Eric M. Jackson

Duplication of 7q34 in Pediatric Low-Grade Astrocytomas Detected by High-Density Single-Nucleotide Polymorphism-Based Genotype Arrays Results in a Novel BRAF Fusion Gene

In the present study, DNA from 28 pediatric low‐grade astrocytomas was analyzed using Illumina HumanHap550K single‐nucleotide polymorphism oligonucleotide arrays. A novel duplication in chromosome band 7q34 was identified in 17 of 22 juvenile pilocytic astrocytomas and three of six fibrillary astrocytomas. The 7q34 duplication spans 2.6 Mb of genomic sequence and contains approximately 20 genes, including two candidate tumor genes, HIPK2 and BRAF. There were no abnormalities in HIPK2, and analysis of two mutation hot‐spots in BRAF revealed a V600E mutation in only one tumor without the duplication. Fluorescence in situ hybridization confirmed the 7q34 copy number change and was suggestive of a tandem duplication. Reverse transcription polymerase chain reaction‐based sequencing revealed a fusion product between KIAA1549 and BRAF. The predicted fusion product includes the BRAF kinase domain and lacks the auto‐inhibitory N‐terminus. Western blot analysis revealed phosphorylated mitogen‐activated protein kinase (MAPK) protein in tumors with the duplication, consistent with BRAF‐induced activation of the pathway. Further studies are required to determine the role of this fusion gene in downstream MAPK signaling and its role in development of pediatric low‐grade astrocytomas.

Genomic Analysis Using High-Density Single Nucleotide Polymorphism-Based Oligonucleotide Arrays and Multiplex Ligation-Dependent Probe Amplification Provides a Comprehensive Analysis of INI1/SMARCB1 in Malignant Rhabdoid Tumors

PURPOSE A high-resolution genomic profiling and comprehensive targeted analysis of INI1/SMARCB1 of a large series of pediatric rhabdoid tumors was done. The aim was to identify regions of copy number change and loss of heterozygosity (LOH) that might pinpoint additional loci involved in the development or progression of rhabdoid tumors and define the spectrum of genomic alterations of INI1 in this malignancy. EXPERIMENTAL DESIGN A multiplatform approach using Illumina single nucleotide polymorphism-based oligonucleotide arrays, multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, and coding sequence analysis was used to characterize genome-wide copy number changes, LOH, and genomic alterations of INI1/SMARCB1 in a series of pediatric rhabdoid tumors. RESULTS The biallelic alterations of INI1 that led to inactivation were elucidated in 50 of 51 tumors. INI1 inactivation was shown by a variety of mechanisms, including deletions, mutations, and LOH. The results from the array studies highlighted the complexity of rearrangements of chromosome 22 compared with the low frequency of alterations involving the other chromosomes. CONCLUSIONS The results from the genome-wide single nucleotide polymorphism array analysis suggest that INI1 is the primary tumor suppressor gene involved in the development of rhabdoid tumors with no second locus identified. In addition, we did not identify hotspots for the breakpoints in sporadic tumors with deletions of chromosome 22q11.2. By employing a multimodality approach, the wide spectrum of alterations of INI1 can be identified in the majority of patients, which increases the clinical utility of molecular diagnostic testing.

Lack of Shunt Response in Suspected Idiopathic Normal Pressure Hydrocephalus with Alzheimer Disease Pathology

To determine the impact of cortical Alzheimer disease pathology on shunt responsiveness in individuals treated for idiopathic normal pressure hydrocephalus (iNPH), 37 patients clinically diagnosed with iNPH participated in a prospective study in which performance on neurologic, psychometric, and gait measures before and 4 months after shunting was correlated with amyloid β plaques, neuritic plaques, and neurofibrillary tangles observed in cortical biopsies obtained during shunt insertion. No complications resulted from biopsy acquisition. Moderate to severe pathology was associated with worse baseline cognitive performance and diminished postoperative improvement on NPH symptom severity scales, gait measures, and cognitive instruments compared to patients lacking pathology. ANN NEUROL 2010

Genomic copy number determination in cancer cells from single nucleotide polymorphism microarrays based on quantitative genotyping corrected for aneuploidy

Microarrays are frequently used to profile genome-wide copy number (CN) aberrations. While generally robust for detecting CN variants in germline DNA, the methods used to derive CN from signal intensity values have been suboptimal when applied to cancer genomes. The complexity of genomic aberrations in cancer makes it more difficult to discriminate between signal and noise, and measuring CN as a discrete variable does not account for tumor heterogeneity. Furthermore, standard normalization approaches detect CN changes relative to the overall DNA content, which is often not diploid in cancer. We propose an algorithm that uses the degree of allelic imbalance as well as probe intensity, with a correction for aneuploidy, for a quantitative CN assessment and scoring of allelic ratios. This algorithm results in a more precise definition of CN and allelic aberration in the cancer genome, which is essential for translational efforts focused on using these tools for molecular diagnostics and for the discovery of therapeutic targets.

High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor

Malignant rhabdoid tumors are highly aggressive neoplasms found primarily in infants and young children. The majority of rhabdoid tumors arise as a result of homozygous inactivating deletions or mutations of the INI1 gene located in chromosome band 22q11.2. Germline mutations of INI1 predispose to the development of rhabdoid tumors of the brain, kidney and extra-renal tissues, consistent with its function as a tumor suppressor gene. We now describe five patients with germline deletions in chromosome band 22q11.2 that included the INI1 gene locus, leading to the development of rhabdoid tumors. Two patients had phenotypic findings that were suggestive but not diagnostic for DiGeorge/Velocardiofacial syndrome (DGS/VCFS). The other three infants had highly aggressive disease with multiple tumors at the time of presentation. The extent of the deletions was determined by fluorescence in situ hybridization and high-density oligonucleotide based single nucleotide polymorphism arrays. The deletions in the two patients with features of DGS/VCFS were distal to the region typically deleted in patients with this genetic disorder. The three infants with multiple primary tumors had smaller but overlapping deletions, primarily involving INI1. The data suggest that the mechanisms underlying the deletions in these patients may be similar to those that lead to DGS/VCFS, as they also appear to be mediated by related, low copy repeats (LCRs) in 22q11.2. These are the first reported cases in which an association has been established between recurrent, interstitial deletions mediated by LCRs in 22q11.2 and a predisposition to cancer.

Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimers disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Aβ1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH.MethodsWe conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Aβ1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Aβ1-42 ratios in the patients in our cohort.ResultsWe found that high ptau/Aβ1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Aβ1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios.ConclusionsLevels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition.

Surgical management of pediatric brain tumors

Brain tumors are the most common cause of cancer-related death and the second most common form of cancer in pediatric patients. Many of these tumors are treated primarily with surgery, either alone or in combination with radiation or chemotherapy. Recent advances have lead to greater survival and decreased morbidities in childhood brain tumor patients. A full understanding of the biology and primary treatment modalities for the particular tumor are essential for any professional treating these patients, including the neurosurgeon. Each tumor type has features in common with, and unique from, other tumors that need to be understood prior to undertaking a rational treatment plan. This article summarizes some of these features.

Surgical treatment of a clival-C2 atypical teratoid/rhabdoid tumor

The authors present the case of en bloc resection of a clival-C2 atypical teratoid/rhabdoid tumor. These aggressive lesions of early childhood generally occur in the cerebellum or cerebral hemispheres. This 7-year-old boy presented with pain on turning his head and was found to have a clival-C2 mass. A metastatic workup was negative for disseminated disease. A transoral biopsy procedure revealed an atypical teratoid/rhabdoid tumor on histological examination. The tumor was resected via a transoral approach, and the patients spine was stabilized with posterior instrumented fusion from the occiput to C-5. Postoperatively, the patient underwent 16 months of chemotherapy along with 6 weeks of overlapping radiation therapy. Twenty-seven months after the initial surgery he presented with leg pain and was found to have a solitary metastatic lesion at the conus medullaris. There was no local recurrence at the clivus. The conus tumor was resected and found to be consistent with the primary tumor. Several months later the patient presented with disseminated intrathecal disease and ultimately died 42 months after the initial resection.

Pial synangiosis in patients with moyamoya younger than 2 years of age.

Object Patients with moyamoya who are younger than 2 years of age represent a therapeutic challenge because of their frequent neurological instability and concomitant anesthetic risks. The authors report their experience with pial synangiosis revascularization in this population. Methods The authors reviewed the clinical and radiographic records of all patients with moyamoya in a consecutive series of patients under 2 years of age, who underwent cerebral revascularization surgery using pial synangiosis at a single institution. Results During a 12-year period (1994-2005), 34 procedures (bilateral in 15 patients, unilateral in 4) were performed in 19 patients younger than 2 years (out of a total of 456 procedures in 240 patients). Eighteen of these patients presented with either stroke or transient ischemic attack. The average age of the 19 patients at first surgery was 1.4 years (range 6 months-1.9 years). Unanticipated staged operations occurred in 3 patients, due to persistent electroencephalographic changes during the initial surgery in 2 cases and due to brain swelling during the procedure requiring ventriculostomy in the other. There were 2 perioperative strokes; both patients had postoperative seizures but made clinical recoveries. The average follow-up was 7 years (range 1-14 years). Long term, at follow-up, 13 patients (68%) were clinically independent for their age, with 8 (42%) having no significant deficit. Late complications included subdural hygroma evacuation (1), additional revascularization procedures performed years later for frontal lobe ischemia (2), late infarction (1), and asymptomatic ischemic change on routine follow-up MRI studies (1). All patients who had both pre- and postoperative angiography demonstrated progression of disease. Conclusions Despite the challenges inherent to this population, the majority of children with moyamoya under the age of 2 years have a good long-term prognosis. The data from this study support the use of pial synangiosis as a safe, effective, and durable method for treatment of moyamoya for most children in this potentially high-risk population.

Atypical teratoid/rhabdoid tumor in a patient with Beckwith–Wiedemann syndrome†

Beckwith–Wiedemann syndrome (BWS) is a genetic disorder associated with an increased risk of childhood tumors. Here we describe a patient with BWS who developed a central nervous system atypical teratoid/rhabdoid tumor (AT/RT). To our knowledge, despite the known cancer predisposition, this patient is the first described with BWS to develop an AT/RT. Due to the high propensity of these patients to develop childhood tumors, in addition to routine diagnostic tests, analysis of the tumor DNA using the Illumina Infinium whole‐genome genotyping 550K Beadchip was performed to investigate a possible common underlying mechanism for his BWS and AT/RT. The only alteration detected was monosomy 22, which was accompanied by a somatic mutation in the INI1 rhabdoid tumor gene. These results suggest that, despite an underlying cancer predisposition, the occurrence of BWS and AT/RT in this patient may be unrelated.