1. |
- Boecker, W., et al.
(author)
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Differentiation and histogenesis of syringomatous tumour of the nipple and low-grade adenosquamous carcinoma: evidence for a common origin
- 2014
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In: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 65:1, s. 9-23
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Journal article (peer-reviewed)abstract
- Aims: Syringomatous tumour of the nipple and low-grade adenosquamous carcinoma (LGAdSC) of the breast are regarded as distinct entities. To clarify the nature of these two lesions, we compared the expression of different lineage/differentiation markers in 12 syringomatous tumours of the nipple, nine LGAdSCs, and normal breast epithelium. Methods and results: Using triple immunofluorescence labelling and quantitative RT-PCR for keratins, p63, and smooth muscle actin, we demonstrated that syringomatous tumour and LGAdSC contain p63+/K5/14+ tumour cells, K10+ squamous cells, and K8/18+ glandular cells, with intermediary cells being found in both lineages. Identical p63+/K5/14+ cells were also found in the normal breast duct epithelium. Conclusions: Our data provide evidence that syringomatous tumour of the nipple and LGAdSC are identical or nearly identical lesions. They contain p63+/K5/14+ cells as the key cells from which the K10+ squamous lineage and the K8/18+ glandular lineage arise. On the basis of our findings in normal breast tissue and associated benign lesions, we suggest that p63+/K5/14+ cells of the normal breast duct epithelium or early related cells might play a key role in the neoplastic transformation of both syringomatous tumour and LGAdSC. We propose that the differentiation patterns found in both lesions reflect the early ontogenetic stages of the normal breast epithelium.
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2. |
- Boecker, W., et al.
(author)
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K5/K14-positive cells contribute to salivary gland-like breast tumors with myoepithelial differentiation
- 2013
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In: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 26:8, s. 1086-1100
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Journal article (peer-reviewed)abstract
- Salivary gland-like tumors of the breast show a great variety of architectural patterns and cellular differentiations such as glandular, myoepithelial, squamous, and even mesenchymal phenotypes. However, currently little is known about the evolution and cellular differentiation of these tumors. For that reason, we performed an in situ triple immunofluorescence lineage/differentiation tracing (isTILT) and qRT-PCR study of basal (K5/K14), glandular (K7/K8/18), and epidermal-specific squamous (K10) keratins, p63, and smooth muscle actin (SMA; myoepithelial marker) with the aim to construct and trace different cell lineages and define their cellular hierarchy in tumors with myoepithelial differentiation. isTILT analysis of a series of 28 breast, salivary, and lacrimal gland tumors, including pleomorphic adenomas (n = 8), epithelial-myoepithelial tumors (n = 9), and adenoid cystic carcinomas (n = 11) revealed that all tumor types contained K5/K14-positive progenitor cells in varying frequencies from a few percent up to 15%. These K5/K14-positive tumor cells were found to differentiate to glandular-(K8/18-positive) and myoepithelial-lineage (SMA-positive)-specific cells and were also shown to generate various heterologeous cell differentiations such as squamous and mesenchymal progenies. p63 was co-expressed with K5/K14 in basal-like progenitor cells, myoepithelial, and squamous cells but not in glandular cells. Our results show that the corresponding counterpart tumors of breast and salivary/lacrimal glands have identical cellular compositions. Taken together, our isTILT and RNA-expression data indicate that look-alike tumors of the breast represent a special subgroup of basal-type tumors with benign or usually low malignant potential.
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3. |
- Brill, L. B., 2nd, et al.
(author)
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Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms
- 2011
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In: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 24:9, s. 1169-76
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Journal article (peer-reviewed)abstract
- Recent studies have shown that the recurrent t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma results in a novel fusion of the MYB proto-oncogene with the transcription factor gene NFIB. To determine the frequency of this finding, we used RT-PCR assays of the MYB and MYB-NFIB fusion transcripts, and immunohistochemistry for the MYB protein, to study adenoid cystic carcinomas and other epithelial tumors of the salivary glands, and head and neck region. MYB-NFIB fusion transcript was detected in 25 of 29 (86%) frozen adenoid cystic carcinoma tumor samples, and in 14 of 32 (44%) formalin-fixed paraffin-embedded adenoid cystic carcinoma tumor specimens. In contrast, the MYB-NFIB fusion was not expressed in non-adenoid cystic carcinoma neoplasms of the head and neck, confirming the high specificity of the MYB-NFIB fusion. Adenoid cystic carcinomas from various anatomic sites, including salivary gland, sinonasal cavity, tracheobronchial tree, larynx, breast, and vulva were repeatedly fusion-positive, indicating that adenoid cystic carcinomas located in different anatomic sites not only have important morphologic features in common, but also probably evolve through activation of the same molecular pathways. Studies of the expression of MYB revealed that 89% of the tumors, including both fusion-positive and fusion-negative cases, overexpressed MYB RNA. Similarly, 82% of adenoid cystic carcinomas stained positive for MYB protein, compared with 14% of non-adenoid cystic carcinoma neoplasms, indicating that MYB immunostaining may be useful for the diagnosis of adenoid cystic carcinoma, but that neoplasms sometimes in the differential diagnosis are also labeled. The latter are, however, fusion-negative. In summary, our studies show that MYB activation through gene fusion or other mechanisms is a major oncogenic event in adenoid cystic carcinoma occurring at various anatomic sites. In addition to being a diagnostically useful biomarker for adenoid cystic carcinoma, MYB and its downstream effectors are also novel potential therapeutic targets.
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4. |
- Carlson, Julie, et al.
(author)
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Salivary gland cancer: an update on present and emerging therapies
- 2013
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In: 2013 ASCO Educational Book. American Society of Clinical Oncology. ; , s. 257-63
-
Book chapter (peer-reviewed)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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5. |
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6. |
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7. |
- Fehr, Andre, et al.
(author)
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The MYB-NFIB gene fusion-a novel genetic link between adenoid cystic carcinoma and dermal cylindroma
- 2011
-
In: The Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 224:3, s. 322-7
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Journal article (peer-reviewed)abstract
- We have recently shown that the recurrent t(6;9)(q22 approximately 23;p23 approximately 24) translocation in adenoid cystic carcinoma (ACC) of the breast and head and neck results in a fusion of the two transcription factor genes MYB and NFIB. Here we demonstrate, for the first time, that benign sporadic, dermal cylindromas also express the MYB-NFIB gene fusion. RT-PCR and immunohistochemical analyses revealed that eight of 12 analysed tumours (67%) expressed MYB-NFIB fusion transcripts and/or stained positive for MYB protein. Nucleotide sequence analyses confirmed that the composition of the chimeric transcript variants identified was identical to that in ACC, suggesting a similar molecular mechanism of activation of MYB in cylindroma as in ACC. In contrast, no evidence for the presence of the MYB-NFIB fusion was found in other types of basaloid skin and salivary gland tumours, indicating that the fusion indeed has a restricted expression pattern. Our findings broaden the spectrum of neoplasms associated with MYB oncogene activation and reveal a novel genetic link between ACC and dermal cylindroma. These results, together with our previous observations, further strengthen the evidence for common molecular pathways of importance for the development of both benign and malignant breast, salivary and adnexal tumours.
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8. |
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9. |
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10. |
- Jee, Kowan Ja, et al.
(author)
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Genomic profiles and CRTC1-MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma.
- 2013
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In: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 26:2, s. 213-222
-
Journal article (peer-reviewed)abstract
- 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. High-resolution 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=0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusion-negative 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; P<0.0001). 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.Modern Pathology advance online publication, 28 September 2012; doi:10.1038/modpathol.2012.154.
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11. |
- Markowski, Dominique Nadine, et al.
(author)
-
MED12 mutations occurring in benign and malignant mammalian smooth muscle tumors.
- 2013
-
In: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 52:3, s. 297-304
-
Journal article (peer-reviewed)abstract
- Mutations of the mediator subcomplex 12 gene (MED12) recently have been described in a large group of uterine leiomyomas (UL) but only in a single malignant uterine smooth muscle tumor. To further address the occurrence of fibroid-type MED12 mutations in smooth muscle tumors, we have analyzed samples from 34 leiomyosarcomas (LMS), 21 UL, two extrauterine leiomyomas (EL), and 10 canine genital leiomyomas for the presence of MED12 mutations of the UL-type. Interestingly, besides UL MED12 mutations were found in one uterine LMS, one EL, and two canine vaginal leiomyomas. The results confirm the occurrence of fibroid-type MED12 mutations in malignant uterine smooth muscle tumors thus suggesting a rare but existing leiomyoma-LMS sequence. In addition, for the first time MED12 mutations are reported in smooth muscle tumors in a non-primate mammalian species. © 2012 Wiley Periodicals, Inc.
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12. |
- Persson, Fredrik, 1973, et al.
(author)
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Studies of genomic imbalances and the MYB-NFIB gene fusion in polymorphous low-grade adenocarcinoma of the head and neck.
- 2012
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In: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 40:1, s. 80-4
-
Journal article (peer-reviewed)abstract
- Polymorphous low-grade adenocarcinoma (PLGA) is a malignancy predominantly originating from the minor salivary glands. The molecular events underlying the pathogenesis of PLGA is poorly understood and no recurrent genetic aberrations have so far been identified. We used genome-wide, high-resolution aCGH analysis to explore genomic imbalances in 9 cases of PLGA. Because of the well-known morphologic similarities between PLGA and adenoid cystic carcinoma (ACC) we also analyzed all tumors for expression of the recently identified ACC-associated MYB-NFIB gene fusion. aCGH analysis revealed that the PLGA genome contains comparatively few copy number alterations (CNAs). Gains/losses of whole chromosomes or chromosome arms were more than twice as common as partial CNAs. Two cases showed gain of chromosome 8 and one case each gain of chromosome 9, loss of chromosome 22 and loss of the Y chromosome. One case showed loss of the entire 6q arm and one case an interstitial deletion of a 33-Mb segment within 6q22.1-q24.3. This region contains the MYB oncogene and the candidate tumor suppressor gene PLAGL1. RT-PCR analysis revealed that one of the 9 PLGAs expressed the ACC-associated MYB-NFIB gene fusion, illustrating the diagnostic difficulties associated with the diagnosis of these morphologically partly overlapping entities. Taken together, our findings indicate that the PLGA genome is genetically stable and contains comparatively few CNAs which is in line with the clinical observation that PLGA is a slow-growing, low-grade carcinoma with low metastatic potential.
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13. |
- Persson, Marta, 1979, et al.
(author)
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Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma.
- 2012
-
In: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 51:8, s. 805-17
-
Journal article (peer-reviewed)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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14. |
- Rasmussen, J. O., et al.
(author)
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Genetic analysis of an orbital metastasis from a primary hepatic neuroendocrine carcinoma
- 2014
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In: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 32:4, s. 1447-1450
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Journal article (peer-reviewed)abstract
- A 71-year-old female with a known history of primary hepatic neuroendocrine carcinoma, presented with a visual defect, proptosis and restricted eye movements of the right eye. Biopsies from the orbit and from the primary hepatic neuroendocrine carcinoma showed similar morphological and immunohistochemical features, and high-resolution, array-based comparative genomic hybridization demonstrated loss of one copy each of chromosomes 3 and 18, and gain of 1q both in the primary hepatic neuroendocrine carcinoma and in the orbital tumour. The orbital mass was diagnosed as a metastasis from the primary hepatic neuroendocrine carcinoma. Primary hepatic neuroendocrine tumours are extremely rare, and the orbit is an extremely rare location for a neuroendocrine carcinoma metastasis. This is the first reported case of an orbital metastasis with origin from a primary hepatic neuroendocrine carcinoma.
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15. |
- Stenman, Göran, 1953, et al.
(author)
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Diagnostic and therapeutic implications of new molecular biomarkers in salivary gland cancers.
- 2014
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In: Oral oncology. - : Elsevier BV. - 1368-8375. ; 50:8, s. 683-690
-
Journal article (peer-reviewed)abstract
- Salivary gland carcinomas (SGCs) are uncommon tumors, constituting approximately 5% of all cancers of the head and neck. They are a heterogeneous group of diseases that pose significant diagnostic and therapeutic challenges. The treatment of patients with SGCs is mainly restricted to surgery and/or radiation therapy and there is only limited data available on the role of conventional systemic and targeted therapies in the management of patients with advanced disease. There is thus a great need to develop new molecular biomarkers to improve the diagnosis, prognostication, and therapeutic options for these patients. In this review, we will discuss the most recent developments in this field, with focus on pathognomonic gene fusions and other driver mutations of clinical significance. Comprehensive cytogenetic and molecular genetic analyses of SGCs have revealed a translocation-generated network of fusion oncogenes. The molecular targets of these fusions are transcription factors, transcriptional coactivators, and tyrosine kinase receptors. Prominent examples of clinically significant fusions are the MYB-NFIB fusion in adenoid cystic carcinoma and the CRTC1-MAML2 fusion in mucoepidermoid carcinoma. The fusions are key events in the molecular pathogenesis of these tumor types and contribute as new diagnostic, prognostic, and therapeutic biomarkers. Moreover, next-generation sequencing analysis of SGCs have revealed new druggable driver mutations, pinpointing alternative therapeutic options for subsets of patients. Continued molecular characterization of these fusions and their down-stream targets will ultimately lead to the identification of novel driver genes in SGCs and will form the basis for development of new therapeutic strategies for these patients.
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16. |
- Stenman, Göran, 1953
(author)
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Fusion oncogenes in salivary gland tumors: molecular and clinical consequences.
- 2013
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In: Head and Neck. - : Springer Science and Business Media LLC. - 1043-3074 .- 1936-055X .- 1936-0568. ; 7:suppl 1
-
Journal article (peer-reviewed)abstract
- Salivary gland tumors constitute a heterogeneous group of uncommon diseases that pose significant diagnostic and therapeutic challenges. However, the recent discovery of a translocation-generated gene fusion network in salivary gland carcinomas as well in benign salivary gland tumors opens up new avenues for improved diagnosis, prognostication, and development of specific targeted therapies. The gene fusions encode novel fusion oncoproteins or ectopically expressed normal or truncated oncoproteins. The major targets of the translocations are transcriptional coactivators, tyrosine kinase receptors, and transcription factors involved in growth factor signaling and cell cycle regulation. Notably, several of these targets or pathways activated by these targets are druggable. Examples of clinically significant gene fusions in salivary gland cancers are the MYB-NFIB fusion specific for adenoid cystic carcinoma, the CRTC1-MAML2 fusion typical of low/intermediate-grade mucoepidermoid carcinoma, and the recently identified ETV6-NTRK3 fusion in mammary analogue secretory carcinoma. Similarly, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas. Continued studies of the molecular consequences of these fusion oncoproteins and their down-stream targets will ultimately lead to the identification of novel driver genes in salivary gland neoplasms and will also form the basis for the development of new therapeutic strategies for salivary gland cancers and, perhaps, other neoplasms.
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17. |
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18. |
- Stenman, Göran, 1953, et al.
(author)
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Skin: Cylindrom
- 2012
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In: Atlas of Genetics and Cytogenetics in Oncology and Haematology.
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Book chapter (peer-reviewed)
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19. |
- von Holstein, Sarah Linéa, et al.
(author)
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Adenoid Cystic Carcinoma of the Lacrimal Gland: MYB Gene Activation, Genomic Imbalances, and Clinical Characteristics
- 2013
-
In: Ophthalmology. - : Elsevier BV. - 0161-6420. ; 120:10, s. 2130-2138
-
Journal article (peer-reviewed)abstract
- Purpose: To investigate genetic alterations in lacrimal gland adenoid cystic carcinomas (ACCs) with emphasis on the MYB-NFIB fusion oncogene and its downstream targets, MYB rearrangements, and copy number alterations in relation to clinical data and survival. Participants and Controls: Fourteen patients with primary lacrimal gland ACC were included. As a control, we also studied the expression of MYB-NFIB in 19 non-ACC lacrimal gland tumors. Methods: The expression and identity of MYB-NFIB fusion transcripts were studied using reverse transcriptase polymerase chain reaction (RT-PCR) and nucleotide sequence analyses. Quantitative polymerase chain reaction (PCR) and immunohistochemistry were used to evaluate the expression of MYB/MYB-NFIB target genes. High-resolution array-based comparative genomic hybridization (arrayCGH) and fluorescence in situ hybridization were used to study copy number alterations and MYB rearrangements. Main Outcome Measures: mRNA or protein expression of MYB-NFIB, MYB, and its down stream targets; copy number alterations; and genomic rearrangements. Results: The median age of the patients was 43 years (equal gender distribution), and the median time of survival was 8.6 years. The MYB-NFIB fusion was expressed in 7 of 14 ACCs. In contrast, all non-ACC tumors were fusion-negative. All 13 ACCs tested stained positive for the MYB protein, and for the MYB targets KIT and BCL2, 12 were positive for MYC and CCNE1, and 9 were positive for CCNB1. Rearrangements of MYB were detected in 8 of 13 cases, including 2 cases with gain of an apparently intact MYB gene. The arrayCGH analysis revealed recurrent copy number alterations with losses involving 6q23-q27, 12q12-q14.1, and 17p13.3-p12, and gains involving 19q12, 19q13.31-qter, 8q24.13-q24.21, 11q12.3-q14.1, and 6q23.3. Neither MYB-NFIB fusion nor any copy number alteration correlated with survival. Conclusions: Lacrimal gland ACCs are frequently positive for the MYB-NFIB fusion, overexpress MYB and its downstream targets, and have genomic profiles characterized by losses involving 6q, 12q, and 17p, and gains involving 19q, 8q, and 11q. Our findings show that lacrimal gland ACCs are genetically and clinically similar to their salivary gland counterparts and that MYB-NFIB is a clinically useful diagnostic biomarker for ACC. Our data also suggest that MYB and its downstream targets are potential therapeutic targets for these tumors. (C) 2013 by the American Academy of Ophthalmology.
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20. |
- von Holstein, Sarah Linéa, et al.
(author)
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CRTC1-MAML2 gene fusion in mucoepidermoid carcinoma of the lacrimal gland.
- 2012
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In: Oncology reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 27:5, s. 1413-6
-
Journal article (peer-reviewed)abstract
- Epithelial tumors of the lacrimal gland are histologically similar to salivary gland tumors. Here we report on a rare case of mucoepidermoid carcinoma (MEC) in a 73‑year-old man with a swelling of the left lacrimal gland. The tumor had a microscopic appearance consistent with a classical low-grade MEC of the lacrimal gland. There were no signs of recurrence or metastases during a five-year follow-up. Using RT-PCR and FISH we demonstrated that the tumor was positive for the CRTC1-MAML2 gene fusion previously shown to be associated with in particular low-grade salivary MECs with favorable prognosis. By immunohistochemistry we showed that the majority of tumor cells, including epidermoid, intermediate and mucous producing cells, expressed the CRTC1-MAML2 fusion protein. In contrast, 15 non-MEC lacrimal neoplasm were fusion-negative. Our findings show that lacrimal MEC is not only clinically and morphologically but also genetically identical to MECs originating from other exocrine glands, including those of the lung, thyroid, cervix and salivary glands. Taken together, the present and previous studies further emphasize the fundamental biologic and genetic similarities among MECs developing from different anatomical sites and organs. Moreover, our findings indicate that the CRTC1-MAML2 fusion may be a useful diagnostic and prognostic biomarker for lacrimal MEC.
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21. |
- von Holstein, Sarah Linéa, et al.
(author)
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Lacrimal gland lesions in Denmark between 1974 and 2007.
- 2013
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In: Acta ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 91:4, s. 349-354
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Journal article (peer-reviewed)abstract
- Purpose: To evaluate the incidence rate, distribution, patient characteristics and indications for surgical intervention of lacrimal gland lesions in Denmark between 1974 and 2007. Material and methods: All biopsied/surgically removed lacrimal gland lesions in Denmark during the period 1974-2007 were identified by searching two population-based registries. Specimens were collected and re-evaluated. The following data were collected: age, gender, indications for surgical intervention and local recurrence. Results: A total of 232 lesions from 210 patients with a histologically verified lesion of the lacrimal gland were included. The incidence rate of lacrimal gland lesions was 1.3/1000000/year. The overall annual age- and gender-adjusted incidence rate more than doubled during the study period, owing to an increase in non-malignant lesions. Approximately half of the lesions were neoplasms (119) and 55% (66) of these were malignant. Dacryops constituted 10% (24), inflammatory lesions 27% (62), normal tissue 12% (27), benign tumours 23% (53) and malignant tumours 29% (66). Patients with malignant neoplasms were significantly older than patients with benign neoplasms (63 versus 48years, p<0.001). The indication for surgical intervention was suspicion of a tumour in more than 90% of the neoplastic lesions and in 30% of the non-neoplastic lesions. Conclusion: Lacrimal gland lesions that require surgical evaluation are rare in the Danish population and represent a wide spectrum of diagnoses, mostly benign. The overall incidence rate of biopsied lacrimal gland lesions is increasing.
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22. |
- von Holstein, Sarah Linéa, et al.
(author)
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Lacrimal Gland Pleomorphic Adenoma and Carcinoma ex Pleomorphic Adenoma Genomic Profiles, Gene Fusions, and Clinical Characteristics
- 2014
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In: Ophthalmology. - : Elsevier BV. - 0161-6420. ; 121:5, s. 1125-1133
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Journal article (peer-reviewed)abstract
- Purpose: To study genetic alterations in lacrimal gland pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (Ca-ex-PA) with focus on copy number changes and expression patterns of the translocation target genes PLAG1, HMGA2, and CRTC1-MAML2 in relation to clinical data. Participants: A total of 36 tumors from 32 patients with lacrimal gland PA or Ca-ex-PA were included in the study. Methods: Genome wide, high-resolution array-based comparative genomic hybridization (arrayCGH) and immunohistochemistry were used to study the genomic profiles and expression patterns of the translocation targets PLAG1, HMGA2, and CRTC1-MAML2. Main Outcome Measures: Copy number alterations (gains/losses) and protein expression of PLAG1, HMGA2, and CRTC1-MAML2. Results: Genome-wide arrayCGH analysis revealed normal genomic profiles in 10 of 17 PA samples. The average number of genomic imbalances per tumor was 3.25 (range, 1-7) in primary and recurrent PAs with alterations compared with 7.7 (range, 4-12) in Ca-ex-PAs. Five recurrent copy number alterations were identified in PAs, including losses of 1pter-p31.3, 6q22.1-q24.3, 8q24.22-q24.3, and 13q21.31-q21.33, and gain of 9p23-p22.3. Gain of 9p23-p22.3 also was seen in a Ca-ex-PA. In Ca-ex-PA, gain of 22q12.3-qter was the only recurrent alteration. Detailed analysis of the array data identified NFIB and PDGFB as the 2 major candidate target oncogenes that may be activated as a result of copy number gains involving 9p and 22q. Both genes have been implicated in the pathogenesis of PA and other types of salivary gland tumors. Immunohistochemical analysis revealed frequent overexpression of the translocation target gene PLAG1 in PAs and in 1 Ca-ex-PA. In contrast, overexpression of HMGA2 was observed in only a small subset of PAs. The CRTC1-MAML2 fusion oncoprotein was overexpressed in 2 mucoepidermoid Ca-ex-PAs. Conclusions: Lacrimal and salivary gland PAs and Ca-ex-PAs have similar genomic profiles and frequently overexpress the PLAG1 oncoprotein. Copy number gains involving 9p23-p22.3 (NFIB) and 22q12-qter (PDGFB) may be of importance for disease progression in a subset of lacrimal gland PAs. (C) 2014 by the American Academy of Ophthalmology.
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23. |
- Wetterskog, Daniel, 1978, et al.
(author)
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Mutation profiling of adenoid cystic carcinomas from multiple anatomical sites identifies mutations in the RAS pathway, but no KIT mutations
- 2013
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In: Histopathology. - : Wiley. - 0309-0167. ; 62:4, s. 543-550
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Journal article (peer-reviewed)abstract
- Aims The majority of adenoid cystic carcinomas (AdCCs), regardless of anatomical site, harbour the MYB–NFIB fusion gene. The aim of this study was to characterize the repertoire of somatic genetic events affecting known cancer genes in AdCCs. Methods and results DNA was extracted from 13 microdissected breast AdCCs, and subjected to a mutation survey using the Sequenom OncoCarta Panel v1.0. Genes found to be mutated in any of the breast AdCCs and genes related to the same canonical molecular pathways, as well as KIT, a proto-oncogene whose protein product is expressed in AdCCs, were sequenced in an additional 68 AdCCs from various anatomical sites by Sanger sequencing. Using the Sequenom MassARRAY platform and Sanger sequencing, mutations in BRAF and HRAS were identified in three and one cases, respectively (breast, and head and neck). KIT, which has previously been reported to be mutated in AdCCs, was also investigated, but no mutations were identified. Conclusions Our results demonstrate that mutations in genes pertaining to the canonical RAS pathway are found in a minority of AdCCs, and that activating KIT mutations are either absent or remarkably rare in these cancers, and unlikely to constitute a driver and therapeutic target for patients with AdCC.
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