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

• Main Authors: Hui Zhao, Bernard Thienpont, Betül Tuba Yesilyurt, Matthieu Moisse, Joke Reumers, Lieve Coenegrachts, Xavier Sagaert, Stefanie Schrauwen, Dominiek Smeets, Gert Matthijs, Stein Aerts, Jan Cools, Alex Metcalf, Amanda Spurdle, ANECS, Frederic Amant, Diether Lambrechts
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2014-08-01
• Series: eLife
• Subjects: whole-genome sequencing; mismatch repair deficiency; mutation pattern; MSI; DNA double-strand break; DSB inducer
• Online Access: https://elifesciences.org/articles/02725

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.