| 1. |
- Enlund, Fredrik, 1968, et al.
(författare)
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Molecular analyses of the candidate tumor suppressor gene, PLAGL1, in benign and malignant salivary gland tumors
- 2004
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Ingår i: EUROPEAN JOURNAL OF ORAL SCIENCES. - : Wiley. - 0909-8836 .- 1600-0722. ; 112:6, s. 545-547
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Tidskriftsartikel (refereegranskat)abstract
- Deletions affecting the long arm of chromosome 6 are a characteristic feature of all major subtypes of malignant salivary gland tumors. Moreover, a subgroup of adenoid cystic carcinomas have t(6;9)(q23-25;p21-24) translocations with breakpoints located within the commonly deleted region. Here we have examined the possible involvement of the candidate tumor suppressor gene, PLAGL1, in these deletions and translocations. Northern blot and fluorescence in situ hybridization (FISH) analyses of a series of 27 salivary gland tumors revealed no significant changes in the gene expression or rearrangements of PLAGL1. FISH analysis also demonstrated that the 6q translocation breakpoint in adenoid cystic carcinomas with t(6;9) is proximal to the PLAGL1 locus. Collectively, these results indicate that PLAGL1 is not likely to be the major target gene of the 6q rearrangements in salivary gland tumors.
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| 2. |
- Persson, Fredrik, 1973, et al.
(författare)
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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
- 2008
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 27:21, s. 3072-3080
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified a subgroup of pleomorphic salivary gland adenomas with ring chromosomes of uncertain derivation. Here, we have used spectral karyotyping (SKY), fluorescence in situ hybridization (FISH) and high-resolution oligonucleotide array-CGH to determine the origin and content of these rings and to identify genes disrupted as a result of ring formation. Of 16 tumors with rings, 11 were derived from chromosome 8, 3 from chromosome 5 and 1 each from chromosomes 1, 6 and 9. Array-CGH revealed that 10/11 r(8) consisted of amplification of a 19 Mb pericentromeric segment with recurrent breakpoints in FGFR1 in 8p12 and in PLAG1 in 8q12.1. Molecular analyses revealed that ring formation consistently generated novel FGFR1-PLAG1 gene fusions in which the 5'-part of FGFR1 is linked to the coding sequence of PLAG1. An alternative mechanism of PLAG1 activation was found in tumors with copy number gain of an intact PLAG1 gene. Rings derived from chromosomes 1, 5, 6 or 9 did not result in gene fusions, but rather resulted in losses indicative of the involvement of putative tumor suppressor genes on 8p, 5p, 5q and/or 6q. Our findings also reveal a novel mechanism by which FGFR1 contributes to oncogenesis and further illustrate the versatility of the FGFR1 and PLAG1 genes in tumorigenesis.
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| 3. |
- Persson, Marta, 1979, et al.
(författare)
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Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma.
- 2012
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 51:8, s. 805-17
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Tidskriftsartikel (refereegranskat)abstract
- Adenoid cystic carcinoma (ACC) of the head and neck is a malignant tumor with poor long-term prognosis. Besides the recently identified MYB-NFIB fusion oncogene generated by a t(6;9) translocation, little is known about other genetic alterations in ACC. Using high-resolution, array-based comparative genomic hybridization, and massively paired-end sequencing, we explored genomic alterations in 40 frozen ACCs. Eighty-six percent of the tumors expressed MYB-NFIB fusion transcripts and 97% overexpressed MYB mRNA, indicating that MYB activation is a hallmark of ACC. Thirty-five recurrent copy number alterations (CNAs) were detected, including losses involving 12q, 6q, 9p, 11q, 14q, 1p, and 5q and gains involving 1q, 9p, and 22q. Grade III tumors had on average a significantly higher number of CNAs/tumor compared to Grade I and II tumors (P = 0.007). Losses of 1p, 6q, and 15q were associated with high-grade tumors, whereas losses of 14q were exclusively seen in Grade I tumors. The t(6;9) rearrangements were associated with a complex pattern of breakpoints, deletions, insertions, inversions, and for 9p also gains. Analyses of fusion-negative ACCs using high-resolution arrays and massively paired-end sequencing revealed that MYB may also be deregulated by other mechanisms in addition to gene fusion. Our studies also identified several down-regulated candidate tumor suppressor genes (CTNNBIP1, CASP9, PRDM2, and SFN) in 1p36.33-p35.3 that may be of clinical significance in high-grade tumors. Further, studies of these and other potential target genes may lead to the identification of novel driver genes in ACC.
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| 4. |
- Persson, Marta, 1979, et al.
(författare)
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Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck
- 2009
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:44, s. 18740-4
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Tidskriftsartikel (refereegranskat)abstract
- 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-of-function activity resulting from the MYB-NFIB fusion is a candidate therapeutic target.
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| 5. |
- Winnes, Marta, 1979, et al.
(författare)
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Frequent fusion of the CRTC1 and MAML2 genes in clear cell variants of cutaneous hidradenomas
- 2007
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Ingår i: Genes Chromosomes Cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 46:6, s. 559-563
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Tidskriftsartikel (refereegranskat)abstract
- Fusion of the CREB regulated transcription coactivator CRTC1 (a.k.a. MECT1, TORC1, or WAMTP1) to the Notch coactivator MAML2 is a characteristic feature of low-grade mucoepidermoid carcinomas of salivary and bronchial glands. The CRTC1-MAML2 fusion protein acts by inducing transcription of cAMP/CREB target genes, and this activity is crucial for the transforming properties of the protein. Here we show that the CRTC1-MAML2 gene fusion is also frequent in benign hidradenomas of the skin. FISH and RT-PCR analyses revealed that hidradenomas are genetically heterogeneous, and that 10 of the 20 tumors analyzed (50%) contained the CRTC1-MAML2 gene fusion and expressed the resulting fusion transcript. Immunohistochemical analysis demonstrated expression of the fusion protein in the majority of tumor cells, including clear cells, poroid cells, and cells with epidermoid and ductal differentiation. In addition, we could show that all fusion-positive tumors were morphologically distinguished by the presence of more or less abundant areas of clear cells whereas all fusion-negative tumors lacked clear cells. Our findings thus demonstrate that the CRTC1-MAML2 gene fusion is frequent in hidradenomas and is associated with clear cell variants of this tumor. Taken together, the present and previous observations indicate that the CRTC1-MAML2 fusion is etiologically linked to benign and low-grade malignant tumors originating from diverse exocrine glands rather than being linked to a separate tumor entity.
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| 6. |
- Alyahya, G. A., et al.
(författare)
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Pleomorphic adenoma arising in an accessory lacrimal gland of Wolfring
- 2006
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Ingår i: Ophthalmology. - : Elsevier BV. - 0161-6420. ; 113:5, s. 879-82
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To describe a patient with pleomorphic adenoma arising in an accessory lacrimal gland of Wolfring in the lower lid and to illustrate the immunohistochemical and molecular cytogenetics. DESIGN: Single interventional case report. METHODS: A 62-year-old man presented with a 20-year history of a painless slowly growing mass at the temporal part of the right lower eyelid. Histological, immunohistochemical, and fluorescence in situ hybridization studies of the excised tumor were performed. RESULTS: Histological evaluation showed many glandular elements embedded in a myxoid stroma. The tumor was situated beneath an area of a normal accessory lacrimal gland of Wolfring and in close association with normal meibomian glands. Myoepithelial tumor cells in the myxoid stroma reacted strongly with an antibody against glial fibrillary acidic protein, which did not bind to normal lacrimal gland tissue. Tumor cells with both epithelial and myoepithelial morphologies reacted positively for both pleomorphic adenoma gene-1 and high-mobility group A2 proteins. Fluorescence in situ hybridization analysis showed no evidence of clonal translocations or numerical abnormalities involving chromosome 8 or 12. CONCLUSIONS: Pleomorphic adenoma of the accessory lacrimal gland is an exceedingly rare tumor of the ocular adnexa. Glial fibrillary acidic protein seems to be a tumor-associated antigen. Genetically, this case of pleomorphic adenoma arising from an accessory lacrimal gland of Wolfring is identical with those originating from salivary glands.
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| 7. |
- Asp, Julia, 1973, et al.
(författare)
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CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas.
- 2006
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 45:9, s. 820-8
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Tidskriftsartikel (refereegranskat)abstract
- Pleomorphic salivary gland adenomas are characterized by recurrent chromosome rearrangements of 8q12, leading to activation of the PLAG1 oncogene. Here we demonstrate that CHCHD7-PLAG1 is a novel and recurrent gene fusion generated by a cytogenetically cryptic rearrangement in pleomorphic adenomas. CHCHD7 is a newly identified member of a multifamily of proteins containing a conserved (coiled coil 1)-(helix 1)-(coiled coil 2)-(helix 2) domain. Northern blot analysis revealed that the gene is ubiquitously expressed. Its biological function is unknown and the gene has hitherto not been associated with neoplasia. CHCHD7 and PLAG1 are located head-to-head about 500 bp apart in 8q12. Molecular analyses of 27 tumors revealed CHCHD7-PLAG1 fusions in three tumors, two of which had t(6;8) and t(8;15) translocations as the sole anomalies and one a normal karyotype. FISH analyses of interphase nuclei and nuclear chromatin fibers of a fourth adenoma with a normal karyotype revealed that a second fusion partner gene, TCEA1, located about 2 Mb centromeric to PLAG1, also is fused to PLAG1 as a result of a cryptic 8q rearrangement. The breakpoints in both fusions occur in the 5'-noncoding regions of the genes, leading to activation of PLAG1 by promoter swapping/substitution. Western blot and immunohistochemical analyses demonstrated that the PLAG1 protein was overexpressed in epithelial, myoepithelial, and mesenchymal-like tumor cells in tumors with both fusions. Our findings further emphasize the significance of PLAG1 activation in pleomorphic adenomas and demonstrate that the gene is more frequently activated than previously anticipated.
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| 8. |
- Carlson, Julie, et al.
(författare)
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Salivary gland cancer: an update on present and emerging therapies
- 2013
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Ingår i: 2013 ASCO Educational Book. American Society of Clinical Oncology. ; , s. 257-63
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Bokkapitel (refereegranskat)abstract
- Malignant salivary gland tumors make up a small proportion of malignancies worldwide, yet vary widely in terms of histology, patterns of spread, and recurrence. A better understanding of this variability will guide appropriate treatment recommendations and lead to improved outcomes. Recent molecular genetic studies have uncovered a translocation-generated gene fusion network in salivary gland carcinomas that can be used for diagnosis, treatment decisions, and development of specific targeted therapies. The gene fusions encode novel fusion oncoproteins that function as transcriptional coactivators, tyrosine kinase receptors, and transcription factors involved in growth-factor signaling and cell-cycle regulation. While surgery currently is the primary therapy for operable tumors, radiation plays an important role in the postoperative setting, as well as in the definitive setting for inoperable lesions. An awareness of the risk factors for tumor recurrence and spread is important for both adjuvant therapy referrals and for radiation treatment planning purposes. Additionally, chemotherapy is being used increasingly in both the concurrent setting as a radiosensitizer, as well as in the palliative setting for metastatic tumors. Future trials investigating concurrent chemotherapy and radiation, as well as the use of targeted agents based on evolving molecular discoveries, will elucidate optimal personalized approaches for this challenging disease.
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| 9. |
- Johanson, Viktor, 1958, et al.
(författare)
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A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis
- 2007
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 14:2, s. 433-444
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.
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| 10. |
- Muth, Andreas, 1974, et al.
(författare)
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Prognostic factors for survival after surgery for adrenal metastasis.
- 2010
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Ingår i: European journal of surgical oncology (EJSO). - : Elsevier BV. - 1532-2157 .- 0748-7983. ; 36:7, s. 699-704
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To better define the indications for adrenalectomy for adrenal metastasis we have analysed factors predicting survival in our institutional series. METHODS: A consecutive series of 30 patients undergoing adrenalectomy for metastasis (1996-2007), excluding patients with simultaneous ipsilateral renal cell carcinoma (RCC), was studied. Metastases were regarded as synchronous (<6 mo), or metachronous (>6 mo), depending on the interval after primary surgery. Survival was calculated from time of adrenalectomy and factors influencing survival were identified. RESULTS: The tumour diagnoses were RCC n = 9, malignant melanoma n = 5, non-small-cell lung cancer n = 5, colorectal carcinoma n = 4, foregut carcinoid n = 2, adrenocortical carcinoma, breast cancer, hepatocellular carcinoma, urothelial carcinoma, and liposarcoma (one each); nine adrenal metastases were synchronous and 21 metachronous. Ten patients had undergone previous surgery for extra-adrenal metastases. Out of 30 adrenalectomies 10 were laparoscopic (LAdx) and 20 open (OAdx) procedures without surgical complications. The local recurrence rate was low: LAdx 1/10, OAdx 1/20, and the median survival was 23 months. Independent prognosticators of favourable survival were adrenalectomy for potential cure (p = 0.01), no previous metastasis surgery (p = 0.02), and tumour type (p = 0.043), with better prognosis for patients with adrenal metastasis from colorectal carcinoma and RCC and worse prognosis in non-small-cell lung cancer and malignant melanoma. CONCLUSIONS: Surgery for adrenal metastasis is safe and the indication for this procedure in an individual patient can be supported by several prognostic factors. The survival benefit in patients with adrenalectomy for potential cure indicates a therapeutic value of adrenalectomy in selected patients.
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