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:
F. Meric-Bernstam serves in a consulting/advisory role for Genentech, Inflection Biosciences, Pieris Pharmaceutical, Xencor, Samsung Bioepis, Sumitomo Group, Spectrum Pharmaceuticals, OrigiMed, Aduro Biotech, and Mersana; and has research funding support from Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, PUMA Biotechnology, Cytomx Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, Abbvie, Daiichi Sankyo, and Guardant Health. R.G. Verhaak owns stock in Pretzel Therapeutics. G.B. Mills is a consultant for AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, MedImmune, Nuevolution, Pfizer, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millenium Pharmaceuticals, and Tarveda; owns stock in Catena Pharmaceuticals, ImmunoMET, SignalChem,
Funding Information:
Spindletop Ventures, and Tarveda; has licensed technology of an HRD assay to Myriad Genetics; and has research sponsored by Abbvie, Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Critical Outcome Technologies, Horizon Diagnostics, Illumina, Immuno-MET, Ionis, Karus Therapuetics, Komen Research Foundation, Nanonstring, Ovarian Cancer Research Foundation, Pfizer, Prospect Creek Foundation, Takeda/Millenium Pharmaceuticals, and Tesaro. W.K.A. Yung is a paid consultant for DNATrix and NBTS and receives honoraria from DNATrix and NBTS. J.F. de Groot has research support from Sanofi-Aventis, AstraZe-neca, EMD-Serono, Eli Lilly, Novartis, Deciphera Pharmacetuicals, and Mundipharma; is a paid consultant for Celldex, Deceiphera Pharmaceuticals, Abbvie, FivePrime Therapuetics Inc., GW Pharma, CArthera, Eli Lilly, Boston Biomedical Inc., Kairos Venture Investments, Syneos Health, and Monteris; serves on the advisory board for Genentech, Celldex, Foundation Medicine, Inc., Novogen, Deciphera, AstraZeneca, Insys Therapeutics, Kadmon, Merck, and Eli Lilly; and owns stock in Ziopharm Oncology and Gilead. J.F. de Groot's spouse is employed by Ziopharm Oncology. No potential conflicts of interest were disclosed by the other authors.
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).
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 -