scholarly journals The integrated multiomic diagnosis of sporadic meningiomas: a review of its clinical implications

2021 ◽  
Author(s):  
Stephanie M. Robert ◽  
Shaurey Vetsa ◽  
Arushii Nadar ◽  
Sagar Vasandani ◽  
Mark W. Youngblood ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Clinical Trials ◽  
Copy Number ◽  
Clinical Characteristics ◽  
Copy Number Variations ◽  
Driver Mutations ◽  
Clinical Implications ◽  
Tumor Characteristics ◽  
And Behavior

Abstract Introduction Meningiomas are generally considered “benign,” however, these tumors can demonstrate variability in behavior and a surprising aggressiveness with elevated rates of recurrence. The advancement of next-generation molecular technologies have led to the understanding of the genomic and epigenomic landscape of meningiomas and more recent correlations with clinical characteristics and behavior. Methods Based on a thorough review of recent peer-reviewed publications (PubMed) and edited texts, we provide a molecular overview of meningiomas with a focus on relevant clinical implications. Results The identification of specific somatic driver mutations has led to the classification of several major genomic subgroups, which account for more than 80% of sporadic meningiomas, and can be distinguished using noninvasive clinical variables to help guide management decisions. Other somatic genomic modifications, including non-coding alterations and copy number variations, have also been correlated with tumor characteristics. Furthermore, epigenomic modifications in meningiomas have recently been described, with DNA methylation being the most widely studied and potentially most clinically relevant. Based on these molecular insights, several clinical trials are currently underway in an effort to establish effective medical therapeutic options for meningioma. Conclusion As we enhance our multiomic understanding of meningiomas, our ability to care for patients with these tumors will continue to improve. Further biological insights will lead to additional progress in precision medicine for meningiomas.

PATH-39. INTEGRATED MOLECULAR-MORPHOLOGICAL MENINGIOMA CLASSIFICATION: A MULTICENTER RETROSPECTIVE ANALYSIS, RETRO- AND PROSPECTIVELY VALIDATED

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi123-vi124
Author(s):  
Sybren Maas ◽  
Damian Stichel ◽  
Thomas Hielscher ◽  
Philipp Sievers ◽  
Anna Berghoff ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Retrospective Cohort ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Molecular Data ◽  
Copy Number Variations ◽  
Who Grade ◽  
Risk Of Progression ◽  
The Individual

Abstract PURPOSE Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from cases with benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for the individual patient is of pivotal importance in clinical management. However, only biomarkers for highly aggressive tumors are established at present (CDKN2A/B and TERT), while no molecularly-based stratification exists for the broad spectrum of low- and intermediate-risk meningioma patients. PATIENTS AND METHODS DNA methylation data and copy-number information were generated for 3,031 meningiomas of 2,868 individual patients, with mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNV), mutations and WHO grading were comparatively analyzed. Prediction power for outcome of these parameters was assessed in an initial retrospective cohort of 514 patients, and validated on a retrospective cohort of 184, and on a prospective cohort of 287 multi-center cases, respectively. RESULTS Both CNV and methylation family- (MF)-based subgrouping independently resulted in an increase in prediction accuracy of risk of recurrence compared to the WHO classification (c-indexes WHO 2016, CNV, and MF 0.699, 0.706 and 0.721, respectively). Merging all independently powerful risk stratification approaches into an integrated molecular-morphological score resulted in a further, substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference p=0.005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (HR 4.56 [2.97;7.00], 4.34 [2.48;7.57] and 3.34 [1.28; 8.72] for discovery, retrospective, and prospective validation cohort, respectively). CONCLUSIONS Merging these layers of histological and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision-making for meningioma patients on the basis of robust outcome prediction.

scholarly journals Clinical implications of copy number variations in autoimmune disorders

2015 ◽  
Vol 30 (3) ◽  
pp. 294 ◽  
Author(s):  
Seon-Hee Yim ◽  
Seung-Hyun Jung ◽  
Boram Chung ◽  
Yeun-Jun Chung
Keyword(s):  
Copy Number ◽  
Copy Number Variations ◽  
Autoimmune Disorders ◽  
Clinical Implications

scholarly journals Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors

2015 ◽  
Vol 22 (6) ◽  
pp. 953-967 ◽  
Author(s):  
Helene Myrtue Nielsen ◽  
Alexandre How-Kit ◽  
Carole Guerin ◽  
Frederic Castinetti ◽  
Hans Kristian Moen Vollan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Methylation Status ◽  
Uniparental Disomy ◽  
Copy Number Variations ◽  
Conclusive Evidence ◽  
Adrenal Tumors ◽  
Benign Tumors ◽  
Parental Origin ◽  
Adrenocortical Carcinomas

Overexpression of insulin growth factor 2 (IGF2) is a hallmark of adrenocortical carcinomas and pheochromocytomas. Previous studies investigating the IGF2/H19 locus have mainly focused on a single molecular level such as genomic alterations or altered DNA methylation levels and the causal changes underlying IGF2 overexpression are still not fully established. In the current study, we analyzed 62 tumors of the adrenal gland from patients with Conn's adenoma (CA, n=12), pheochromocytomas (PCC, n=10), adrenocortical benign tumors (ACBT, n=20), and adrenocortical carcinomas (ACC, n=20). Gene expression, somatic copy number variation of chr11p15.5, and DNA methylation status of three differential methylated regions of the IGF2/H19 locus including the H19 imprinting control region were integratively analyzed. IGF2 overexpression was found in 85% of the ACCs and 100% of the PCCs compared to 23% observed in CAs and ACBTs. Copy number aberrations of chr11p15.5 were abundant in both PCCs and ACCs but while PCCs retained a diploid state, ACCs were frequently tetraploid (7/19). Loss of either a single allele or loss of two alleles of the same parental origin in tetraploid samples resulted in a uniparental disomy-like genotype. These copy number changes correlated with hypermethylation of the H19 ICR suggesting that the lost alleles were the unmethylated maternal alleles. Our data provide conclusive evidence that loss of the maternal allele correlates with IGF2 overexpression in adrenal tumors and that hypermethylation of the H19 ICR is a consequence thereof.

Recurrent copy number variations as risk factors for autism spectrum disorders: analysis of the clinical implications

2016 ◽  
Vol 89 (6) ◽  
pp. 708-718 ◽  
Author(s):  
V. Oikonomakis ◽  
K. Kosma ◽  
A. Mitrakos ◽  
C. Sofocleous ◽  
P. Pervanidou ◽  
...  
Keyword(s):  
Risk Factors ◽  
Autism Spectrum Disorders ◽  
Copy Number ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Clinical Implications ◽  
Spectrum Disorders

scholarly journals MON-LB48 The Genomic Landscape of Sporadic Thyrotrophinomas

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Angeline shen ◽  
Paul Wang ◽  
Sunita M C De Sousa ◽  
David J Torpy ◽  
Hamish Scott ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Rna Polymerase Ii ◽  
Copy Number ◽  
Large Scale ◽  
Neutral Loss ◽  
Copy Number Variations ◽  
Driver Mutations ◽  
Chromosomal Anomalies ◽  
Tumour Type ◽  
Genomic Landscape

Abstract Background: Thyrotrophinoma (TSHoma) is rare and knowledge on the genomic landscape of this tumour type is very limited. Aim: To perform whole-exome sequencing (WES) in a population of TSHomas to identify recurrent somatic genetic events Method: WES was performed on paired tumour and germline DNA of 7 patients with TSHomas. Three tissue samples were formalin-fixed paraffin-embedded and 4 fresh frozen tumour samples. Fresh blood samples were also collected from each patient. The average of mean depth of coverage amongst all samples was 129X, and 97% of target bases were covered ≥20X. Results:Four (57%) of the seven patients were male and median age at diagnosis was 52 years. (IQR 46, 60) Six patients (86%) had macroadenomas. Four patients (57%) had central thyrotoxicosis at diagnosis and three patients’ tumour stained positive for TSH on histology examination. Two patients (29%) had growth hormone co-secreting tumours. In total, 69 somatic variants were identified to be of potential interest, averaging 1.4 variants per million base-pair of DNA read. No variants were observed in more than one individual. According to the GTEx database, 9 of 69 genes (DRC3, HDAC5, KDM1A, POLR21, TCF25, THAP7, TTC13, UNC5D, UNC13A) were highly expressed in the pituitary (top 10%). Four of these genes appear to contribute to tumour development via epigenetic pathway. Specifically, three of these genes (HDAC5, KDM1A, THAP7) either interact with or form part of histone deacetylases whilst POLR21 encodes a subunit of RNA polymerase II which is responsible for mRNA synthesis. On the other hand, TCF25 gene is thought to act as transcriptional repressor and UNC5D plays a role in cell-cell adhesion. Large scale copy number variations involving gain or loss of whole chromosome or chromosome (chr) arm were observed in six (86%) tumour samples. Chr 5, 9, 13 and 19 were most commonly affected by chromosomal gains. Deletion of chr 1p was seen in two cases and mutations in KDM1A (p.Glu161fs/c.482_491delAGGAAGAAAA) and ADGRB2 gene (p.Leu1565Gln/c.4694T>A) were found in each of the remaining single copy of chr 1p. ADGRB2 gene is thought to be involved in cell adhesion and angiogenesis inhibition. Copy neutral loss-of-heterozygosity were present in two (29%) of the tumour samples (chr 2 and 12q). However, no somatic mutation was found in these regions. Gene level copy number analysis identified a potential deletion in TTI2 gene which encodes for a regulator in DNA damaging response as well as telomere length regulation. ConclusionOverall, the rate of somatic variant mutations in TSHomas is low, consistent with the relative benign nature of this tumour type. No classical driver mutations were identified by this study however, chromosomal anomalies and epigenetics may play an important part in TSHoma development.

scholarly journals DNA Methylation Status of SHOX-Flanking CpG Islands in Healthy Individuals and Short Stature Patients with Pseudoautosomal Copy Number Variations

2019 ◽  
Vol 158 (2) ◽  
pp. 56-62 ◽  
Author(s):  
Kenichiro Ogushi ◽  
Atsushi Hattori ◽  
Erina Suzuki ◽  
Hirohito Shima ◽  
Masako Izawa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Short Stature ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Copy Number ◽  
Methylation Status ◽  
Cpg Islands ◽  
Copy Number Variations ◽  
Peripheral Blood Cells ◽  
Healthy Individuals

SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.

Quantitation of DNA methylation and copy number variations by targeted sequencing of retrotransposon.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e23139-e23139
Author(s):  
Jeffrey Buis ◽  
Tom Goodman ◽  
Julie Kim ◽  
Adele Kruger ◽  
Brendan Tarrier ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Copy Number Variations ◽  
Targeted Sequencing

scholarly journals Identification of factors regulating the gene expression of alcohol dehydrogenases in hepatocellular carcinoma

2021 ◽  
Author(s):  
Jinghe Xie ◽  
Yaqi Qiu ◽  
Shuai Zhang ◽  
Keqing Ma ◽  
Yimeng Ou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Dna Methylation ◽  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Gene Copy ◽  
Excessive Alcohol Consumption ◽  
Alcohol Dehydrogenases

Abstract Background Excessive alcohol consumption has been documented to increase the risk of liver hepatocellular carcinoma (HCC) development. Accordingly, a broad interest pointed to alcohol dehydrogenases (ADHs), which display essential roles in alcohol metabolism. Despite the relevance of ADHs expression and the prognosis of HCC has been estimated, so far, limited research concerning the factors that are responsible for the regulation of ADHs expression has been reported. Methods In this study, using The Cancer Genome Atlas (TCGA) and RegNetwork database, we predicted potential factors consisting of DNA methylation, gene copy number variations, transcription factors (TFs) and microRNAs (miRNAs) that might impact ADHs gene expression in HCC. Results We found that DNA methylation induced the down-regulated expression of ADH1B. Of note, our results implicated that gene copy number variation might not have effects on ADHs expression. Regarding TFs, we speculated that NFYA modulated ADH1C, E2F1 and TFAP2A regulated ADH6 expression based on their expression and prognostic value. Moreover, miR-185 and miR-561 might elicit the repression of ADH4, and miR-105 might impair ADH6 expression. Conclusion This study revealed that multiple factors, including DNA methylation, TFs and microRNAs, affect the expression of ADH family members, which provided new insights into discovering promising HCC-suppressive targets.

scholarly journals Automated prediction of the clinical impact of structural copy number variations

2020 ◽  
Author(s):  
Michaela Gaziova ◽  
Tomas Sladecek ◽  
Ondrej Pos ◽  
Martin Stevko ◽  
Werner Krampl ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Diseases ◽  
Copy Number Variants ◽  
Copy Number Gain ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Clinical Impact ◽  
Copy Number Loss ◽  
Pathogenicity Prediction

Introduction: Copy number variants (CNVs) play an important role in many biological processes, including the development of genetic diseases, making them attractive targets for genetic analyses. The interpretation of the effect of structural variants is a challenging problem due to highly variable numbers of gene, regulatory or other genomic elements affected by the CNV. This led to the demand for the interpretation tools that would relieve researchers, laboratory diagnosticians, genetic counselors, and clinical geneticists from the laborious process of annotation and classification of CNVs. Materials and Methods: We designed a classifier method based on the annotations of CNVs from several publicly available databases. The attributes take into account gene elements, regulatory elements affected by the CNV, as well as other CNVs with known clinical significance that overlap the candidate CNV. We also describe the process of model selection and the construction of training, validation, and test set. Results: The presented approach achieved more than 98% prediction accuracy on both copy number loss and copy number gain variants and can be improved by imposing probability thresholds to eliminate low confidence predictions. Discussion: Method has shown considerable performance in predicting the clinical impact of CNVs and therefore has a great potential to guide users to more precise conclusions. The CNV annotation and pathogenicity prediction can be fully automated, relieving users of tedious interpretation processes. Availability and Implementation: The results can be reproduced by following instructions at {{https://github.com/tsladecek/isv}}.

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