Prospective clinical sequencing of adult glioma

Siyuan Zheng, Kristin Alfaro-Munoz, Wei Wei, Xiaojing Wang, Fang Wang, Agda Karina Eterovic, Kenna R.Mills Shaw, Funda Meric-Bernstam, Gregory N. Fuller, Ken Chen, Roel G. Verhaak, Gordon B. Mills, W. K.Alfred Yung, Shiao Pei Weathers, John F. De Groot

    Research output: Contribution to journalArticle

    2 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)991-1000
    Number of pages10
    JournalMolecular cancer therapeutics
    Volume18
    Issue number5
    DOIs
    StatePublished - Jan 1 2019

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Zheng, S., Alfaro-Munoz, K., Wei, W., Wang, X., Wang, F., Eterovic, A. K., Shaw, K. R. M., Meric-Bernstam, F., Fuller, G. N., Chen, K., Verhaak, R. G., Mills, G. B., Yung, W. K. A., Weathers, S. P., & De Groot, J. F. (2019). Prospective clinical sequencing of adult glioma. Molecular cancer therapeutics, 18(5), 991-1000. https://doi.org/10.1158/1535-7163.MCT-18-1122