RT Journal Article SR Electronic T1 Prospective Clinical Sequencing of Adult Glioma JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 991 OP 1000 DO 10.1158/1535-7163.MCT-18-1122 VO 18 IS 5 A1 Zheng, Siyuan A1 Alfaro-Munoz, Kristin A1 Wei, Wei A1 Wang, Xiaojing A1 Wang, Fang A1 Eterovic, Agda Karina A1 Shaw, Kenna R. Mills A1 Meric-Bernstam, Funda A1 Fuller, Gregory N. A1 Chen, Ken A1 Verhaak, Roel G. A1 Mills, Gordon B. A1 Yung, W.K. Alfred A1 Weathers, Shiao-Pei A1 de Groot, John F. YR 2019 UL http://mct.aacrjournals.org/content/18/5/991.abstract AB Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here, we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2,485 somatic mutations, including single-nucleotide substitutions and small indels, using a validated in-house protocol. Sixty-one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors and had comparable outcome, and most were associated with temozolomide exposure. TP53 was the most frequently mutated gene in our cohort, followed by IDH1 and EGFR. We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in The Cancer Genome Atlas, a pattern that can be partially explained by the different patient composition and sequencing depth. IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation. We predicted 1p/19q status using the panel sequencing data and received only modest performance by benchmarking the prediction to FISH results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting.This article is featured in Highlights of This Issue, p. 871