Prospective Clinical Sequencing of Adult Glioma

Prospective Clinical Sequencing of Adult Glioma. 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. Mol Cancer Ther, 18(5):991-1000, 2019. 1538-8514 Zheng, Siyuan Orcid: 0000-0002-1031-9424 Alfaro-Munoz, Kristin Wei, Wei Wang, Xiaojing Wang, Fang Eterovic, Agda Karina Shaw, Kenna R Mills Meric-Bernstam, Funda Fuller, Gregory N Orcid: 0000-0001-9447-2647 Chen, Ken Orcid: 0000-0003-4013-5279 Verhaak, Roel G Mills, Gordon B Orcid: 0000-0002-0144-9614 Yung, W K Alfred Weathers, Shiao-Pei de Groot, John F P30 CA016672/CA/NCI NIH HHS/United States P50 CA127001/CA/NCI NIH HHS/United States U01 CA217842/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States 2019/03/31 Mol Cancer Ther. 2019 May;18(5):991-1000. doi: 10.1158/1535-7163.MCT-18-1122. Epub 2019 Mar 29.
doi abstract bibtex

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.

@article{RN6086,
   author = {Zheng, S. and Alfaro-Munoz, K. and Wei, W. and Wang, X. and Wang, F. and Eterovic, A. K. and Shaw, K. R. M. and Meric-Bernstam, F. and Fuller, G. N. and Chen, K. and Verhaak, R. G. and Mills, G. B. and Yung, W. K. A. and Weathers, S. P. and de Groot, J. F.},
   title = {Prospective Clinical Sequencing of Adult Glioma},
   journal = {Mol Cancer Ther},
   volume = {18},
   number = {5},
   pages = {991-1000},
   note = {1538-8514
Zheng, Siyuan
Orcid: 0000-0002-1031-9424
Alfaro-Munoz, Kristin
Wei, Wei
Wang, Xiaojing
Wang, Fang
Eterovic, Agda Karina
Shaw, Kenna R Mills
Meric-Bernstam, Funda
Fuller, Gregory N
Orcid: 0000-0001-9447-2647
Chen, Ken
Orcid: 0000-0003-4013-5279
Verhaak, Roel G
Mills, Gordon B
Orcid: 0000-0002-0144-9614
Yung, W K Alfred
Weathers, Shiao-Pei
de Groot, John F
P30 CA016672/CA/NCI NIH HHS/United States
P50 CA127001/CA/NCI NIH HHS/United States
U01 CA217842/CA/NCI NIH HHS/United States
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
United States
2019/03/31
Mol Cancer Ther. 2019 May;18(5):991-1000. doi: 10.1158/1535-7163.MCT-18-1122. Epub 2019 Mar 29.},
   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.},
   keywords = {Adult
Aged
Cell Line, Tumor
Female
Genome, Human/genetics
Glioblastoma/*genetics/pathology
Glioma/*genetics/pathology
*High-Throughput Nucleotide Sequencing
Humans
Isocitrate Dehydrogenase/genetics
Male
Middle Aged
Molecular Sequence Annotation
Mutation/genetics
Neoplasm Grading
Neoplasm Recurrence, Local/genetics/pathology
*Prognosis},
   ISSN = {1535-7163 (Print)
1535-7163},
   DOI = {10.1158/1535-7163.Mct-18-1122},
   year = {2019},
   type = {Journal Article}
}

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