Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors

Abstract

Single nucleotide polymorphism (SNP) array analysis is currently used as a first tier test for pediatric brain tumors at The Children's Hospital of Philadelphia. The results from 100 consecutive patients are summarized in the present report. Eighty-seven percent of the tumors had at least one pathogenic copy number alteration. Nineteen of 56 low grade gliomas (LGGs) demonstrated a duplication in 7q34, which resulted in a KIAA1549-BRAF fusion. Chromosome band 7q34 deletions, which resulted in a FAM131B-BRAF fusion, were identified in one pilocytic astrocytoma and one dysembryoplastic neuroepithelial tumor (DNT). One ganglioglioma (GG) demonstrated a 6q23.3q26 deletion that was predicted to result in a MYB-QKI fusion. Gains of chromosomes 5, 6, 7, 11, and 20 were seen in a subset of LGGs. Monosomy 6, deletion of 9q and 10q, and an i(17)(q10) were each detected in the medulloblastomas (MBs). Deletions and regions of loss of heterozygosity that encompassed TP53, RB1, CDKN2A/B, CHEK2, NF1, and NF2 were identified in a variety of tumors, which led to a recommendation for germline testing. A BRAF p.Thr599dup or p.V600E mutation was identified by Sanger sequencing in one and five LGGs, respectively, and a somatic TP53 mutation was identified in a fibrillary astrocytoma. No TP53 hot-spot mutations were detected in the MBs. SNP array analysis of pediatric brain tumors can be combined with pathologic examination and molecular analyses to further refine diagnoses, offer more accurate prognostic assessments, and identify patients who should be referred for cancer risk assessment.

Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology

“…Such alterations result in constitutively activated signaling pathways downstream of FGFR1 [55,67]. Published studies of genetic alterations in DNETs are limited, focusing on BRAF , rather then FGFR1 [10,43,51]. These find BRAF alterations at a higher frequency than in our dataset (Table 1).…”

Copy number alterations determined by single nucleotide polymorphism array testing in the clinical laboratory are indicative of gene fusions in pediatric cancer patients

“…The LogR ratio and B allele frequency (BAF) plots created in the array software were visually inspected to determine copy number alterations (CNAs) and regions of homozygosity (ROH). The criteria for reporting CNAs (minimum of 20 SNPs unless in a known cancer gene) and ROH (minimum of 5Mb in length unless it encompasses a known cancer gene) have previously been described for the Human610‐Quad and HumanOmni1‐Quad arrays . Prior to employing the Infinium CytoSNP‐850K array in the clinical laboratory, the reporting criteria for CNAs and ROH were reevaluated in 32 previously run clinical samples, and resulted in an adjustment to the criteria for CNAs to a minimum of 15 SNPs unless located within a cancer gene.…”

“…Cytogenetic testing was performed in the clinical laboratory as part of the diagnostic testing requested by the clinician at the time of submission or as follow‐up testing and was not performed as a validation of the array results. The reverse transcription‐PCR (RT‐PCR) testing of some of the rare BRAF fusions has been previously described …”

The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care

“…Notably, CMA can detect this cryptic deletion and provide genomic information critical for patient management. Similarly, in brain tumors, the most common genetic alteration identified in low-grade gliomas is an approximately 2-Mb tandem duplication at 7q34 resulting in the KIAA1549-BRAF fusion [Roth et al, 2014]. Due to the size and the nature of the aberration, this fusion cannot be detected by conventional cytogenetics or FISH.…”