Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks
- VIB Vesalius Research Center, KU Leuven, Belgium
- University Hospital Gasthuisberg, Belgium
- KU Leuven, Belgium
- University of Leuven, Belgium
- Queensland Institute of Medical Research, Australia
- PO Royal Brisbane Hospital, Australia
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 -exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, confirming 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.
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Ethics
Human subjects: Informed consent and consent to publish was obtained from all patients. Ethical approval was obtained at the ethical committee of University Hospital Gasthuisberg of Leuven with identifier ML2266.
Copyright
© 2014, Zhao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks
eLife 3:e02725.
https://doi.org/10.7554/eLife.02725
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