TY - JOUR
T1 - Comprehensive genetic alteration profiling in primary and recurrent glioblastoma
AU - Neilsen, Beth K.
AU - Sleightholm, Richard
AU - McComb, Rodney
AU - Ramkissoon, Shakti H.
AU - Ross, Jeffrey S.
AU - Corona, Robert J.
AU - Miller, Vincent A.
AU - Cooke, Matthew
AU - Aizenberg, Michele R.
N1 - Funding Information:
Funding This work was supported by NCI F30 CA203397 to B.K.N. The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/3/15
Y1 - 2019/3/15
N2 - Introduction: Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM. Methods: We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC). Results: All matched tumor pairs demonstrated differences in GA between the primary and recurrence including one resected without any intervening therapy. This suggests that time and/or therapeutic intervention contribute to GA. Although mutations were common to both the primary and recurrence, the percent reads varied substantially suggesting clonal expansions and contractions. For example, EGFR mutations were significantly expanded in three patients, and CNAs were increased in two patients at recurrence. Four genes that were commonly altered in both primary and recurrent GBM were more prevalent in our cohort than reported in COSMIC: CDKN2A (86% vs. 53%) and CDKN2B (86% vs. 54%) deletions, EGFR activating mutation (52% vs. 10%) or amplification (81% vs. 45%), and TERT mutation (95% vs. 51%). Lastly, PI3K pathway activating mutations were also commonly seen in our cohort (67%). Conclusions: CGP revealed that GA identified in GBM changed over time and with treatment. Mutations in TERT, CDKN2A/CDKN2B, EGFR, and PI3K pathway were commonly observed in both primary and recurrent GBM revealing their prognostic and therapeutic potential. This may have important implications for individualized therapies and needs further evaluation.
AB - Introduction: Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM. Methods: We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC). Results: All matched tumor pairs demonstrated differences in GA between the primary and recurrence including one resected without any intervening therapy. This suggests that time and/or therapeutic intervention contribute to GA. Although mutations were common to both the primary and recurrence, the percent reads varied substantially suggesting clonal expansions and contractions. For example, EGFR mutations were significantly expanded in three patients, and CNAs were increased in two patients at recurrence. Four genes that were commonly altered in both primary and recurrent GBM were more prevalent in our cohort than reported in COSMIC: CDKN2A (86% vs. 53%) and CDKN2B (86% vs. 54%) deletions, EGFR activating mutation (52% vs. 10%) or amplification (81% vs. 45%), and TERT mutation (95% vs. 51%). Lastly, PI3K pathway activating mutations were also commonly seen in our cohort (67%). Conclusions: CGP revealed that GA identified in GBM changed over time and with treatment. Mutations in TERT, CDKN2A/CDKN2B, EGFR, and PI3K pathway were commonly observed in both primary and recurrent GBM revealing their prognostic and therapeutic potential. This may have important implications for individualized therapies and needs further evaluation.
KW - EGFR
KW - Genomic profiling
KW - Glioblastoma
KW - Recurrent glioblastoma
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U2 - 10.1007/s11060-018-03070-2
DO - 10.1007/s11060-018-03070-2
M3 - Article
C2 - 30535594
AN - SCOPUS:85058071352
SN - 0167-594X
VL - 142
SP - 111
EP - 118
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 1
ER -