High‐resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of <i>HMGA2</i>

Persson, Fredrik; Andrén, Ywonne; Winnes, Marta; Wedell, Barbro; Nordkvist, Anders; Gudnadottir, Gunnhildur; Dahlenfors, Rigmor; Sjögren, Helene; Mark, Joachim; Stenman, Göran

doi:10.1002/gcc.20619

Cited by 126 publications

(139 citation statements)

References 41 publications

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“…4 Mb segment in 8q12.1, containing the PLAG1 gene, is of importance for malignant transformation of benign salivary pleomorphic adenomas. 43,44 In summary, we have shown that low-grade mucoepidermoid carcinomas have normal or nearnormal genomic profiles, express the CRTC1-MAML2 fusion, and have a favorable clinical outcome. In contrast, the majority of high-grade tumors had multiple genomic imbalances, were negative for the CRTC1-MAML2 fusion, and developed frequent metastasis and/or recurrences.…”

Section: Discussionmentioning

confidence: 91%

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: Discussionmentioning

confidence: 91%

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

et al. 2013

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“…There are a handful of salivary gland tumors that have been demonstrated to have recurring cytogenetic abnormalities including adenoid cystic carcinomas [t(6;9) (MYB-NFIB)] [8][9][10], mucoepidermoid carcinomas [t(11:19) (MECT1-MAML2)] [11,12], pleomorphic adenomas (PLAG1 and HMGA2 rearrangements) [13][14][15][16][17], and hyalinizing clear cell carcinoma [t(12;22) (EWSR1-ATF)] [18,19]. In the majority of these tumors, the morphology is distinctive enough to allow for a diagnosis and molecular confirmation is typically not necessary.…”

Section: Introductionmentioning

confidence: 99%

Morphology in Conjunction with Immunohistochemistry is Sufficient for the Diagnosis of Mammary Analogue Secretory Carcinoma

Shah

Wenig

LeGallo

et al. 2014

Head and Neck Pathol

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The recently described mammary analogue secretory carcinoma (MASC) is a low-grade salivary gland malignancy that harbors the recurrent cytogenetic abnormality t(12;15) (p13;q25) ETV6-NTRK3. Confirmation of this is currently considered the gold standard for diagnosis. Some have postulated that morphology together with supporting immunohistochemistry is sufficient to diagnose MASC. In this study we retrospectively review a series of 19 MASCs diagnosed based on histology in conjunction with immunohistochemistry; subsequently we performed in situ hybridization using an ETV6 break-apart probe. Immunohistochemistry for S100 protein and mammaglobin as well as fluorescence in situ hybridization using the Vysis ETV6 Dual Color Break-Apart FISH Probe Kit were performed on all cases. The 19 cases were from 12 females and 7 males with ages ranging from 16 to 76 years (mean = 45 years). Sixteen cases were from the parotid gland, 1 case was from a periparotid lymph node and 2 cases were from the submandibular gland. All 19 cases demonstrated moderate to strong expression of S100 protein. Eighteen cases demonstrated strong, diffuse expression of mammaglobin, while one case had only rare tumor cells that strongly expressed mammaglobin. Eighteen of 19 cases (95 %) demonstrated the ETV6 rearrangement by fluorescence in situ hybridization. Given that morphology together with immunohistochemistry is highly correlated with the ETV6 gene rearrangement, we conclude that molecular confirmation is not required to diagnose MASC.Keywords Mammary analogue secretory carcinoma Á Salivary gland Á ETV6 Á Fluorescence in situ hybridization Á Immunohistochemistry Á Mammaglobin

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“…HMGA2 is ascribed an important role in the control of stem-cell development and proliferation, and also high levels of HMGA2 is found in many benign, as well as malignant, tumours [33,34]. HMG proteins are the most abundant non-histone DNAbinding chromatin factors in the eukaryotic nucleus involved in up-and downregulation of several genes [33].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, epithelial-mesenchymal transition (EMT) has been suggested as a novel pathway playing a key role in the pathogenesis of tubulointerstitial fibrosis in DN and blockage of EMT has been shown to delay progression to DN [33,34]. Of note, transcriptomic analyses of TGF-β-stimulated EMT in NAMRU mouse mammary gland (NMuMG) cells identified HMGA2 as a main target involved in the control of epithelial differentiation [36].…”

Section: Discussionmentioning

confidence: 99%

“…Of note, transcriptomic analyses of TGF-β-stimulated EMT in NAMRU mouse mammary gland (NMuMG) cells identified HMGA2 as a main target involved in the control of epithelial differentiation [36]. TGF-β is a pro-sclerotic cytokine strongly associated with the development of fibrosis in DN [34]. The induction of cytokines, chemokines and growth factors, particularly TGFβ1 and connective tissue growth factor (CTGF), leads to glomerular basement membrane thickening, podocyte injury and mesangial matrix expansion.…”

Section: Discussionmentioning

confidence: 99%

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Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes

et al. 2012

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Aims/hypothesis Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. Methods We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro-or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Results In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p00.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n01,233 cases, n02,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p00.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n02,499, β±SEM, −3.7±1.2 ml/min, p00.002) and also in non-diabetic individuals (n017,602, β±SEM, −0.008± 0.003 ml/min (log e ), p00.006). Conclusions/interpretation These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and nondiabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.

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High‐resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2

Cited by 126 publications

References 41 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

Morphology in Conjunction with Immunohistochemistry is Sufficient for the Diagnosis of Mammary Analogue Secretory Carcinoma

Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes

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