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 language | English (US) |
|---|---|
| Pages (from-to) | 991-1000 |
| Number of pages | 10 |
| Journal | Molecular cancer therapeutics |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Prospective Clinical Sequencing of Adult Glioma. / Zheng, Siyuan; Alfaro-Munoz, Kristin; Wei, Wei; Wang, Xiaojing; Wang, Fang; Eterovic, Agda Karina; Shaw, Kenna R.Mills; Meric-Bernstam, Funda; Fuller, Gregory N.; Chen, Ken; Verhaak, Roel G.; Mills, Gordon; Yung, W. K.Alfred; Weathers, Shiao Pei; de Groot, John F.
In: Molecular cancer therapeutics, Vol. 18, No. 5, 01.05.2019, p. 991-1000.Research output: Contribution to journal › Article
}
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
AU - Yung, W. K.Alfred
AU - Weathers, Shiao Pei
AU - de Groot, John F.
PY - 2019/5/1
Y1 - 2019/5/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85065508469&partnerID=8YFLogxK
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U2 - 10.1158/1535-7163.MCT-18-1122
DO - 10.1158/1535-7163.MCT-18-1122
M3 - Article
VL - 18
SP - 991
EP - 1000
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 5
ER -