Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Targetable molecular alterations in congenital glioblastoma

Abstract

Introduction

Congenital glioblastomas (cGBMs) are uncommon tumors presenting in early infancy, variably defined as diagnosed at birth or at age less than 3 months by strict criteria, or more loosely, as occurring in very young children less than 12 months of age. Previous studies have shown that cGBMs are histologically indistinguishable from GBMs in older children or adults, but may have a more favorable clinical outcome, suggesting biological differences between congenital versus other GBMs. Due to the infrequency of cGBMs, especially when employing strict inclusion criteria, molecular features have not been sufficiently explored.

Methods

Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit, Illumina RNAseq were utilized to study cGBMs seen at our institution since 2002. A strict definition for cGBM was utilized, with only infants less than age 3 months at clinical presentation sought for this study.

Results

Of the 8 cGBM cases identified in our files, 7 had sufficient materials for molecular analyses, and 3 of 7 cases analyzed showed fusions of the ALK gene (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners). One case showed ROS1 fusion. Somatic mutations in TSC22D1, BMG1 and DGCR6 were identified in 1 case. None of the cases showed alterations in IDH1/2, histone genes, or the TERT gene, alterations which can be associated with GBMs in older children or adults.

Conclusions

Our results show that cGBMs are genetically heterogeneous and biologically different from pediatric and adult GBMs. Identification of ALK and ROS1 raise the possibility of targeted therapy with FDA-approved targeted inhibitors.

Congenital glioblastomas (cGBMs), defined by presentation prenatally or in early infancy [1], are uncommon tumors with less than one hundred cases reported [2,3,4,5,6,7,8,9,10,11,12,13,14]. cGBMs differ from other pediatric brain tumors in several important respects. First, most cGBMs are supratentorial, in contrast to the infratentorial predilection of many other pediatric brain tumors such as ependymoma, medulloblastoma, diffuse midline glioma. Second, cGBMs respond favorably to surgery and chemotherapy and have a more favorable outcome as compared to pediatric and adult GBMs, leading to long-term survival (greater than 5 years) in a large number of patients [5, 7]. Third, cGBMs do not show the characteristic molecular alterations of either pediatric or adult gliomas in the limited studies published to date [5, 7, 15].

Previously, we reported clinicopathologic features of 5 patients with cGBM with favorable outcome following subtotal resection and moderate intensity chemotherapy, indicating biological differences compared to pediatric and adult glioblastoma [7]. The wide availability of next generation sequencing (NGS) technologies encouraged us to further explore the molecular features of cGBM. We now present further molecular characterization and of our 5 previously-reported cases [7] with 3 additional cGBMs.

Cases were identified by electronic medical record search from 2002 to 2018 inclusive. Appropriate informed consent was obtained at the time of surgery and the study was approved by the University of Colorado Institutional Review Board (IRB protocol number 95-500). All cases were reviewed at the University of Colorado Children’s Hospital. Five out of 8 cases underwent surgical resection at our institution and 3 had received surgery at outside hospitals and patients and slides had been sent to us for consultation.

The 8 cases consisted of 4 males and 4 females. Given the known debate about the definition of congenital GBM, we used the definition of Solitaire and Krigman [1], who in 1964 provided one of the most stringent definitions of cGBM, defining three distinct categories of congenital brain tumor, namely: (1) definitely congenital with symptoms occurring at birth, (2) probably congenital with symptoms occurring within the first week of life, and (3) possibly congenital with symptoms occurring within the first few months of life. All of our cases presented within the first 3 months of life (range: 1–12 weeks) and hence corresponded to at least the “possibly congenital” category according to the Solitaire and Krigman classification [1]. It is noteworthy that many researchers today use a less stringent cut off of presentation before 1 year of age for “congenital/infantile” gliomas [9, 15, 16].

Clinical features such as age at presentation, gender, location of tumor, tumor recurrence and survival duration were noted for each patient. All tumors occurred in the supratentorial compartment; 6 were hemispheric and 2 thalamic (Fig. 1a, b), neither of which showed H3 K27M mutation by immunohistochemical or molecular analysis. Clinical, radiologic and survival data are summarized in Table 1. Selected examples of imaging and histopathologic findings are shown in Fig. 1.

Fig. 1
figure1

Radiologic and Histopathologic findings in cGBM: a case 1 showed a large right fronto-parietal mass; b a right thalamic tumor extending into the lateral ventricle is seen in case 2; c, d histologic features differed but included cytologic atypical cells with increased mitosis in case 2 (c), and necrosis or microvascular proliferation with frequent evidence of hemosiderin/hematoidin deposition in case 4 (d)

Table 1 Clinical and radiologic features and survival in cGBM patients

Mutational and fusion analyses were undertaken for 7 of 8 cases with available tissue, using Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit and Illumina RNA-seq as previously detailed [6]. In short, a total of 53 genes (listed in Table 2), known to be involved in tumor-associated fusion events were examined using Anchored Multiplex PCR technology from ArcherDx (Boulder, CO). This assay utilizes a proprietary Anchored Multiplex PCR (AMP TM) based enrichment to detect all fusions associated with the genes in a single sequencing assay, without prior knowledge of fusion partners or breakpoints. The VariantPlex assay tests for mutations in 69 genes (Table 3) with known involvement in oncogenesis using AMP technology.

Table 2 List of genes tested in archer FusionPlex solid tumor panel
Table 3 List of genes tested in archer VariantPlex solid tumor panel

In addition to these CLIA-certified clinically-available panels, all cases also received research based RNA sequencing. Methods are briefly described here. RNA libraries were synthesized from PolyA-selected total RNA using the Nugen Universal Plus mRNA-Seq kit and sequenced using either HiSeq 4000 or NovaSeq 6000 (Illumina). Reads were aligned to the human genome assembly GRCh38 using GSNAP (Genomic Short-read Nucleotide Alignment Program, version 2014-12-17). Fusion events in RNAseq data were identified using EricScript fusion finding software [17]. Somatic variants were isolated by filtering out germline from tumor variants that were identified using FreeBayes (v1.0.1-2-g0cb2697).

Three cases of the 7 evaluable cases exhibited ALK fusions (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners, see Table 1). Fusion breakpoints are shown in Fig. 2. One case demonstrated a ROS1 fusion (clinical findings for the ROS1 fusion positive case are described in detail in an upcoming publication [18]). One additional case (case 3) harbored somatic mutations in TSC22D1 (c.2711A>C; p.G;m904Pro), BMS1 (c.2572C>G; p.Gln858Glu) and DGCR6 (c.424G>A; p.Val142Ile) genes. Each of these variants is of unknown clinical significance; however TSC22D1, a transcription factor with suppressor activity, is relatively well studied in cancer [19]. As reported previously by us [7], and others [16, 20, 21], none of the cases showed alterations in IDH1/2, ATRX, TERT, EGFR amplification or PTEN loss/chromosome 7 gain, alterations common in adult GBMs. In addition, there was an absence of mutations in histone 3 genes or TP53, which are frequently seen in pediatric and adolescent GBMs. Molecular features of low grade gliomas such as BRAF-KIAA1549 fusion were also not identified in cGBM.

Fig. 2
figure2

Fusion breakpoints in cGBM cases: a case 2 showed fusion between exon 2 of EML4 and the exon 21 of ALK; b case 4 showed fusion between exon 16 of MAP4 and the exon 17 of ALK; c case 5 showed fusion between exon 2 of MZT2B and the exon 20 of ALK

As reported previously [7, 16], all 8 cases met WHO 2016 histological criteria for GBM, including presence of cytologically atypical astrocytic cells (Fig. 1c, d) with increased proliferative index and presence of necrosis or microvascular proliferation. These features are not significantly different from those seen in many adult and pediatric GBMs. Variably present were frequent fresh and chronic hemorrhage (Fig. 1d), vascular thromboses and microvascular proliferation. Histopathologic examination and immunohistochemical stains were utilized to exclude diagnosis of other common congenital/early neonatal brain tumors such as teratoma, choroid plexus tumors, craniopharyngioma, and embryonal (formerly primitive neuroectodermal) tumors [4]. The histologic findings were not predictive of the specific molecular alterations consistent to our findings in pediatric glial and glioneuronal tumors [6].

Clinical outcome including recurrence and survival was variable but markedly more favorable as a whole than that for GBMs in many older pediatric patients [22, 23]. Long term follow-up shows that 6 out of 8 patients are alive and free of recurrence (range: 1.5–17 years) at the time of this report, following receipt of moderately-intense adjuvant chemotherapy treatment without radiation. Specific individual survival durations are 1.5 years, 4 years, 10 years, 10 years, 11 years and 17 years (Table 1). Two of 8 deceased patients died within 6 weeks of surgery with 1 expiring at the time of the operation due to massive intratumoral bleeding (see Table 1). The second patient died of progressive disease 6 weeks after diagnosis after the family declined surgical resection or any other therapeutic intervention. None of the 6 surviving patients have experienced a recurrence requiring second surgical resection, to date. Three patients have mild to moderate developmental delay and 3 have other neurologic abnormalities, but all have an otherwise normal quality of life (Table 1).

These indicators of clinical behavior (response to treatment, recurrence and survival) in our cohort are consistent with many studies that generally report a relatively favorable prognosis for cGBMs [5, 12] with only a minority resulting in rapid deterioration and death [2, 10, 13]. In rare instances, spontaneous regression [24] or recurrence of cGBM as a ganglioglioma has been reported [9, 25]. This is in contrast to pediatric and adult glioblastoma that are characterized by rapid progression and recurrence and are usually fatal in 15–18 months, with less than 5% of adult GBM patients and less than 20% of pediatric GBM patients surviving more than 5 years [22, 23].

Genomic fusions were the most frequent molecular finding in our cohort, including 4 of 7 assessable cases with ALK fusion and 1 with ROS1 fusion. These findings are similar to recent publications that reported frequent alterations in ALK, ROS1 [3], NTRK, MET [5], as well as RAS/MAPK pathway in congenital and infant gliomas [15]. Unlike the study by Guerriero Stucklin et al. [15], our study did not include low grade congenital/infantile gliomas and utilized a stringent cut off for congenital GBMs of < age 3 months as opposed to 1 year. Although our cohort is small, we observed that survival for our ALK/ROS1-altered congenital GBMs was markedly better at 100% versus 42% reported for high grade tumors with ALK/ROS1, as reported in the literature [15]. Whether this difference is due to differences in patient age or simply secondary to small case numbers is uncertain.

It is important to emphasize that while ROS1, ALK, NTRK and MET alterations are enriched in cGBMs, none of these alterations is exclusive to this age group [6, 26]. Thus, a full panel of mutational/fusion testing is optimal for any pediatric high grade glioma when seeking possible targets for therapy.

Genetic alterations are frequently observed in tumors of the CNS [6] as well as in systemic solid organ tumors [27, 28]. Genetic rearrangements that create ROS1 fusion proteins in which the kinase domain of ROS1 becomes constitutively activated and drive cellular proliferation have been found in a variety of tumors including glioblastoma, non-small cell lung cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, and epithelioid hemangioendothelioma [27]. The transforming potential of ROS1 fusion proteins is well established. Expression of ROS1 fusion variants in fibroblasts was shown to result in anchorage-independent growth, foci formation, and tumorigenicity (for review see [27]). Similarly, ALK gene rearrangements initially discovered in a subset of anaplastic large-cell lymphomas have subsequently been found in a variety of tumors including non–small cell lung cancers [28] and CNS tumors [26]. The fusion partner in ALK fused genes provides a dimerization domain that induces constitutive oligomerization and thus activation of the kinase [29]. Targeting of ROS1 and ALK fusion proteins with the small-molecule inhibitor crizotinib has shown promise as an effective therapy in patients. In non-small cell lung cancer, crizotinib induces remissions and extends the lives of patients [28].

Our cohort of cGBM patients from a single institution shows that a majority of these infants enjoy a long term, recurrence-free survival when treated with resection followed by chemotherapy, favoring this approach as opposed to surgical resection alone [2]. In addition, a substantial proportion of cGBM harbor ALK or ROS1 alterations, allowing for potential therapy with Food and Drug Administration (FDA)-approved drugs such as entrectinib [30], larotrectinib or Crizotinib [31]. Although patients in our cohort were treated with tumor excision followed by carboplatin/etoposide therapy, and none have yet been treated with or have required ALK—targeted therapy, this remains a possibility in case of future tumor recurrence.

In summary, our molecular studies further extend our original work with cGBM [7] and confirm that these tumors are genetically heterogeneous and different from pediatric and adult HGG. We present extended follow-up of patients with cGBM and show that cGBM is compatible with long-term recurrence-free survival. Furthermore, actionable fusions, particularly in the ALK gene, can be frequently identified, which provides an additional potential target for therapy [15].

References

  1. 1.

    Solitare GB, Krigman MR (1964) Congenital intracranial neoplasm. A case report and review of the literature. J Neuropathol Exp Neurol 23:280–292

  2. 2.

    Anestis DM, Tsitsopoulos PP, Ble CA, Tsitouras V, Tsonidis CA (2017) Congenital glioblastoma multiforme: an unusual and challenging tumor. Neuropediatrics 48:403–412. https://doi.org/10.1055/s-0037-1601858

  3. 3.

    Cocce MC, Mardin BR, Bens S, Stutz AM, Lubieniecki F, Vater I, Korbel JO, Siebert R, Alonso CN, Gallego MS (2016) Identification of ZCCHC8 as fusion partner of ROS1 in a case of congenital glioblastoma multiforme with a t(6;12)(q21;q24.3). Genes Chromosom Cancer 55:677–687. https://doi.org/10.1002/gcc.22369

  4. 4.

    Isaacs H Jr (2016) Perinatal (fetal and neonatal) astrocytoma: a review. Childs Nerv Syst 32:2085–2096. https://doi.org/10.1007/s00381-016-3215-y

  5. 5.

    Kameda M, Otani Y, Ichikawa T, Shimada A, Ichimura K, Date I (2017) Congenital glioblastoma with distinct clinical and molecular characteristics: case reports and a literature review. World Neurosurg 101:817. https://doi.org/10.1016/j.wneu.2017.02.026

  6. 6.

    Lake JA, Donson AM, Prince E, Davies KD, Nellan A, Green AL, Mulcahy Levy J, Dorris K, Vibhakar R, Hankinson TC, Foreman NK, Ewalt MD, Kleinschmidt-DeMasters BK, Hoffman LM, Gilani A (2019) Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.28028

  7. 7.

    Macy ME, Birks DK, Barton VN, Chan MH, Donson AM, Kleinschmidt-Demasters BK, Bemis LT, Handler MH, Foreman NK (2012) Clinical and molecular characteristics of congenital glioblastoma. Neuro Oncol 14:931–941. https://doi.org/10.1093/neuonc/nos125

  8. 8.

    Milano GM, Cerri C, Ferruzzi V, Capolsini I, Mastrodicasa E, Genitori L, Aversa F (2009) Congenital glioblastoma. Pediatr Blood Cancer 53:124–126. https://doi.org/10.1002/pbc.22008

  9. 9.

    Ng A, Levy ML, Malicki DM, Crawford JR (2019) Unusual high-grade and low-grade glioma in an infant with PPP1CB-ALK gene fusion. BMJ Case Rep. https://doi.org/10.1136/bcr-2018-228248

  10. 10.

    Nsir AB, Darmoul M, Hadhri R, Hattab N (2017) Congenital glioblastoma: lessons learned from a rare case with unusual presentation. Turk Neurosurg 27:464–467. https://doi.org/10.5137/1019-5149.JTN.13047-14.3

  11. 11.

    Olsen TK, Panagopoulos I, Meling TR, Micci F, Gorunova L, Thorsen J, Due-Tonnessen B, Scheie D, Lund-Iversen M, Krossnes B, Saxhaug C, Heim S, Brandal P (2015) Fusion genes with ALK as recurrent partner in ependymoma-like gliomas: a new brain tumor entity? Neuro Oncol 17:1365–1373. https://doi.org/10.1093/neuonc/nov039

  12. 12.

    Shimamura N, Asano K, Ogane K, Yagihashi A, Ohkuma H, Suzuki S (2003) A case of definitely congenital glioblastoma manifested by intratumoral hemorrhage. Childs Nerv Syst 19:778–781. https://doi.org/10.1007/s00381-003-0807-0

  13. 13.

    Thankamony A, Harlow FH, Ponnampalam J, Clarke P (2007) Congenital brain tumour mimicking fetal intracranial haemorrhage. J Obstet Gynaecol 27:314–317. https://doi.org/10.1080/01443610701241217

  14. 14.

    Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna R, Kim H, Verhaak RG (2015) The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene 34:4845–4854. https://doi.org/10.1038/onc.2014.406

  15. 15.

    Guerreiro Stucklin AS, Ryall S, Fukuoka K, Zapotocky M, Lassaletta A, Li C, Bridge T, Kim B, Arnoldo A, Kowalski PE, Zhong Y, Johnson M, Li C, Ramani AK, Siddaway R, Nobre LF, de Antonellis P, Dunham C, Cheng S, Boue DR, Finlay JL, Coven SL, de Prada I, Perez-Somarriba M, Faria CC, Grotzer MA, Rushing E, Sumerauer D, Zamecnik J, Krskova L, Garcia Ariza M, Cruz O, Morales La Madrid A, Solano P, Terashima K, Nakano Y, Ichimura K, Nagane M, Sakamoto H, Gil-da-Costa MJ, Silva R, Johnston DL, Michaud J, Wilson B, van Landeghem FKH, Oviedo A, McNeely PD, Crooks B, Fried I, Zhukova N, Hansford JR, Nageswararao A, Garzia L, Shago M, Brudno M, Irwin MS, Bartels U, Ramaswamy V, Bouffet E, Taylor MD, Tabori U, Hawkins C (2019) Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun 10:4343. https://doi.org/10.1038/s41467-019-12187-5

  16. 16.

    Brat DJ, Shehata BM, Castellano-Sanchez AA, Hawkins C, Yost RB, Greco C, Mazewski C, Janss A, Ohgaki H, Perry A (2007) Congenital glioblastoma: a clinicopathologic and genetic analysis. Brain Pathol 17:276–281. https://doi.org/10.1111/j.1750-3639.2007.00071.x

  17. 17.

    Benelli M, Pescucci C, Marseglia G, Severgnini M, Torricelli F, Magi A (2012) Discovering chimeric transcripts in paired-end RNA-seq data by using EricScript. Bioinformatics 28:3232–3239. https://doi.org/10.1093/bioinformatics/bts617

  18. 18.

    Whiteway SL, Betts AM, O’Neil ER, Green AL, Gilani A, Orr BA, Mathis DA (2020) Oncogenic GOPC-ROS1 fusion identified in a congenital glioblastoma case. J Pediatr Hematol Oncol (accepted for publication)

  19. 19.

    Nakashiro K, Kawamata H, Hino S, Uchida D, Miwa Y, Hamano H, Omotehara F, Yoshida H, Sato M (1998) Down-regulation of TSC-22 (transforming growth factor beta-stimulated clone 22) markedly enhances the growth of a human salivary gland cancer cell line in vitro and in vivo. Cancer Res 58:549–555

  20. 20.

    El-Ayadi M, Ansari M, Sturm D, Gielen GH, Warmuth-Metz M, Kramm CM, von Bueren AO (2017) High-grade glioma in very young children: a rare and particular patient population. Oncotarget 8:64564–64578. https://doi.org/10.18632/oncotarget.18478

  21. 21.

    Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, Kleinschmidt-DeMasters BK, Perry A, Reifenberger G, Stupp R, von Deimling A, Weller M (2018) cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol 136:805–810. https://doi.org/10.1007/s00401-018-1913-0

  22. 22.

    Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 14(Suppl 5):v1–49. https://doi.org/10.1093/neuonc/nos218

  23. 23.

    Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA, Zheludkova O, Milde T, Witt O, Kulozik AE, Reifenberger G, Jabado N, Perry A, Lichter P, von Deimling A, Pfister SM, Jones DT (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678. https://doi.org/10.1007/s00401-015-1405-4

  24. 24.

    Davis T, Doyle H, Tobias V, Ellison DW, Ziegler DS (2016) Case report of spontaneous resolution of a congenital glioblastoma. Pediatrics. https://doi.org/10.1542/peds.2015-1241

  25. 25.

    Scheuermann A, Belongia M, Lawlor MW, Suchi M, Kaufman B, Vasudevaraja V, Serrano J, Snuderl M, Knipstein J (2019) Ganglioglioma in a survivor of infantile glioblastoma. J Pediatr Hematol Oncol. https://doi.org/10.1097/MPH.0000000000001417

  26. 26.

    Johnson A, Severson E, Gay L, Vergilio JA, Elvin J, Suh J, Daniel S, Covert M, Frampton GM, Hsu S, Lesser GJ, Stogner-Underwood K, Mott RT, Rush SZ, Stanke JJ, Dahiya S, Sun J, Reddy P, Chalmers ZR, Erlich R, Chudnovsky Y, Fabrizio D, Schrock AB, Ali S, Miller V, Stephens PJ, Ross J, Crawford JR, Ramkissoon SH (2017) Comprehensive genomic profiling of 282 pediatric low- and high-grade gliomas reveals genomic drivers, tumor mutational burden, and hypermutation signatures. Oncologist 22:1478–1490. https://doi.org/10.1634/theoncologist.2017-0242

  27. 27.

    Davies KD, Doebele RC (2013) Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res 19:4040–4045. https://doi.org/10.1158/1078-0432.CCR-12-2851

  28. 28.

    Shaw AT, Engelman JA (2013) ALK in lung cancer: past, present, and future. J Clin Oncol 31:1105–1111. https://doi.org/10.1200/JCO.2012.44.5353

  29. 29.

    Camidge DR, Doebele RC (2012) Treating ALK-positive lung cancer–early successes and future challenges. Nat Rev Clin Oncol 9:268–277. https://doi.org/10.1038/nrclinonc.2012.43

  30. 30.

    Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer TM, Farago AF, Wheler JJ, Liu SV, Doebele R, Giannetta L, Cerea G, Marrapese G, Schirru M, Amatu A, Bencardino K, Palmeri L, Sartore-Bianchi A, Vanzulli A, Cresta S, Damian S, Duca M, Ardini E, Li G, Christiansen J, Kowalski K, Johnson AD, Patel R, Luo D, Chow-Maneval E, Hornby Z, Multani PS, Shaw AT, De Braud FG (2017) Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov 7:400–409. https://doi.org/10.1158/2159-8290.CD-16-1237

  31. 31.

    Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, Nagasubramanian R, Davis JL, Rudzinski E, Feraco AM, Tuch BB, Ebata KT, Reynolds M, Smith S, Cruickshank S, Cox MC, Pappo AS, Hawkins DS (2018) Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 19:705–714. https://doi.org/10.1016/S1470-2045(18)30119-0

Download references

Acknowledgements

This work was supported, in part, by the UCD Molecular Pathology Shared Resource (MPSR) and the UCD Genomics and Microarray Core (National Cancer Institute Cancer Center Support Grant No. P30-CA046934). Additional financial assistance was received from the Morgan Adams Foundation, and the Olivia Caldwell Foundation.

Author information

AD, KDD, SLW, JL, JDS, LH, NKF, BKKDM, ALG, and AG: Substantial contributions to the conception and design of the study; acquisition, analysis, and interpretation of data; AD, KDD, BKKDM and AG provided images for figures. AD, NKF and AG prepared the manuscript. AG, AD, NKF, BKKDM and ALG: critical manuscript review and revisions. AG: Contribution as per journal requirements; KDD: Supervised molecular testing, provided images of fusion breakpoints for figure.

Correspondence to Ahmed Gilani.

Ethics declarations

Conflict of interest

Kurt D. Davis has received sponsored travel from ArcherDx. Other authors report no conflicts of interest related to this study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Human and animal rights statement

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gilani, A., Donson, A., Davies, K.D. et al. Targetable molecular alterations in congenital glioblastoma. J Neurooncol 146, 247–252 (2020). https://doi.org/10.1007/s11060-019-03377-8

Download citation

Keywords

  • ALK
  • ROS1
  • Glioblastoma
  • Congenital
  • Pediatric
  • Neonatal
  • Infant
  • Fetal
  • NTRK
  • Astrocytoma