Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences With the Adult Disease

Purpose To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). Patients and Methods We conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for 53 tumors. Results were compared with publicly available data from adult tumors. Results Significant differences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregulated PDGFRα signaling in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showed minimal copy number changes. Conclusion Integrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFRα may be a useful target for pediatric HGG, including diffuse pontine gliomas.

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Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-Grade and High-Grade Carcinomas

Cancer Research ◽

10.1158/0008-5472.can-08-3913 ◽

2009 ◽

Vol 69 (9) ◽

pp. 4036-4042 ◽

Cited By ~ 118

Author(s):

Kuan-Ting Kuo ◽

Bin Guan ◽

Yuanjian Feng ◽

Tsui-Lien Mao ◽

Xu Chen ◽

...

Keyword(s):

Copy Number ◽

Molecular Genetic ◽

Low Grade ◽

High Grade ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Genetic Changes ◽

Dna Copy Number Alterations ◽

Serous Tumors

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Nonequivalent Gene Expression and Copy Number Alterations in High-Grade Serous Ovarian Cancers with BRCA1 and BRCA2 Mutations

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-13-0066 ◽

2013 ◽

Vol 19 (13) ◽

pp. 3474-3484 ◽

Cited By ~ 54

Author(s):

Joshy George ◽

Kathryn Alsop ◽

Dariush Etemadmoghadam ◽

Heather Hondow ◽

Thomas Mikeska ◽

...

Keyword(s):

Gene Expression ◽

Copy Number ◽

High Grade ◽

Copy Number Alterations ◽

Brca1 And Brca2 ◽

Ovarian Cancers ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

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Insights into dispersed duplications and complex structural mutations from whole genome sequencing 706 families

10.1101/2020.08.03.235358 ◽

2020 ◽

Author(s):

Christopher W. Whelan ◽

Robert E. Handsaker ◽

Giulio Genovese ◽

Seva Kashin ◽

Monkol Lek ◽

...

Keyword(s):

Gene Expression ◽

Copy Number Variation ◽

Copy Number ◽

De Novo ◽

Whole Genome ◽

Sequencing Data ◽

Number Variation ◽

Structural Mutations ◽

Or Gene ◽

Genomic Locations

AbstractTwo intriguing forms of genome structural variation (SV) – dispersed duplications, and de novo rearrangements of complex, multi-allelic loci – have long escaped genomic analysis. We describe a new way to find and characterize such variation by utilizing identity-by-descent (IBD) relationships between siblings together with high-precision measurements of segmental copy number. Analyzing whole-genome sequence data from 706 families, we find hundreds of “IBD-discordant” (IBDD) CNVs: loci at which siblings’ CNV measurements and IBD states are mathematically inconsistent. We found that commonly-IBDD CNVs identify dispersed duplications; we mapped 95 of these common dispersed duplications to their true genomic locations through family-based linkage and population linkage disequilibrium (LD), and found several to be in strong LD with genome-wide association (GWAS) signals for common diseases or gene expression variation at their revealed genomic locations. Other CNVs that were IBDD in a single family appear to involve de novo mutations in complex and multi-allelic loci; we identified 26 de novo structural mutations that had not been previously detected in earlier analyses of the same families by diverse SV analysis methods. These included a de novo mutation of the amylase gene locus and multiple de novo mutations at chromosome 15q14. Combining these complex mutations with more-conventional CNVs, we estimate that segmental mutations larger than 1kb arise in about one per 22 human meioses. These methods are complementary to previous techniques in that they interrogate genomic regions that are home to segmental duplication, high CNV allele frequencies, and multi-allelic CNVs.Author SummaryCopy number variation is an important form of genetic variation in which individuals differ in the number of copies of segments of their genomes. Certain aspects of copy number variation have traditionally been difficult to study using short-read sequencing data. For example, standard analyses often cannot tell whether the duplicated copies of a segment are located near the original copy or are dispersed to other regions of the genome. Another aspect of copy number variation that has been difficult to study is the detection of mutations in the copy number of DNA segments passed down from parents to their children, particularly when the mutations affect genome segments which already display common copy number variation in the population. We develop an analytical approach to solving these problems when sequencing data is available for all members of families with at least two children. This method is based on determining the number of parental haplotypes the two siblings share at each location in their genome, and using that information to determine the possible inheritance patterns that might explain the copy numbers we observe in each family member. We show that dispersed duplications and mutations can be identified by looking for copy number variants that do not follow these expected inheritance patterns. We use this approach to determine the location of 95 common duplications which are dispersed to distant regions of the genome, and demonstrate that these duplications are linked to genetic variants that affect disease risk or gene expression levels. We also identify a set of copy number mutations not detected by previous analyses of sequencing data from a large cohort of families, and show that repetitive and complex regions of the genome undergo frequent mutations in copy number.

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HGG-41. STRUCTURAL VARIANT DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.322 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii351-iii351

Author(s):

Frank Dubois ◽

Ofer Shapira ◽

Noah Greenwald ◽

Travis Zack ◽

Jessica W Tsai ◽

...

Keyword(s):

Copy Number ◽

High Grade Glioma ◽

High Grade ◽

Structural Variants ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Effector Domains ◽

Topologically Associating Domains ◽

Genome Wide ◽

Pediatric High Grade Glioma

Abstract BACKGROUND Driver single nucleotide variants (SNV) and somatic copy number aberrations (SCNA) of pediatric high-grade glioma (pHGGs), including Diffuse Midline Gliomas (DMGs) are characterized. However, structural variants (SVs) in pHGGs and the mechanisms through which they contribute to glioma formation have not been systematically analyzed genome-wide. METHODS Using SvABA for SVs as well as the latest pipelines for SCNAs and SNVs we analyzed whole-genome sequencing from 174 patients. This includes 60 previously unpublished samples, 43 of which are DMGs. Signature analysis allowed us to define pHGG groups with shared SV characteristics. Significantly recurring SV breakpoints and juxtapositions were identified with algorithms we recently developed and the findings were correlated with RNAseq and H3K27ac ChIPseq. RESULTS The SV characteristics in pHGG showed three groups defined by either complex, intermediate or simple signature activities. These associated with distinct combinations of known driver oncogenes. Our statistical analysis revealed recurring SVs in the topologically associating domains of MYCN, MYC, EGFR, PDGFRA & MET. These correlated with increased mRNA expression and amplification of H3K27ac peaks. Complex recurring amplifications showed characteristics of extrachromosomal amplicons and were enriched in coding SVs splitting protein regulatory from effector domains. Integrative analysis of all SCNAs, SNVs & SVs revealed patterns of characteristic combinations between potential drivers and signatures. This included two distinct groups of H3K27M DMGs with either complex or simple signatures and different combinations of associated variants. CONCLUSION Recurrent SVs associate with signatures shaped by an underlying process, which can lead to distinct mechanisms to activate the same oncogene.

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Lessons from a decade of integrating cancer copy number alterations with gene expression profiles

Briefings in Bioinformatics ◽

10.1093/bib/bbr056 ◽

2011 ◽

Vol 13 (3) ◽

pp. 305-316 ◽

Cited By ~ 32

Author(s):

N. Huang ◽

P. K. Shah ◽

C. Li

Keyword(s):

Gene Expression ◽

Copy Number ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Copy Number Alterations

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PATH-41. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG WITH FGFR3-TACC3 FUSION MIMICKING HIGH-GRADE GLIOMA: CASE REPORT AND SERIES OF HIGH-GRADE CORRELATES

Neuro-Oncology ◽

10.1093/neuonc/noab196.493 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi124-vi124

Author(s):

Danielle Golub ◽

Peter C Pan ◽

Benjamin Liechty ◽

Cheyanne Slocum ◽

Tejus Bale ◽

...

Keyword(s):

Progression Free Survival ◽

High Grade Glioma ◽

Proliferation Index ◽

Molecular Profile ◽

Low Grade ◽

High Grade ◽

Molecular Features ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently-described entity that can occasionally histologically and molecularly mimic high-grade glioma. The histologic and molecular features that predict aggressive behavior in FGFR3-TACC3 altered tumors are unclear. CASES We present a rare case of an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of high-grade glioma and analyze common molecular features between this case and a series of high-grade gliomas. After total resection, pathology of the case patient revealed predominantly low-grade cytomorphology, abundant microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34 immunoreactive and harbored both an FGFR3-TACC3 fusion and a TERT promoter mutation. Based on the overall histologic and molecular profile, a diagnosis of PLNTY was favored. The patient was thereafter observed without adjuvant therapy with no evidence of progression at 15-month follow-up. In contrast, a series of eight adult patients with glioblastomas harboring FGFR3-TACC3 fusions and correspondingly aggressive clinical courses are also presented. Common molecular findings included IDH-wildtype status, absence of 1p19q codeletion, and CDKN2A loss. TERT promoter mutations and lack of MGMT promoter methylation were also frequently observed. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.

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Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms

Biomedicines ◽

10.3390/biomedicines8120574 ◽

2020 ◽

Vol 8 (12) ◽

pp. 574

Author(s):

Ege Ülgen ◽

Sıla Karacan ◽

Umut Gerlevik ◽

Özge Can ◽

Kaya Bilguvar ◽

...

Keyword(s):

Copy Number ◽

Copy Number Alteration ◽

Age At Diagnosis ◽

Copy Number Alterations ◽

Primary Tumors ◽

Double Minutes ◽

Molecular Features ◽

Genetic Landscape ◽

Underlying Mechanisms ◽

Mutational Processes

Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and “Others” differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.

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