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