Mosaic Amplification of Multiple Receptor Tyrosine Kinase Genes in Glioblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Matija Snuderl
PROVIDER: E-GEOD-33483 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Here we present a novel example of genetic heterogeneity in human malignant brain tumors, in which multiple closely-related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to 3 different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. However, these subpopulations cannot be always observed with a genome wide studies such as aCGH. Here we include aCGH on three such mosaic cases. Analyses were performed on 350 archival specimens of glioblastoma, WHO Grade IV, seen at the Department of Pathology, Massachusetts General Hospital from 2009 to 2011.
2012-01-01 | GSE33483 | GEO
Project description:Breast cancer is the most prevalent cancer in women 1, and most cases are believed to have a sporadic, rather than heritable basis 2. To identify breast cancer driver genes, we exploited the C3H-Mcm4Chaos3/Chaos3 (“Chaos3”) mouse model that, by virtue of bearing a defective DNA replicative helicase subunit that causes elevated genomic instability (GIN), sustains somatic alterations ultimately causing mammary adenocarcinomas 6. Array Comparative Genomic Hybridization (aCGH) analysis of Chaos3 mammary tumors revealed recurrent copy number alterations (CNAs), most notably deletion of the Neurofibromin 1 (Nf1) tumor suppressor gene in all cases. NF1, a negative regulator of RAS, is traditionally recognized for its role in driving the development of neurofibromas in the context of the human disease Neurofibromatosis Type 1, but not breast cancer. Genomic DNA from tumor and reference samples were hybridized to NimbleGen 3x720K mouse CGH arrays. Two reference samples were used independently. CNAs were visualized using Nimblegen, IGV, and KCsmart software 32. Select genes were validated via qPCR. Critical regions within each Chaos3 CNA were identified as the region with the greatest overlap across multiple Chaos3 tumors. Recurring Copy Number Variations (CNVs) for 12 Chaos3 tumors and 2 MMTV-Neu mammary tumors analyzed by aCGH are indicated. Samples analyzed are primary tumors except where indicated.
2012-10-01 | E-GEOD-37607 | biostudies-arrayexpress
Project description:We used microarray CGH analysis with a tiling path BAC DNA microarray to profile DNA copy number alterations in 164 serous ovarian adenocarcinomas. Survival probabilities modelled by proportional hazards were used to stratify cases into good, intermediate or poor survival groups. Comparison of aCGH data from these groups was used to identify genomic alterations associated with patient survival. A total of 984 cases of serous ovarian adenocarcinoma from three different studies were combined and Cox proportional hazards used to model survival using patient age, tumour stage and residual disease status as covariates. Survival probabilities (Pr) were extracted for all cases and used to stratify 384 cases for which microarray CGH data was available. From these, we identified 70 cases with poor survival (Pr>0.784) and 70 cases with good survival (Pr<0.35). aCGH data from these cases was provided to an iterative Support Vector Machine (SVM) routine to detect copy number changes associated with survival. Candidate regions were then validated by survival analysis in all 384 cases for which aCGH data was available. This series contains aCGH data from 164 tumours from the MALOVA collection.
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2023-02-24 | E-MTAB-12670 | biostudies-arrayexpress
Project description:Endometrial stromal sarcomas (ESSs) are a genetically heterogeneous group of rare uterine neoplasms that are frequently driven by recurrent gene rearrangements. In conventional low-grade ESSs, JAZF1-SUZ12, PHF1-JAZF1, EPC1-PHF1 and MEAF6-PHF1 chimeric fusions have been reported in > 50% of cases. The recently described t(10;17)(q22;p13) translocation yields YWHAE-FAM22A/B chimeric proteins that are associated with histologically high-grade and clinically more aggressive ESS. Integrating whole-transcriptome paired-end RNA sequencing with fluorescence in situ hybridization (FISH) and conventional cytogenetics, we identified MBTD1 (Malignant Brain Tumor Domain-containing 1) and CXorf67 (Chromosome X open reading frame 67) as the genes involved in the novel reciprocal t(X;17)(p11.2;q21.33) translocation in two independent low-grade ESS of classical histology. The presence of the MBTD1-CXorf67 fusion transcript was validated in both cases using RT-PCR followed by Sanger sequencing. A specific FISH assay to be used on paraffin tissues was developed to detect the novel t(X;17) translocation, and resulted in identification of an additional low-grade ESS case positive for the MBTD1-CXorf67 fusion among 14 uterine stromal tumours [9 ESSs and 5 undifferentiated endometrial sarcomas (UESs)] that were negative for JAZF1 and YWHAE rearrangements. Gene expression profiles of 3 ESSs with YWHAE- and 4 classical ESSs with JAZF1-rearrangements, and 4 UESs without known gene rearrangements, indicated clustering of tumours with MBTD1-CXorf67 fusion together with low-grade JAZF1-associated ESSs. The chimeric MBTD1-CXorf67 fusion identifies yet another cytogenetically distinct subgroup of low-grade ESS and offers the opportunity to shed light on the functions of two poorly characterized genes. Genomic DNA extracted from 2 low-grade ESS frozen tumor samples; Agilent CGH+SNP 4x180K array. Reference female DNA supplied with the SureTag Complete DNA Labeling Kit was used for the aCGH experiments.
2015-03-31 | E-GEOD-46284 | biostudies-arrayexpress
Project description:Background Array-Comparative-Genomic-Hybridization (aCGH) is recommended as first-tier genetic test for children with autism spectrum disorder (ASD). However, result interpretation can be challenging as copy number variants (CNVs) in non-European ASD patients is not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. Methods DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. Results Ten pathogenic and one likely-pathogenic CNVs were found in nine patients, with an overall diagnostic yield of 3.5%. A 138kb duplication involving 3â exons of DPP10 (hg[19]chr2:116534689-116672358), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of unknown significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified amongst our ancestry-matched control with frequency of 6/653 (0.92%) as well as from literature and genomic databases. Conclusions DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings.
2017-04-07 | E-MTAB-5672 | biostudies-arrayexpress
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2014-03-03 | E-GEOD-54080 | biostudies-arrayexpress
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