Mutational analysis of matched initial and recurrent TP53 WT primary GBM.
Year: 2015
Type: conference-abstract
Abstract: 2043 Background: Glioblastoma (GBM) present as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Tumours at diagnosis are distinct from their recurrences, the latter being more therapy resistant. Pinpointing the associated molecular alterations may better inform new therapeutic options to tackle resistance of recurrent disease. Methods: A study cohort of 29 patients with primary, TP53 wild-type GBM, with associated annotated clinical data were examined. Of these, 409 cancer associated genes, were examined in 21 paired primary/relapse FFPE extracted DNA specimens using the Comprehensive Cancer Panel (Life Technologies) with sequencing to a mean depth of 1200x. Whole exome sequencing (WES; Illumina HiSeq 2000) was conducted on an additional eight patients (paired primary/relapse) to an average of 70-fold coverage. Results: An average of 67±3 (range 49-101) non-synonymous variants or frameshift insertion/deletions were detected in tumour specimens at diagnosis and 53±4 (range 32-127) at relapse. Of these, an average of 27±2 and 13±3 variants were unique to tumours at diagnosis and relapse respectively and 50% of variants that were detected in the initial tumour were also present at relapse. WES revealed an average of 9112 somatic mutations across the genome per sample (range 603-47701). As distinct from recent reports of recurrent lower grade glioma very few patients showed a “hypermutable” signature that is characterized by numerous temozolamide (TMZ) associated specific mutations after treatment. In total, only 2/29 samples (7%) appeared to be hypermutated at relapse, with 55.6% of these mutations being attributable to TMZ-associated mutagenesis in the first patient and 44.3% in the second. Conclusions: Overallwe observed few consistent differences between paired diagnosis and relapse specimens. In contrast to previous studies we found evidence of hypermutation associated with TMZ treatment in the minority of patients. We propose that this may be related to the wild-type TP53 status in these patient's tumours.
Source: Journal of Clinical Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2803814167