A Different View on DNA Amplifications Indicates Frequent, Highly Complex, and Stable Amplicons on 12q13-21 in Glioma

Fischer, Ulrike; Keller, Andreas; Leidinger, Petra; Deutscher, Stephanie; Heisel, Sabrina; Urbschat, Steffi; Lenhof, Hans‐Peter; Meese, Eckart

doi:10.1158/1541-7786.mcr-07-0283

Cited by 42 publications

(32 citation statements)

References 21 publications

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“…FRS2 gene amplification has been shown in pleomorphic adenomas (Di Palma et al, 2007), gliomas (Fischer et al, 2008), osteosarcoma (Mejia-Guerrero et al, 2010). Four previous studies have described FRS2 amplification in liposarcomas.…”

Section: Discussionmentioning

confidence: 96%

High‐resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well‐differentiated and dedifferentiated liposarcoma

Wang

Asmann

Erickson-Johnson

et al. 2011

Genes Chromosomes & Cancer

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Well-differentiated liposarcoma (WDLS) is one of the most common malignant mesenchymal tumors and dedifferentiated liposarcoma (DDLS) is a malignant tumor consisting of both WDLS and a transformed nonlipogenic sarcomatous component. Cytogenetically, WDLS is characterized by the presence of ring or giant rod chromosomes containing several amplified genes, including MDM2, TSPAN31, CDK4, and others mainly derived from chromosome bands 12q13-15. However, the 12q13-15 amplicon is large and discontinuous. The focus of this study was to identify novel critical genes that are consistently amplified in primary (nonrecurrent) WDLS and with potential relevance for future targeted therapy. Using a high-resolution (5.0 kb) "single nucleotide polymorphism"/copy number variation microarray to screen the whole genome in a series of primary WDLS, two consistently amplified areas were found on chromosome 12: one region containing the MDM2 and CPM genes, and another region containing the FRS2 gene. Based on these findings, we further validated FRS2 amplification in both WDLS and DDLS. Fluorescence in situ hybridization confirmed FRS2 amplification in all WDLS and DDLS tested (n = 57). Real time PCR showed FRS2 mRNA transcriptional upregulation in WDLS (n = 19) and DDLS (n = 13) but not in lipoma (n = 5) and normal fat (n = 9). Immunoblotting revealed high expression levels of phospho-FRS2 at Y436 and slightly overexpression of total FRS2 protein in liposarcoma but not in normal fat or preadipocytes. Considering the critical role of FRS2 in mediating fibroblast growth factor receptor signaling, our findings indicate that FRS2 signaling should be further investigated as a potential therapeutic target for liposarcoma.

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Section: Discussionmentioning

confidence: 96%

High‐resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well‐differentiated and dedifferentiated liposarcoma

Wang

Asmann

Erickson-Johnson

et al. 2011

Genes Chromosomes & Cancer

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“…HOTAIR is transcribed from the intergenic region of HOXC11 and HOXC12 at 12q13.13. Accumulating studies have reported amplification of this region in a spectrum of malignancies including bladder cancer, glioma, and lipoma [29][30][31]. Courjal F et al also found that there were 4 out of 61 breast cancer patients had the amplification of this locus detected by Southern blot [32].…”

Section: Discussionmentioning

confidence: 99%

“…Since it has been shown that the chromosomal locus transcribing HOTAIR is amplified in many cancers [29][30][31][32], we hypothesized that the circulating DNA of HOTAIR could be a biomarker for distinguishing breast cancer patients from healthy individuals.…”

Section: Circulating Hotair Dna Distinguishes Breast Cancer Patients mentioning

confidence: 99%

Circulating DNA of HOTAIR in serum is a novel biomarker for breast cancer

Zhang

Song

Wang

et al. 2015

Breast Cancer Res Treat

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Long non-coding HOX transcript antisense intergenic RNA (HOTAIR) plays an important role in breast cancer. The purpose of this study was to determine whether circulating HOTAIR can be used for breast cancer diagnosis. HOTAIR in serum was measured by PCR-based direct detection. Reverse transcriptase and DNase I treatment were used to distinguish the DNA and RNA forms of HOTAIR. To determine whether circulating HOTAIR is a biomarker for breast cancer, the DNA of HOTAIR from breast cancer patients and healthy controls was measured at both the discovery stage (48 individuals) and an independent validation stage (156 individuals). The diagnostic accuracy was assessed by the receiver operating characteristic curve (ROC) and the area under the curve (AUC). We showed that the major form of HOTAIR-derived fragment in serum is DNA rather than RNA in our study, the same as for MALAT-1, another well-described lincRNA. A higher circulating DNA level of HOTAIR was found in patients at the discovery stage (P = 0.0008). ROC analysis revealed that the circulating HOTAIR DNA distinguished breast cancer patients from healthy individuals (AUC = 0.799). This finding was confirmed at the validation stage. Though circulating MALAT-1 DNA was altered in the discovery stage, it showed no significant difference in the validation stage. In the entire set of 204 samples, the circulating HOTAIR DNA showed a 2.15-fold change in patients compared with healthy controls (P < 0.0001, AUC = 0.786). The optimal cutoff value for diagnosis was 0.30 with sensitivity of 80.0 % and specificity of 68.3 %. Moreover, a correlation between the DNA level of circulating HOTAIR and the progress of breast cancer was established. We have demonstrated that the circulating DNA of HOTAIR is a potential biomarker for breast cancer.

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“…In particular, a common mechanism of silencing by means of CpG island methylation upstream of EVL has been reported for mir-342/EVL in colorectal cancer and, as already mentioned, amplification of the MCM7 locus at the origin of the mir106b$25 cluster and its host gene overexpression have been identified in prostate cancer. miR-26a, which has been reported to be overexpressed in leiomyoma in comparison with paired myometrium (Pan et al, 2008), may also have oncogenic properties, as may its host gene CTDSP2, a phosphatase that is frequently amplified and overexpressed in sarcomas and brain tumors (Su et al, 1997;Fischer et al, 2008). Interestingly, monitoring the expression levels of MCM7 and CTDSP2 host genes in a database including transcriptional profiles of 24 normal, 34 MGUS, 269 MM, and 9 PCL samples revealed that MCM7 and CTDSP2 are extremely variably expressed in MM patients, and highly deregulated in a considerable fraction of MM and PCL samples, in comparison with MGUS and normal plasma cells (Ronchetti et al, 2008 and data not shown).…”

Section: Discussionmentioning

confidence: 99%

Integrative high‐resolution microarray analysis of human myeloma cell lines reveals deregulated miRNA expression associated with allelic imbalances and gene expression profiles

Lionetti

Agnelli

Mosca

et al. 2009

Genes Chromosomes & Cancer

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It is thought that altered microRNA (miRNA) expression due to various mechanisms plays a critical role in the pathogenesis of most human cancers. Notably, about half of the known miRNAs are intragenic and frequently coexpressed with their host genes. To date there is little evidence concerning miRNA expression in multiple myeloma (MM). In an attempt to provide insights into miRNA deregulation in MM, we profiled global miRNA expression in a panel of molecularly well-characterized human myeloma cell lines (HMCLs) using high-resolution microarrays, and then used integrative analyses to identify altered patterns correlated with DNA copy number (CN) or gene expression profiles. We identified 16 miRNAs mapped to chromosomal regions frequently involved in numerical imbalances in MM, whose expression significantly correlated with the CN of the corresponding miRNA genes; among these, miR-22 expression was also affected by chromosome arm 17p loss in a representative panel of primary MM tumors. The expression of 32 intronic miRNAs significantly correlated with that of their host transcripts, some of which were highly deregulated in MM patients. The expression of some of the miRNAs was validated by quantitative RT-PCR. Finally, a number of the identified miRNAs have previously been reported to play important roles in tumorigenesis. Overall, our data highlight that genomic alterations may significantly affect miRNA expression in HMCLs and demonstrate a frequent coexpression of intronic miRNAs with their host genes that may have a pathogenetic relevance in plasma cell transformation.

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A Different View on DNA Amplifications Indicates Frequent, Highly Complex, and Stable Amplicons on 12q13-21 in Glioma

Cited by 42 publications

References 21 publications

High‐resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well‐differentiated and dedifferentiated liposarcoma

High‐resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well‐differentiated and dedifferentiated liposarcoma

Circulating DNA of HOTAIR in serum is a novel biomarker for breast cancer

Integrative high‐resolution microarray analysis of human myeloma cell lines reveals deregulated miRNA expression associated with allelic imbalances and gene expression profiles

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