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Targeted sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas

ABSTRACT: Constitutional LZTR1 or SMARCB1 pathogenic variants have been found in ~86% of familial and ~40% of sporadic schwannomatosis cases. Hence, we performed massively parallel sequencing of the entire LZTR1, SMARCB1 and NF2 genomic loci in 35 individuals with schwannomas negative for constitutional first-hit pathogenic variants in the LZTR1/SMARCB1/NF2 coding sequences, however with 22q deletion and/or a different NF2 pathogenic variant in each tumor, including six cases with only one tumor available. Furthermore, we verified whether any other LZTR1/SMARCB1/NF2 (likely) pathogenic variant(s) could be found in 16 cases carrying a SMARCB1 constitutional variant in the 3Ã¢Â€Â™ untranslated region (3Ã¢Â€Â™-UTR) c.*17C>T, c.*70C>T or c.*82C>T. As no additional variants were found, functional studies were performed to clarify the effect of these 3Ã¢Â€Â™-UTR variants on the transcript. The 3Ã¢Â€Â™-UTR variants c.*17C>T and c.*82C>T showed pathogenicity by negatively affecting SMARCB1 transcript level. Two novel deep intronic SMARCB1 variants, c.500+883T>G and c.500+887G>A, resulting in out-of-frame missplicing of intron 4, were identified in two unrelated individuals. Further resequencing of the entire repeat - masked genomics sequences of chromosome 22q in individuals negative for pathogenic variants in the SMARCB1/LZTR1/NF2 coding- and non-coding regions revealed five potential schwannomatosis-predisposing candidate genes, i.e. MYO18B, NEFH, SGSM1, SGSM3 and SBF1, pending further verification.

PROVIDER: EGAS00001005680 | EGA |

REPOSITORIES: EGA

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GSTM1 null genotype underpins recurrence of NF2 meningiomas

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2024-12-09 | GSE283616 | GEO

Molecular profiling of rhabdoid tumors in a Smarcb1-deficient mouse model

Project description:Germline mutations of the SMARCB1 gene predispose to two distinct tumor syndromes: rhabdoid tumor predisposition syndrome, with malignant pediatric tumors mostly developing in brain and kidney, and familial schwannomatosis, with adulthood benign tumors involving cranial and peripheral nerves. The mechanisms by which SMARCB1 germline mutations predispose to rhabdoid tumors versus schwannomas are still unknown. Here, to understand the origin of these two types of SMARCB1-associated tumors, we generated different tissue- and developmental stage-specific conditional knockout mice carrying Smarcb1 and/or Nf2 deletion. Smarcb1 loss in early neural crest was necessary to initiate tumorigenesis in the cranial nerves and meninges with typical histological features and molecular profiles of human rhabdoid tumors. By inducing Smarcb1 loss at later developmental stage in the Schwann cell lineage, in addition to biallelic Nf2 gene inactivation, we generated the first mouse model developing schwannomas with the same underlying gene mutations found in schwannomatosis patients.

2017-10-31 | GSE94082 | GEO

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Project description:Copy number variants (CNVs) are a major source of genetic variation in human health and disease. Previous studies have suggested replication stress, such as that caused by the polymerase inhibitor aphidicolin, as a causative factor in CNV formation, but existing data are technically limited in the quality of the comparisons which can be made to experimentally induced variants. Here we used 1M feature single-nucleotide polymorphism (SNP) arrays and mate-pair sequencing as high resolution methods for characterizing CNVs in a common set of samples, to compare both the properties of constitutional and induced CNVs as well as the utility of the two methods in an experimental setting. Although the optimized methods provided complementary information, sequencing was more sensitive to small variants and provided superior structural descriptions that allowed some CNVs to be associated with inversions, ectopic duplications or LINE insertions. The majority of constitutional and all aphidicolin-induced CNVs appear to be formed via homology-independent mechanisms, while aphidicolin-induced CNVs were of a larger median size than constitutional events even when mate-pair data were considered. Aphidicolin thus appears to stimulate formation of CNVs that closely resemble human pathogenic CNVs and the subset of larger nonhomologous constitutional CNVs. One untreated and one aphidicolin-treated subclone of human fibroblast cell line HGMDFN090 were analyzed by Illumina HumanOmni1-Quad SNP array and low-density mate-pair sequencing.

2010-12-18 | E-GEOD-26121 | biostudies-arrayexpress

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2019-04-18 | E-MTAB-7848 | biostudies-arrayexpress

Comparison of constitutional and replication stress-induced genome structural variation by SNP array and mate-pair sequencing

2010-12-18 | GSE26121 | GEO

Comprehensive constitutional genetic and epigenetic characterization of Lynch-like individuals [FFPE]

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2019-03-09 | GSE128067 | GEO

Comprehensive constitutional genetic and epigenetic characterization of Lynch-like individuals [Blood]

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Microarray Analysis in Vestibular Schwannomas

Project description:Vestibular Schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of NF2. Transcriptomic alterations, such as the Nrg1/ErbB2 pathway, have been described in Schwannomas. Here, we have performed a whole transcriptomic analysis in 31 vestibular Schwannomas and 9 control nerves in the Affymetrix Gene 1.0ST platform, validated by quantitative Real-Time PCR using TaqMan Low Density Arrays. We performed a mutational analysis of NF2 by PCR/dHPLC and MLPA as well as a microsatellite marker analysis of the loss of heterozygosity of chromosome 22q. The microarray analysis showed that 1516 genes were deregulated, and 48 of the genes were validated by qRT-PCR. At least two genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed one hit and eight tumors showed no NF2 alteration. As conclusion, MET and associated genes such as ITGA4/B6, PLEXNB3/SEMA5 and CAV1 showed a clear deregulation in vestibular Schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in Merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in Schwannoma Merlin depletion. Finally, no major differences were found between tumors of different sizes, histological types or NF2 status, which suggests that at the mRNA level all Schwannomas, regardless of molecular and clinical characteristics, may share common features that can be used in the fight against them. In order to find target to fight against vestibular schwannoma, we performed an analysis of gene expression by microarrays.

2013-03-01 | E-GEOD-39645 | biostudies-arrayexpress

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2016-08-21 | E-GEOD-85133 | biostudies-arrayexpress

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