TY - JOUR
T1 - Integrated genomic analysis of survival outliers in glioblastoma
AU - Peng, Sen
AU - Dhruv, Harshil
AU - Armstrong, Brock
AU - Salhia, Bodour
AU - Legendre, Christophe
AU - Kiefer, Jeffrey
AU - Parks, Julianna
AU - Virk, Selene
AU - Sloan, Andrew E.
AU - Ostrom, Quinn T.
AU - Barnholtz-Sloan, Jill S.
AU - Tran, Nhan L.
AU - Berens, Michael E.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017
Y1 - 2017
N2 - Background. To elucidate molecular features associated with disproportionate survival of glioblastoma (GB) patients, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide); "GB outliers" were identifed: long-term survivor of 33 months (LTS; n = 8) versus short-term survivor of 7 months (STS; n = 10). Methods. We implemented exome, RNA, whole genome sequencing, and DNA methylation for collection of deep genomic data from STS and LTS GB patients. Results. LTS GB showed frequent chromosomal gains in 4q12 (platelet derived growth factor receptor alpha and KIT) and 12q14.1 (cyclin-dependent kinase 4), and deletion in 19q13.33 (BAX, branched chain amino-acid transaminase 2, and cluster of differentiation 33). STS GB showed frequent deletion in 9p11.2 (forkhead box D4-like 2 and aquaporin 7 pseudogene 3) and 22q11.21 (Hypermethylated In Cancer 2). LTS GB showed 2-fold more frequent copy number deletions compared with STS GB. Gene expression differences showed the STS cohort with altered transcriptional regulators: activation of signal transducer and activator of transcription (STAT)5a/b, nuclear factor-kappaB (NF-?B), and interferon-gamma (IFNG), and inhibition of mitogen-activated protein kinase (MAPK1), extracellular signal-regulated kinase (ERK)1/2, and estrogen receptor (ESR)1. Expression-based biological concepts prominent in the STS cohort include metabolic processes, anaphase-promoting complex degradation, and immune processes associated with major histocompatibility complex class I antigen presentation; the LTS cohort features genes related to development, morphogenesis, and the mammalian target of rapamycin signaling pathway. Whole genome methylation analyses showed that a methylation signature of 89 probes distinctly separates LTS from STS GB tumors. Conclusion. We posit that genomic instability is associated with longer survival of GB (possibly with vulnerability to standard therapy); conversely, genomic and epigenetic signatures may identify patients where up-front entry into alternative, targeted regimens would be a preferred, more effcacious management.
AB - Background. To elucidate molecular features associated with disproportionate survival of glioblastoma (GB) patients, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide); "GB outliers" were identifed: long-term survivor of 33 months (LTS; n = 8) versus short-term survivor of 7 months (STS; n = 10). Methods. We implemented exome, RNA, whole genome sequencing, and DNA methylation for collection of deep genomic data from STS and LTS GB patients. Results. LTS GB showed frequent chromosomal gains in 4q12 (platelet derived growth factor receptor alpha and KIT) and 12q14.1 (cyclin-dependent kinase 4), and deletion in 19q13.33 (BAX, branched chain amino-acid transaminase 2, and cluster of differentiation 33). STS GB showed frequent deletion in 9p11.2 (forkhead box D4-like 2 and aquaporin 7 pseudogene 3) and 22q11.21 (Hypermethylated In Cancer 2). LTS GB showed 2-fold more frequent copy number deletions compared with STS GB. Gene expression differences showed the STS cohort with altered transcriptional regulators: activation of signal transducer and activator of transcription (STAT)5a/b, nuclear factor-kappaB (NF-?B), and interferon-gamma (IFNG), and inhibition of mitogen-activated protein kinase (MAPK1), extracellular signal-regulated kinase (ERK)1/2, and estrogen receptor (ESR)1. Expression-based biological concepts prominent in the STS cohort include metabolic processes, anaphase-promoting complex degradation, and immune processes associated with major histocompatibility complex class I antigen presentation; the LTS cohort features genes related to development, morphogenesis, and the mammalian target of rapamycin signaling pathway. Whole genome methylation analyses showed that a methylation signature of 89 probes distinctly separates LTS from STS GB tumors. Conclusion. We posit that genomic instability is associated with longer survival of GB (possibly with vulnerability to standard therapy); conversely, genomic and epigenetic signatures may identify patients where up-front entry into alternative, targeted regimens would be a preferred, more effcacious management.
KW - Genome sequencing
KW - Glioblastoma
KW - Outlier
KW - Responders
KW - Survival difference
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U2 - 10.1093/neuonc/now269
DO - 10.1093/neuonc/now269
M3 - Article
C2 - 27932423
AN - SCOPUS:85020316314
SN - 1522-8517
VL - 19
SP - 833
EP - 844
JO - Neuro-oncology
JF - Neuro-oncology
IS - 6
ER -