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Clinically Integrated Sequencing Alters Therapy in Children and Young Adults With High-Risk Glial Brain Tumors.

ABSTRACT: Purpose:Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors. Patients and Methods:Fifty-two children and young adults with brain tumors designated by the treating neuro-oncologist to be high risk (> 25% chance for treatment failure; mean age, 10.2 years; range, 0 to 39 years) were enrolled in a prospective, observational, consecutive case series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference. Results:Sequencing revealed a potentially actionable germline or tumor alteration in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Platelet-derived growth factor receptor or fibroblast growth factor receptor pathway alterations were seen in nine of 20 (45%) glial tumors. Eight (20%) sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Patients with recurrent brain tumors receiving targeted therapy had a median progression-free survival (from time on therapy) of 4 months. Conclusion:Selection of personalized agents for children and young adults with highrisk brain tumors on the basis of integrative clinical sequencing is feasible and resulted in a change in therapy in more than two thirds of children and young adults with high-risk glial tumors.

SUBMITTER: Koschmann C

PROVIDER: S-EPMC7434092 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Clinically Integrated Sequencing Alters Therapy in Children and Young Adults With High-Risk Glial Brain Tumors.

Koschmann Carl C Wu Yi-Mi YM Kumar-Sinha Chandan C Lonigro Robert R Vats Pankaj P Kasaian Katayoon K Cieslik Marcin M Cao Xuhong X Anderson Bailey B Frank Kevin K Zhao Lili L Prensner John R JR Zureick Andrew H AH Everett Jessica J Mullan Brendan B Marini Bernard B Camelo-Piragua Sandra S Venneti Sriram S McKeever Paul P McFadden Kathryn K Lieberman Andrew P AP Leonard Marcia M Maher Cormac O CO Garton Hugh H Muraszko Karin K Robertson Patricia P Robinson Dan D Chinnaiyan Arul M AM Mody Rajen R

JCO precision oncology 20180504

<h4>Purpose</h4>Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors.<h4>Patients and methods</h4>Fifty-two children and young adults with brain tumors designated by t ...[more]

PMID: 32832832

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Project description:BACKGROUND:The neuroanatomic basis for cognitive impairment in chronic kidney disease (CKD) is incompletely characterized. We performed advanced quantitative structural magnetic resonance imaging (MRI) to determine whether CKD affects brain structure and whether poorer neurocognitive performance in CKD is associated with structural brain differences. STUDY DESIGN:Cross-sectional. SETTING & PARTICIPANTS:85 individuals with CKD stages 2 to 5 and 63 healthy controls, aged 8 to 25 years PREDICTORS: CKD versus control, estimated glomerular filtration rate (eGFR), and kidney transplant status were analyzed as predictors of MRI findings. MRI volumes in 19 prespecified regions of gray matter (GM), white matter (WM), and cerebrospinal fluid were analyzed as predictors of neurocognitive performance (median z scores) in 7 prespecified domains. OUTCOMES:19 prespecified brain regions of interest (ROIs) in 7 prespecified domains. Neurocognitive performance in 7 prespecified domains. MEASUREMENTS:ROI volumes were compared in CKD versus controls using unadjusted t tests and analysis of covariance (ANCOVA). Associations of ROI volumes with eGFR and kidney transplant status in participants with CKD were analyzed using ANCOVA and linear regression. Associations of neurocognitive performance and ROI volumes were analyzed by linear regression. RESULTS:Participants with CKD had lower whole-brain, cortical, and left parietal GM volumes than controls in unadjusted analyses, but no differences were found in adjusted analysis. In participants with CKD, lower eGFR was associated with higher WM volume in whole-brain (P=0.05) and frontal (P=0.04) ROIs, but differences were not significant after multiple comparisons correction. Kidney transplant recipients had lower GM volumes in whole-brain (P=0.01; Q=0.06), frontal (P=0.02; Q=0.08), and left and right parietal (P=0.01; Q=0.06; and P=0.03; Q=0.1) ROIs and higher whole-brain WM volume (P=0.04; Q=0.1). Neurocognitive performance in the CKD group was not associated with ROI volumes. LIMITATIONS:Unable to assess changes in brain structure and kidney function over time; analysis limited to prespecified ROIs and neurocognitive domains. CONCLUSIONS:CKD in children and young adults may be associated with lower GM and higher WM volumes in some ROIs. Differences were relatively subtle in the CKD group as a whole, but were more prominent in recipients of a kidney transplant. However, neurocognitive performance was not explained by differences in brain ROI volumes, suggesting a functional rather than structural basis for neurocognitive impairment in CKD.

Dataset Information

Clinically Integrated Sequencing Alters Therapy in Children and Young Adults With High-Risk Glial Brain Tumors.

Publications

Clinically Integrated Sequencing Alters Therapy in Children and Young Adults With High-Risk Glial Brain Tumors.

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