-kuleuven.be.

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.

KEYWORDS:

DNA double-strand breaks; DSB inducers; MSI; mismatch repair deficiency; mutation pattern; whole-genome sequencing

PMID:
25085081
PMCID:
PMC4141275
DOI:
10.7554/eLife.02725
[Indexed for MEDLINE]
Free PMC Article

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