PMID- 38252427
OWN - NLM
STAT- MEDLINE
DCOM- 20240403
LR  - 20240403
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 30
IP  - 7
DP  - 2024 Apr 1
TI  - Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed 
      Glioblastoma.
PG  - 1327-1337
LID - 10.1158/1078-0432.CCR-23-3018 [doi]
AB  - PURPOSE: Adverse clinical events cause significant morbidity in patients with GBM 
      (GBM). We examined whether genomic alterations were associated with AE (AE) in 
      patients with GBM. EXPERIMENTAL DESIGN: We identified adults with histologically 
      confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) 
      at Dana Farber Cancer Institute from 2013 to 2019. Seizure at presentation, 
      lymphopenia, thromboembolic events, pseudoprogression, and early progression 
      (within 6 months of diagnosis) were identified as AE. The biologic function of 
      genetic variants was categorized as loss-of-function (LoF), no change in 
      function, or gain-of-function (GoF) using a somatic tumor mutation knowledge base 
      (OncoKB) and consensus protein function predictions. Associations between 
      functional genomic alterations and AE were examined using univariate logistic 
      regressions and multivariable regressions adjusted for additional clinical 
      predictors. RESULTS: Our study included 470 patients diagnosed with GBM who met 
      the study criteria. We focused on 105 genes that had sequencing data available 
      for >/= 90% of the patients and were altered in >/=10% of the cohort. Following 
      false-discovery rate (FDR) correction and multivariable adjustment, the TP53, 
      RB1, IGF1R, and DIS3 LoF alterations were associated with lower odds of seizures, 
      while EGFR, SMARCA4, GNA11, BRD4, and TCF3 GoF and SETD2 LoF alterations were 
      associated with higher odds of seizures. For all other AE of interest, no 
      significant associations were found with genomic alterations following FDR 
      correction. CONCLUSIONS: Genomic biomarkers based on functional variant analysis 
      of a routine clinical panel may help identify AE in GBM, particularly seizures. 
      Identifying these risk factors could improve the management of patients through 
      better supportive care and consideration of prophylactic therapies.
CI  - (c)2024 American Association for Cancer Research.
FAU - Lim-Fat, Mary Jane
AU  - Lim-Fat MJ
AUID- ORCID: 0000-0002-4317-5770
AD  - Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, 
      University of Toronto, Toronto, Ontario, Canada.
FAU - Iorgulescu, J Bryan
AU  - Iorgulescu JB
AUID- ORCID: 0000-0003-1405-3667
AD  - Molecular Diagnostics Laboratory, Department of Hematopathology, Division of 
      Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer 
      Center, Houston, Texas.
FAU - Rahman, Rifaquat
AU  - Rahman R
AUID- ORCID: 0000-0002-9443-1797
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Bhave, Varun
AU  - Bhave V
AUID- ORCID: 0000-0003-4442-3454
AD  - Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts.
FAU - Muzikansky, Alona
AU  - Muzikansky A
AUID- ORCID: 0000-0001-7585-8181
AD  - Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, 
      Massachusetts.
FAU - Woodward, Eleanor
AU  - Woodward E
AUID- ORCID: 0000-0003-3089-022X
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Whorral, Sydney
AU  - Whorral S
AUID- ORCID: 0009-0002-3861-6444
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Allen, Marie
AU  - Allen M
AUID- ORCID: 0009-0005-9917-1751
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Touat, Mehdi
AU  - Touat M
AUID- ORCID: 0000-0002-5910-7799
AD  - Sorbonne Universite, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la 
      Moelle epiniere, ICM, AP-HP, Hopitaux Universitaires La Pitie Salpetriere - 
      Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
FAU - Li, Xiaomei
AU  - Li X
AUID- ORCID: 0000-0002-3221-5888
AD  - Shandong University, Jinan, China.
FAU - Xy, Gongwen
AU  - Xy G
AUID- ORCID: 0000-0003-4518-9911
AD  - Shandong University, Jinan, China.
FAU - Patel, Jay
AU  - Patel J
AUID- ORCID: 0000-0002-8507-795X
AD  - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, 
      Massachusetts General Hospital, Boston, Massachusetts.
FAU - Gerstner, Elizabeth R
AU  - Gerstner ER
AUID- ORCID: 0000-0003-2382-3838
AD  - Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts.
AD  - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, 
      Massachusetts General Hospital, Boston, Massachusetts.
FAU - Kalpathy-Cramer, Jayashree
AU  - Kalpathy-Cramer J
AUID- ORCID: 0000-0001-8906-9618
AD  - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, 
      Massachusetts General Hospital, Boston, Massachusetts.
FAU - Youssef, Gilbert
AU  - Youssef G
AUID- ORCID: 0000-0001-6109-7692
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Chukwueke, Ugonma
AU  - Chukwueke U
AUID- ORCID: 0000-0003-0598-9535
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - McFaline-Figueroa, J Ricardo
AU  - McFaline-Figueroa JR
AUID- ORCID: 0000-0002-6670-1841
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Nayak, Lakshmi
AU  - Nayak L
AUID- ORCID: 0000-0003-2725-8717
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Lee, Eudocia Q
AU  - Lee EQ
AUID- ORCID: 0000-0003-3355-5179
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Reardon, David A
AU  - Reardon DA
AUID- ORCID: 0000-0001-6674-0157
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Beroukhim, Rameen
AU  - Beroukhim R
AUID- ORCID: 0000-0001-6303-3609
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Huang, Raymond Y
AU  - Huang RY
AUID- ORCID: 0000-0001-7661-797X
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Bi, Wenya Linda
AU  - Bi WL
AUID- ORCID: 0000-0002-4635-0247
AD  - Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts.
FAU - Ligon, Keith L
AU  - Ligon KL
AUID- ORCID: 0000-0002-7733-600X
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Wen, Patrick Y
AU  - Wen PY
AUID- ORCID: 0000-0002-0774-7700
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital and Harvard Medical School, Boston, Massachusetts.
LA  - eng
GR  - n/a/
GR  - n/a/
GR  - n/a/
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 3.6.1.- (SMARCA4 protein, human)
RN  - EC 3.6.4.- (DNA Helicases)
RN  - 0 (BRD4 protein, human)
RN  - 0 (Bromodomain Containing Proteins)
RN  - 0 (Cell Cycle Proteins)
SB  - IM
MH  - Adult
MH  - Humans
MH  - *Glioblastoma/genetics/pathology
MH  - Nuclear Proteins/genetics
MH  - Transcription Factors/genetics
MH  - *Brain Neoplasms/genetics/pathology
MH  - Genomics
MH  - Seizures/genetics
MH  - Mutation
MH  - DNA Helicases/genetics
MH  - Bromodomain Containing Proteins
MH  - Cell Cycle Proteins/genetics
EDAT- 2024/01/22 12:42
MHDA- 2024/04/03 06:44
CRDT- 2024/01/22 11:36
PHST- 2023/10/02 00:00 [received]
PHST- 2023/12/01 00:00 [revised]
PHST- 2024/01/18 00:00 [accepted]
PHST- 2024/04/03 06:44 [medline]
PHST- 2024/01/22 12:42 [pubmed]
PHST- 2024/01/22 11:36 [entrez]
AID - 733612 [pii]
AID - 10.1158/1078-0432.CCR-23-3018 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2024 Apr 1;30(7):1327-1337. doi: 10.1158/1078-0432.CCR-23-3018.