Data from A Hypermutation Phenotype and Somatic <i>MSH6</i> Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy

• DOI: 10.1158/0008-5472.c.6495272.v1
• Publication Date: 2023-03-30T20:49:37Z
• Authors: Chris Hunter; Raffaella Smith; Daniel P. Cahill; Philip Stephens; Claire Stevens; Jon Teague; Chris Greenman; Sarah Edkins; Graham Bignell; Helen Davies; Sarah O'Meara; Adrian Parker; Tim Avis; Syd Barthorpe; Lisa Brackenbury; Gemma Buck; Adam Butler; Jody Clements; Jennifer Cole; Ed Dicks; Simon Forbes; Matthew Gorton; Kristian Gray; Kelly Halliday; Rachel Harrison; Katy Hills; Jonathon Hinton; Andy Jenkinson; David Jones; Vivienne Kosmidou; Ross Laman; Richard Lugg; Andrew Menzies; Janet Perry; Robert Petty; Keiran Raine; David Richardson; Rebecca Shepherd; Alexandra Small; Helen Solomon; Calli Tofts; Jennifer Varian; Sofie West; Sara Widaa; Andy Yates; Douglas F. Easton; Gregory Riggins; Jennifer E. Roy; Kymberly K. Levine; Wolf Mueller; Tracy T. Batchelor; David N. Louis; Michael R. Stratton; P. Andrew Futreal; Richard Wooster
• Keywords: Temozolomide; MSH6; Synthetic Lethality

&lt;div&gt;Abstract&lt;p&gt;Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although statistically significant increase in survival has been reported this regimen, nearly all recur become insensitive to further class agents. We sequenced 500 kb genomic DNA corresponding kinase domains 518 protein kinases each nine gliomas. Large numbers somatic mutations were observed two recurrent treatment. pattern cases showed strong similarity that induced by agents experimental systems. Further investigation revealed inactivating mismatch repair gene &lt;i&gt;MSH6&lt;/i&gt; case. propose confer resistance &lt;i&gt;in vivo&lt;/i&gt; concurrently unleash accelerated mutagenesis resistant clones as consequence continued exposure presence defective repair. evidence therefore suggests when is inactivated gliomas, convert from induction tumor cell death promotion neoplastic progression. These observations highlight potential large scale sequencing revealing elucidating mutagenic processes operative individual human cancers. (Cancer Res 2006; 66(8): 3987-91)&lt;/p&gt;&lt;/div&gt;