High-resolution array CGH analysis of salivary gland tumors reveals fusion and amplification of the FGFR1 and PLAG1 genes in ring chromosomes

Persson, Fredrik; Winnes, Marta; Andrén, Ywonne; Wedell, Barbro; Dahlenfors, Rigmor; Asp, Julia; Mark, Joachim; Enlund, Fredrik; Stenman, Göran

doi:10.1038/sj.onc.1210961

Cited by 61 publications

(71 citation statements)

References 34 publications

(37 reference statements)

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“…Genomic DNA was extracted from formalin-fixed paraffin-embedded and freshfrozen tumor tissues as previously described. 25,26 A pool of normal female or male genomic DNAs obtained from peripheral blood cells (each from five normal individuals) was used as reference DNA. arrayCGH analysis was performed using the Human Genome CGH Microarray 44K and 244K oligonucleotide arrays (Agilent Technologies, Palo Alto, CA) as previously described and as recommended by the manufacturer.…”

Section: Arraycgh Analysismentioning

confidence: 99%

“…arrayCGH analysis was performed using the Human Genome CGH Microarray 44K and 244K oligonucleotide arrays (Agilent Technologies, Palo Alto, CA) as previously described and as recommended by the manufacturer. 26 The slides were subsequently scanned using the Agilent microarray confocal scanner G2565AA (Agilent Technologies). Images were analyzed using the Feature Extraction software (v7.5; Agilent Technologies) with intensity-dependent linear normalization to reduce inter-experimental variation.…”

Section: Arraycgh Analysismentioning

confidence: 99%

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Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

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Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1-MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion-positive whereas only 3 of 13 high-grade tumors were fusion-positive. Highresolution array-based comparative genomic hybridization revealed that fusion-positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P ¼ 0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusionnegative tumors lacked copy number alterations. The profiles of fusion-positive and fusion-negative tumors were very similar to those of low-and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; Po0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients.

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Section: Arraycgh Analysismentioning

confidence: 99%

Section: Arraycgh Analysismentioning

confidence: 99%

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

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“…Chromosomes were G-banded and analyzed using standard procedures. Spectral karyotype analysis was performed on all 6 cases as previously described (30). FISH analysis was performed on metaphase chromosomes (30) using a series of BAC clones derived from 6q22-24 (available on request) as well as a panel of YAC clones derived from 9p23-24 (6).…”

Section: Methodsmentioning

confidence: 99%

“…Primary cultures were established from fresh, unfixed tumor specimens of 6 ACCs (ACC1-2 and -4 -7) as previously described (3,30). Chromosome preparations were made from primary cultures or early-passage cells.…”

Section: Methodsmentioning

confidence: 99%

Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck

Persson

Andrén

Mark

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

695

639

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The transcription factor gene MYB was identified recently as an oncogene that is rearranged/duplicated in some human leukemias. Here we describe a new mechanism of activation of MYB in human cancer involving gene fusion. We show that the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB. The minimal common part of MYB deleted as the result of fusion was exon 15 including the 3 -UTR, which contains several highly conserved target sites for miR-15a/16 and miR-150 microRNAs. These microRNAs recently were shown to regulate MYB expression negatively. We suggest that deletion of these target sites may disrupt repression of MYB leading to overexpression of MYB-NFIB transcripts and protein and to activation of critical MYB targets, including genes associated with apoptosis, cell cycle control, cell growth/angiogenesis, and cell adhesion. Forced overexpression of miR-15a/16 and miR-150 in primary fusion-positive ACC cells did not significantly alter the expression of MYB as compared with leukemic cells with MYB activation/duplication. Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC. Our findings also suggest that the gain-offunction activity resulting from the MYB-NFIB fusion is a candidate therapeutic target.chromosome translocation ͉ fusion oncogene ͉ miRNA ͉ adenoid cystic carcinoma F usion genes are potent oncogenes resulting from chromosome rearrangements, in particular translocations. Most fusion genes identified thus far have been in hematological disorders and mesenchymal neoplasms, and only a few have been found in carcinomas (1). This paucity probably results from an inability to discover these rearrangements rather than from a true lack of such genes in carcinomas. The recent discovery that the majority of prostate cancers harbor ETS gene fusions (2) is in line with this reasoning. Finding as yet unidentified fusion oncogenes in other carcinomas could provide important insights into the molecular pathogenesis of these cancers and also might facilitate the development of new targeted therapies.We previously have identified a recurrent and tumor-specific t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma (ACC) of the head and neck (3). The translocation has been found as the sole cytogenetic anomaly in several cases, indicating that it is a primary rearrangement in this carcinoma.ACC has been known as a histologically distinctive neoplasm for nearly 150 years. It is among the most common carcinomas of the salivary glands (4) but also may arise in other exocrine glands, such as in the breast, and in the cervix, vulva, and tracheobronchial tree (5). ACC usually is an aggressive, although slowly growing, cancer with a long-term poor prognosis. Most patients (80-90%) with ACC ...

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“…8 A majority of the cases with abnormal karyotypes have rearrangements affecting chromosome band 8q12, resulting in activation of PLAG1 expression through exchange of promoter sequences. 9 In close to 10% of the cases, chromosome region 12q13-15 is affected instead, resulting in deregulated expression of the HMGA2 gene. 8 The remaining cases show other rearrangements of unknown molecular significance or normal karyotypes.…”

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confidence: 99%

Heterogeneous genetic profiles in soft tissue myoepitheliomas

et al. 2008

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Myoepithelioma, mixed tumor and parachordoma are uncommon soft tissue tumors thought to represent morphological variants of a single tumor type. The genetic basis of these neoplasms is poorly understood. However, they morphologically resemble mixed tumor of the salivary glands (also known as pleomorphic adenoma), a tumor characterized by deregulated expression of PLAG1 or HMGA2. To evaluate a possible genetic relationship between these soft tissue and salivary gland tumors, PLAG1 expression levels and the genomic status of PLAG1 and HMGA2 were investigated in five soft tissue myoepitheliomas and one pleomorphic adenoma. In addition, all tumors were cytogenetically investigated and whole genome DNA copy number imbalances were studied in five of them. The genetic profiles were heterogeneous and the only aberration common to all soft tissue myoepitheliomas was a minimally deleted region of 3.55 Mb in chromosome band 19p13. Recurrent deletion of CDKN2A suggests that inactivation of this tumor suppressor gene is pathogenetically important in a subset. Furthermore, PLAG1 rearrangement was found in a soft tissue tumor from a patient previously treated for a salivary pleomorphic adenoma, indicating either metastasis of the salivary gland lesion or that some soft tissue tumors develop through the same mechanisms as their salivary gland counterparts.

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High-resolution array CGH analysis of salivary gland tumors reveals fusion and amplification of the FGFR1 and PLAG1 genes in ring chromosomes

Cited by 61 publications

References 34 publications

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck

Heterogeneous genetic profiles in soft tissue myoepitheliomas

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