Targeted Sequencing of Malignant Supratentorial Pediatric Brain Tumors Demonstrates a High Frequency of Clinically Relevant Mutations

Abstract

Pediatric brain tumors cause more deaths than any other childhood malignancy, and the identification of potentially actionable genomic alterations in this rare heterogeneous group of tumors may improve treatment and outcome. The genetic landscape of common posterior fossa tumors has been described in the past several years, yet the classification of malignant pediatric supratentorial tumors remains controversial. Next-generation sequencing (NGS) is a promising tool to evaluate multiple genes concurrently. The clinical utility of NGS has not been proven in pediatric brain tumors. We identified patients diagnosed with high-grade supratentorial pediatric brain tumors resected between 2008 and 2012 at our institution. DNA from 12 formalin-fixed paraffin-embedded tumor samples from 9 patients was analyzed, including 3 paired samples from diagnosis and relapse. A panel of 194 cancer-related genes was sequenced using targeted next-generation deep sequencing. Genetic findings were correlated with histology, immunohistochemistry, treatment, and survival. We found one or more pathologic genetic change (mutation, amplification, or deletion) in 8 of 9 (89%) of patients studied. Epidermal Growth Factor Receptor (EGFR) mutations were found in 3 patients, 2 of which had an exon 20 insertion not previously described in pediatric malignancy. Additional genetic changes were found in EGFR and Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) at relapse not present in the initial samples. Familial cancer predisposition syndromes were suggested by mutations found in 3 genes in 4 patients, including TP53, MSH2, and CHEK2. Seven of 9 patients in this study died of their disease. In summary, targeted deep sequencing may be used in rare pediatric brain tumors to identify driver mutations for targeted therapy, suggest constitutional and familial testing for cancer predisposition syndromes, and select molecular targets worthy of further study.

Keywords

pediatric brain tumors genetics supratentorial malignant

Get full access to this article

View all access options for this article.

References

Packer

Gajjar

Vezina

, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006; 24(25): 4202–4208.

Cohen

Pollack

Zhou

, et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol 2011; 13(3): 317–323.

Reddy

Janss

Phillips

, et al. Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 2000; 88(9): 2189–2193.

Perry

Miller

Gujrati

, et al. Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases. Brain Pathol 2009; 19(1): 81–90.

Louis

Perry

Reifenberger

, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016; 131(6): 803–20.

Sturm

Witt

Hovestadt

, et al. Hotpot mutations in H3F3 and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012; 22(4): 425–437.

Sturm

Orr

Toprak

, et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016; 164(5): 1060–1072.

Picard

Miller

Hawkins

, et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol 2012; 13(8): 838–848.

Taylor

Northcott

Korshunov

, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012; 123(4): 465–472.

10.

St Jude Children’s Research Hospital. A clinical and molecular risk-directed therapy for newly diagnosed medulloblastoma/PNET. Bethesda, MD: National Library of Medicine. http://clinicaltrials.gov/ct2/show/NCT01878617. Accessed 10 November 2017.

11.

Sidney Kummel Comprehensive Cancer Center. Study assessing the feasibility of a surgery and chemotherapy-only in children with wnt positive medulloblastoma. Bethesda, MD: National Library of Medicine. http://clinicaltrials.gov/ct2/show/NCT02212574. Accessed 10 November 2017.

12.

Pritchard

Salipante

Koehler

, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn 2014; 16(1): 56–67.

13.

Park

Lee

Phi

, et al. Prognostic classification of pediatric medulloblastoma based on chromosome 17p loss, expression of MYCC and MYCN, and Wnt pathway activation. Neuro Oncol 2012; 14(2): 203–214.

14.

Relling

Gardner

Sandborn

, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011; 89(3): 387–391.

15.

Metzker

. Sequencing technologies – the next generation. Nat Rev Genet 2010; 11(1): 31–46.

16.

Pollack

Jakacki

Blaney

, et al. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro Oncol 2007; 9(2): 145–160.

17.

Peyrl

Azizi

Czech

, et al. Tumor stabilization under treatment with imatinib in progressive hypothalamic-chiasmatic glioma. Pediatr Blood Cancer 2009; 52(4): 476–480.

18.

Pediatric Brain Tumor Consortium. NCI. Palbociclib isethionate in treating younger patients with recurrent, progressive, or refractory central nervous system tumors. Bethesda, MD: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT02255461 Accessed August 25, 2017.

19.

Bouffet

Larouche

Campbell

. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 2016; 34(49): 2206–2211.

20.

Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro-Oncology. 2015;17(Suppl 4): iv1–iv62.

21.

Pajtler

Will

Sill

, et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 2015; 27(5): 728–743.

22.

Mody

Prenser

Everett

, et al. Precision medicine in pediatric oncology: lessons learned and next steps. Pediatr Blood Cancer 2017; 64(3).

23.

Downing

Wilson

Zhang

, et al. The Pediatric Cancer Genome Project. Nat Genet 2012; 44(6): 619–622.

24.

Yasuda

Kobayashi

Costa

. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012; 13(1): e23–e31.

25.

Park

Cohen

Lopex

, et al. EGFR Exon 20 insertion/duplication mutations characterize fibrous hamartoma of infancy. Am J Surg Pathol 2016; 40(12): 1713–1718.

26.

Zhang

Walsh

. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med 2015; 373(24): 2336–2346.

27.

Samuel

Villani

Fernandez

, et al. Management of familial cancer: sequencing, surveillance and society. Nat Rev Clin Oncol 2014; 11(12): 723–731.

28.

Mangold

Pagenstescher

Friedl

, et al. Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol 2005; 207(4): 385–395.

29.

Sallinen

Ikonen

Haapasalo

, et al. CHEK2 mutations in primary glioblastomas. J Neurooncol 2005; 74(1): 93–95.

30.

Weischer

Bojesen

Ellervik

, et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 2008; 26(4): 542–548.

31.

Lynch

Lanspa

, et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009; 76(1): 1–18.

32.

Stefanaki

Alexiou

Stefanaki

, et al. Tumors of central and peripheral nervous system associated with inherited genetic syndromes. Pediatr Neurosurg 2012; 48(5): 271–285.

33.

Khuong-Quang

Buczkowicz

Rakopoulos

, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathologica 2012; 124(3): 439–447.

34.

Schwartzentruber

Korshunov

Liu

, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482(7384): 226–231.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.09 MB