Title: Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks
Authors: Zhao, Hui ×
Thienpont, Bernard
Yesilyurt, Betül T
Moisse, Matthieu
Reumers, Joke
Coenegrachts, Lieve
Sagaert, Xavier
Schrauwen, Stefanie
Smeets, Dominiek
Matthijs, Gert
Aerts, Stein
Cools, Jan
Metcalf, Alex
Spurdle, Amanda
Amant, Frederic
Lambrechts, Diether #
Issue Date: Aug-2014
Series Title: eLife vol:3 pages:e02725
Article number: 10.7554/eLife.02725
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.
ISSN: 2050-084X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Translational Genetics (Vesalius Research Center) (+)
Translational Cell & Tissue Research
Gynaecological Oncology
× corresponding author
# (joint) last author

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