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

作者：Zhao Hui; Thienpont Bernard; Yesilyurt Betul Tuba; 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^*

来源：eLife, 2014, 3: e02725.

DOI：10.7554/eLife.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.

• 出版日期2014-8-22
• 单位河北医科大学