TY - JOUR
T1 - Prospective clinical sequencing of adult glioma
AU - Zheng, Siyuan
AU - Alfaro-Munoz, Kristin
AU - Wei, Wei
AU - Wang, Xiaojing
AU - Wang, Fang
AU - Eterovic, Agda Karina
AU - Shaw, Kenna R.Mills
AU - Meric-Bernstam, Funda
AU - Fuller, Gregory N.
AU - Chen, Ken
AU - Verhaak, Roel G.
AU - Mills, Gordon B.
AU - Yung, W. K.Alfred
AU - Weathers, Shiao Pei
AU - De Groot, John F.
N1 - Funding Information:
We thank all patients who donated their samples to this project. This work is funded by Sheikh Khalifa Bin Zayed al Nahyan Institute for Personalized Cancer Therapy (IPCT) and Khalifa Bin Zayed Al Nahyan Foundation Grant (F. Meric-Bernstam, K.R.M. Shaw), MD Anderson Glioblastoma Moonshots Program (J.F. de Groot), Marnie Rose Foundation (J.F. de Groot), and Naz Moez Sarrafzadeh Glioma Research Account (W.K.A. Yung). S. Zheng is supported by CPRIT (RR170055) and a Career Enhancement Award of the Brain SPORE at MD Anderson (P50 CA127001).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
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.
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U2 - 10.1158/1535-7163.MCT-18-1122
DO - 10.1158/1535-7163.MCT-18-1122
M3 - Article
C2 - 30926639
AN - SCOPUS:85065508469
VL - 18
SP - 991
EP - 1000
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 5
ER -