Abstract
Introduction:
A key step of cancer development is the progressive accumulation of genomic changes resulting in disruption of several biological mechanisms. Carcinoma ex-pleomorphic adenoma (CXPA) is an aggressive neoplasm that arises from a pleomorphic adenoma. CXPA derived from a recurrent PA (RPA) has been rarely reported, and the genomic changes associated with these tumors have not yet been studied.
Objective:
We analyzed CXPA from RPAs and RPAs without malignant transformation using array-comparative genomic hybridization (array-CGH) to identify somatic copy number alterations and affected genes.
Methods:
DNA samples extracted from FFPE tumors were submitted to array-CGH investigation, and data was analyzed by Nexus Copy Number Discovery Edition v.7.
Results:
No somatic copy number alterations were found in RPAs without malignant transformation. As for CXPA from RPA, although genomic profiles were unique for each case, we detected some chromosomal regions that appear to be preferentially affected by copy number alterations. The first case of CXPA-RPA (frankly invasive myoepithelial carcinoma) showed copy number alterations affecting 1p36.33p13, 5p and chromosomes 3 and 8. The second case of CXPA-RPA (frankly invasive epithelial-myoepithelial carcinoma) showed several alterations at chromosomes 3, 8, and 16, with two amplifications at 8p12p11.21 and 12q14.3q21.2. The third case of CXPA-RPA (minimally invasive epithelial-myoepithelial carcinoma) exhibited amplifications at 12q13.3q14.1, 12q14.3, and 12q15.
Conclusion:
The occurrence of gains at chromosomes 3 and 8 and genomic amplifications at 8p and 12q, mainly those encompassing the HMGA2, MDM2, WIF1, WHSC1L1, LIRG3, CDK4 in CXAP from RPA can be a significant promotional factor in malignant transformation.
KEYWORDS
Carcinoma ex-pleomorphic adenoma; Recurrent pleomorphic adenoma; Somatic copy number alterations; aCGH
Resumo
Introdução:
Uma etapa fundamental do desenvolvimento do câncer é o acúmulo progressivo de alterações genômicas, resultando na ruptura de vários mecanismos biológicos. Carcinoma ex-adenoma pleomórfico (CXAP) é uma neoplasia agressiva que surge a partir de um adenoma pleomórfico. O CXAP derivado de um AP recorrente (APR) foi raramente relatado e, até o momento, as alterações genômicas associadas a esses tumores não foram estudados.
Objetivo:
Avaliar as diferenças entre os CXAPs decorrentes de APRs e os APRs sem transformações malignas usando hibridização genômica comparativa em microarrays (array Comparative Genomic Hibridization - aCGH) a fim de identificar alterações no número de cópias somáticas e os genes afetados.
Método:
Amostras de DNA extraídas de tumores provenientes de tecido emblocado em parafina foram submetidos à investigação com a técnica aCGH, e os dados foram analisados com o Nexus Copy Number Discovery Edition v.7.
Resultados:
Não observamos alterações no numero de cópias somáticas nos APRs sem transformação maligna. Quanto ao CXAP de APR, embora os perfis genômicos sejam exclusivos para cada caso, detectamos algumas regiões cromossômicas que pareciam ser preferencialmente afetadas por alterações no número de cópias. O primeiro caso de CXAP-APR (carcinoma mioepitelial francamente invasivo) apresentou alterações no numero de cópias afetando 1p36.33p13, 5p e cromossomos 3 e 8. O segundo caso de CXAP-APR (carcinoma epitelialmioepitelial francamente invasivo) apresentou várias alterações nos cromossomos 3, 8 e 16, com duas amplificações em 8p12p11.21 e 12q14.3q21.2. O terceiro caso de CXAP-APR (carcinoma epitelial-mioepitelial minimamente invasivo) apresentou amplificações em 12q13.3q14.1, 12q14.3, e 12q15.
Conclusão:
A ocorrência de ganhos de cromossomos 3 e 8, e as amplificações genômicas em 8p e 12q, principalmente aquelas que englobam os HMGA2, MDM2, WIF1, WHSC1L1, RG3, CDK4 no CXAP decorrente de APR podem ser fatores promocionais significativos para a transformação maligna.
PALAVRAS-CHAVE
Carcinoma ex-adenoma pleomórfico; Adenoma pleomórfico recorrente; Alterações no número de cópias somáticas; aCGH
Introduction
Pleomorphic adenoma (PA) is the most common tumor of the salivary glands, accounting for about 60-70% of such neoplasms. It is a benign tumor with high risk of recurrence and malignant transformation.11 Eveson JW, Reichart P, Sidransky D. Pleomorphic adenoma. World health Organization Classification of Tumors. Pathology & Genetics: head and neck tumours. Lyon: IARC Press; 2005. p. 254-8. The recurrence risk ranges from 0.4% to 45%, depending on the surgical technique22 Zbären P, Tschumi I, Nuyens M, Stauffer E. Recurrent pleomorphic adenoma of the parotid gland. Am J Surg. 2005;189:203-7.: 20-45% after enucleation, 2-5% following parotid lobectomy, and up to 0.4% after radical parotidectomy.33 Laccourreye H, Laccourreye O, Cauchois R, Jouffre V, Menard M, Brasnu D. Total conservative parotidectomy for primary benign pleomorphic adenoma of the parotid gland: a 25-year experience with 229 patients. Laryngoscope. 1994;104:1487-94. Recurrent Pleomorphic adenoma (RPA) presumably derives either from capsule rupture, incomplete resection of microscopic extensions beyond the pseudocapsule, or multifocal origin.44 Leonetti JP, Marzo SJ, Petruzzelli GJ, Herr B. Recurrent pleomorphic adenoma of the parotid gland. Otolaryngol Head Neck Surg. 2005;133:319-22.
Permanent facial nerve injury risk, multinodular feature, and increased frequency of new recurrence are factors that make the treatment of RPA difficult.55 Laskawi R, Schott T, Schroder M. Recurrent pleomorphic adenomas of the parotid gland: clinical evaluation and long-term follow-up. Br J Oral Maxillofac Surg. 1998;36:48-51. Furthermore, the risk of malignant transformation increases with the duration of the disease.66 Eneroth CM, Zetterberg A. Malignancy in pleomorphic adenoma. A clinical and micro-spectrophotometric study. Acta Otolaryngol. 1974;77:426-32.,77 Phillips PP, Olsen KD. Recurrent pleomorphic adenoma of the parotid gland: report of 126 cases and a review of the literature. Ann Otol Rhinol Laryngol. 1995;104:100-4. To date, CXPA arising from RPA has been rarely reported and these studies have focused on the histopathological and clinical features of the lesions.88 Gupta A, Manipadam MT, Michael R. Myoepithelial carcinoma arising in recurrent pleomorphic adenoma in maxillary sinus. J Oral Maxillofac Pathol. 2013;17:427-30.
The recurrence of tumor can be caused by either increase in the number or complexity of genetic abnormalities or acquisition of promoting mutations to the malignant change. Cancer is driven by somatically acquired mutations, and chromosomal rearrangements are thought to accumulate gradually over time.99 Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GL, Mudie JL, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27-40. Whole-genome screening such as array-CGH can be applied to disclose copy number alterations which could identify molecular basis for carcinogenesis.
Herein, the aim of this study was to investigate by array comparative genomic hybridization (aCGH) the genomic profile of copy number alterations associated with three cases of carcinoma ex-pleomorphic adenoma (CXPA) originated from RPA, discover their involved genes, and compare these findings to four cases of RPA without malignant transformation.
Methods
The current study was carried out in accordance with the ethical guidelines of our institution (Process n° CEP/FOP 002/2011). DNA samples were extracted from a 1.5 mm diameter punch of paraffin embedded tumor tissues using Qiagen extraction kit (Qiagen GmbH, Hilden, Germany), according to the manufacturer's recommendations. The protocol included deparaffinization with xylene, followed by methanol washings, and 24-hour incubation in 1moL/L sodium thiocyanate. Subsequently, the tissue pellet was dried and digested for 1.5 day in a lysis buffer with high proteinase K level (60 µL). Samples were column-purified before buffer elution.
Tumor and reference DNA (pooled from blood of different healthy donors; Promega, Madison, WI, USA) samples were differently labeled using the Enzo Genomic DNA Labeling kit according to the manufacturer's instructions. Five hundred ηg of labeled tumor and reference DNA were co-hybridized to a 180 K oligonucleotide array (SurePrint G3 Human CGH Microarray Kit 4 × 180 K design 22060, Agilent Technologies, Palo Alto, CA, USA), following manufacturer procedures. This design contains 24,011 exonic probes. Microarray images were obtained by Agilent Microarray Scanner Bundle, and data was extracted using the Feature Extraction software v.9.1 (Agilent Technologies, Santa Clara, CA, USA).
Array-CGH data was analyzed using the software Nexus Copy Number Discovery edition v.7.0. Genomic copy number alterations were called based on the FASST2 segmentation algorithm (significance threshold set on 5 × 10−8) with threshold log2 ratios of 0.2 or 0.8 for gains or high-copy gains, respectively, and −0.2 or −1.0 for losses or homozygous losses, respectively.
Results
Clinic-pathological data of the CXPA from RPA
The first patient (case 1) was a 72 year-old man referred to our hospital for evaluation of a nodule in the parotid gland measuring 9.0 cm × 8.0 cm with a reported time of evolution of two years. The patient had undergone resection of a PA five years ago. During clinical examination, palpable lymph nodes and subjacent skin invasion were observed. There was absence of oral lesions. Fine needle aspiration biopsy revealed a PA. Tumor was excised with positive surgical margins. Histological examination showed presence of PA and CXPA regions. The neoplasm was classified as a frankly invasive myoepithelial carcinoma (Fig. 1A and B). The patient was submitted to radiotherapy and no recurrence was observed in 58 months of follow-up.
Frankly invasive myoepithelial carcinoma: (A) Island of myoepithelial cells infiltrating the tissue (H&E × 10); (B) cords of pleomorphic myoepithelial cells surrounded by myxoid stroma. Note the reaction against thread suture from previous surgery in the top right side of the image (H&E 20×). Frankly invasive epithelial-myoepithelial carcinoma: (C) Proliferation of epithelial and myoepithelial cells in a nodular growth (H&E 10×); (D) Small lumen bounded by eosinophilic, cuboidal, intercalated duct-like cells. These cells are surrounded by small and non-staining cytoplasm cells. Note the maintenance of basal cells in the periphery of nest cells surrounded by fibrous septa (H&E 20×). Minimally invasive epithelial-myoepithelial carcinoma: (E) Epithelial-myoepithelial proliferation arising in pleomorphic adenoma residual (H&E 10×); (F) eosinophilic, hyalinized basal lamina material surrounds nests of tumor cells and ductal structures comprised of epithelial and myoepithelial cells (H&E 20×).
The second patient (case 2) was a 66 year-old woman referred to our hospital complaining of a tumor in the parotid region for an unknown time. The patient had undergone resection of a PA 11 years ago. Clinical examination rules out the presence of palpable lymph nodes and oral lesions. Fine needle aspiration biopsy confirmed the presence of a PA. Tumor excision was performed but the margins were positive surgically. Histological examination showed presence of PA and CXPA, which were classified as frankly invasive epithelial-myoepithelial carcinoma (Fig. 1C and D). There is no follow-up of this patient.
The third patient (case 3) was a 30 year-old woman referred to our hospital complaining of a tumor in the parotid gland with two years of duration. The patient had undergone resection of a PA 16 years ago. During clinical examination, palpable lymph nodes and oral lesions were not observed. Fine needle aspiration biopsy showed presence of PA. The tumor was excised with negative surgical margins. The histopathological analysis showed PA and CXAP regions. The latter was a minimally invasive epithelial-myoepithelial carcinoma (Fig. 1E and F). There is no follow-up of this patient.
Array-CGH analysis
The cases of RPAs did not show somatic copy number alterations. All somatic chromosomal alterations detected in CXPAs from cases 1, 2 and 3 are detailed in Table 1, as well as affected known cancer genes according to the Cancer Gene Census Sanger (https://www.sanger.ac.uk/research/projects/cancergenome/census.html). Fig. 2 presents the global genomic profile of copy number alterations identified in CXPA cases 1, 2 and 3. The first CXPA from RPA exhibited 1p36.33p13 loss, chromosomes 3 and 8 gains, and two adjacent chromosomal rearrangements affecting 5p15.33p13.1 (loss) and 5p13.1q13.1 (gain), respectively.
Copy number alterations detected by array-CGH in the CXPAs from RPA cases. Array-CGH genomic profile exhibiting the identified copy number alterations of case 1 (A), case 2 (B) and case 3 (C). The x-axis represents probes ordered according to their genomic position from chromosomes 1p to Xq (each chromosome is labeled with a different color). The y-axis denotes the log2 test/reference values (genomic gains and losses are plotted above or below the 0 baseline, respectively; images adapted from the software Nexus Copy Number 7.0, Biodiscovery). The arrows indicate the high copy gains (amplifications).
The second case of CXPA from RPA showed a more complex genomic pattern with several copy number alterations (gains and losses) affecting chromosomes 3, 8 and 16. Additionally, this sample harbor losses at 5q14.3q33.1, 5q35.3, 10p15.3p13, 14q11.2q32.2, 20q13.12, and gains at 6p22.2, 22q11.1q13. Regions of high copy number gains (amplifications) were found at 8p12p11.21 and 12q14.3q21.2 (Fig. 3A). The amplified genes included among others WHSCILI and FGFR1 at 8p, and HMGA2 and MDM2 at 12q.
(A) Array-CGH profile of chromosome 12 showing the high copy number gain (amplification) of 1Mb at 12q14.3q21.2 in case 1. (B) Array-CGH profile of chromosome 12 showing a complex pattern consisting of three genomic regions exhibiting high copy number (amplifications) at 12q13.3q14.1 (0.2 Mb), 12q14.3 (0.1 Mb) and 12q15 (0.2 Mb), interpolated with copy number losses of low amplitude.
The third case exhibited losses at 12q14.1q14.2 and 12q14.3q15, and amplifications at 12q13.3q14.1, 12q.14.3 and 12q15, encompassing CDK4, LRIG3, WIF1, HMGA2 and MDM2 (Fig. 3B).
Discussion
The carcinogenesis occurs in several steps through genomic changes that result in loss of tumor suppressor functions, the activation of oncogenes and/or the generation of fusion genes with oncogenic potential.1010 Forment JV, Kaidi A, Jackson SP. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer. 2012;12:663-70. These alterations generate clonal expansion resulting in phenotype of malignant cancer cells.1111 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. Although such changes can occur by mutations or genomic rearrangements, abnormal chromosome numbers and structures have also been well reported in neoplastic cells, indicating that chromosome instability is an important aspect of cancer cell biology.1010 Forment JV, Kaidi A, Jackson SP. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer. 2012;12:663-70. Therefore, copy number alterations can be an auxiliary tool in the understanding about carcinogenesis.
Malignant transformation of recurrent pleomorphic adenoma is reported in 1.5-23% of cases, and the risk appears to increase with time and number of recurrences.1212 Bradley P. Recurrent salivary gland pleomorphic adenoma: etiology, management, and results. Curr Opin Otol Head Neck Surg. 2001;9:100-8. The occurrence of malignant change from recurrence of the pleomorphic adenoma must involve the acquisition of mutations over a period of time.
The current cases exhibited different patterns of copy number alterations, and it is important to emphasize that histopathological and invasiveness classifications were also distinct. However, data analysis could pinpoint some recurrent copy number alterations such as 3q and 8q gains (cases 1 and 2), and importantly, an amplification with a minimum common region at 12q14.3 (cases 2 and 3). Cases 1 and 2 were frankly invasive carcinomas, and 3q and 8q gains can be implicated in the invasiveness degree. Cases 2 and 3 were epithelial-myoepithelial carcinomas, and the 12q14.3 amplification is maybe involved with histopathological subtype, or even recurrence. Case 2 exhibited a more complex pattern of rearrangements consistent with the histopathological subtype and degree of invasiveness.
Losses of 1p21.3-p21.1, 5q23.2-q31.2, 8p, 10q21.3 and 15q11.2 were found by Persson et al.1313 Persson F, Andrén Y, Winnes M, Wedell B, Nordkvist A, Gudnadottir G, et al. High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosom Cancer. 2009;48:69-82. in a study of a group of 10 CXPAs; however, no histopathological classification was performed. We find losses at 1p36.33-p13, 5p15.33-p13.1, 5q14.3-q33.1, 5q35.3, 8p and 10p15.3-p13. Gain of 8q12.1 (PLAG1), here detected in two cases, has been reported by several authors.1313 Persson F, Andrén Y, Winnes M, Wedell B, Nordkvist A, Gudnadottir G, et al. High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosom Cancer. 2009;48:69-82.
14 Matsuyama A, Hisaoka M, Nagao Y, Hashimoto H. Aberrant PLAG1 expression in pleomorphic adenomas of the salivary gland: a molecular genetic and immunohistochemical study. Virchows Arch. 2011;458:583-92.-1515 Bahrami A, Dalton JD, Shivakumar B, Krane JF. PLAG1 alteration in carcinoma ex pleomorphic adenoma: immunohistochemical and fluorescence in situ hybridization studies of 22 cases. Head Neck Pathol. 2012;6:328-35.
Amplifications of HMGA2, MDM2, and deletions of 5q23.2q31.2 and 8q22.1q24.1 were described as important in the transition from PA to CXPA.1313 Persson F, Andrén Y, Winnes M, Wedell B, Nordkvist A, Gudnadottir G, et al. High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosom Cancer. 2009;48:69-82. We observed high copy gain of HMGA2, MDM2, CDK4, WHSCIL1, LRIG3 and WIF1. All the amplified genes are cancer related, according to the Cancer Gene Census Sanger (https://www.sanger.ac.uk/research/projects/cancergenome/census.html). HMGA2 and MDM2 amplification were found in two of our cases, reinforcing their role as driver genes associated with recurrence in CXPA.
HMGA2 (human high mobility group A) gene encodes a non-histone chromatin protein that belongs to a family of the HMG proteins, which are overexpressed in malignant neoplasms as lung, pancreatic, oral squamous cell carcinoma and breast cancer.1616 Abe N, Watanabe T, Masaki T, Mori T, Sugiyama M, Uchimura H, et al. Pancreatic duct cell carcinomas express high levels of high mobility group I(Y) proteins. Cancer Res. 2000;60:3117-22.
17 Miyazawa J, Mitoro A, Kawashiri S, Chada KK, Imai K. Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res. 2004;64:2024-9.
18 Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, et al. HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog. 2007;46:503-11.-1919 Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K, Mori M. Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family. Clin Cancer Res. 2008;14:2334-40. HMGA2 proteins have oncogenic activity through several mechanisms, such as induction of E2F1 and AP1 activity, induction of cyclin A expression, inactivation of p53 induced apoptosis, impairment of DNA repair, enhancement of the expression of proteins involved in inflammation, and modulation of the expression of microRNAs and genes involved in epithelial-mesenchymal transition.2020 Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer. 2007;7:899-910. Additionally, HMGA proteins have a crucial role in cell transformation because when their synthesis is blocked, suppression of the malignant phenotype occurs. This hypothesis is in line with our finding, because we showed the amplification of HMAG2 from a minimally invasive case.
The MDM2 (mouse double minute 2 homolog), also known as E3 ubiquitin protein ligase Mdm2, is an oncogene which encodes a Mdm2 protein, which is a key negative regulator of the p53 tumor suppressor, degrading p53 protein or inhibiting p53 activity.2121 Zhao Y, Yu H, Hu W. The regulation of MDM2 oncogene and its impact on human cancers. Acta Biochim Biophys Sin. 2014;46:180-9. Inhibition of tumor suppressor genes or insensitivity to antigrowth signals occurs in most of the tumors. Incipient cancer cells must evade these antiproliferative signals if they are to prosper.1111 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. The current work showed MDM2 already amplified in our minimally invasive case. The over expression of MDM2 has been also observed in a wide variety of human tumors, as sarcoma, leukemia, breast carcinoma, melanoma, and glioblastoma.2222 Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453-9.
WHSC1L1 (Wolf-Hirschhorn syndrome candidate gene-1) encodes a short protein containing one PWWP domain and is expressed in many tissues. The function of this encoded protein is unclear, but the presence of PWWP domain, a putative site for protein-protein interaction, suggests a regulatory role.2323 Stec I, van Ommen GJ, den Dunnen JT. WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. Genomics. 2001;76:5-8. WHSC1L1 has already been identified as an oncogene and it is amplified and overexpressed in lung carcinoma.2424 Tonon G, Wong KK, Maulik G, Brennan C, Feng B, Zhang Y, et al. High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci U S A. 2005;102:9625-30.
FGFRs (fibroblast growth factor receptors), encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4), are associated with many biological processes such as organ development, cell proliferation and migration. Several studies have described a role of FGFRs in tumorigenesis due to the regulation of diverse tumorigenesis-related processes, including cell survival, proliferation, inflammation, metastasis and angiogenesis. FGFR1 amplification has been identified mainly in lung cancer.2525 Lee Y, Dominy JE, Choi YJ, Jurczak M, Tolliday N, Camporez JP, et al. Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature. 2014;510:547-51.
CDK4 (cyclin-dependent kinases 4) is directly involved in driving the cell cycle.2525 Lee Y, Dominy JE, Choi YJ, Jurczak M, Tolliday N, Camporez JP, et al. Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature. 2014;510:547-51. Amplification of CDK4 has been observed in several malignancies including glioma, breast cancer, lymphoma, melanoma, and sarcoma. Sometimes CDK4 is co-amplified with MDM2. The protein encoded by this gene is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression.2626 Malumbres M, Barbacid M. Cell cycle. CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153-66.
LRIG (human leucine-rich repeats and immunoglobulin-like domains) gene family includes: LRIG1, LRIG2 and LRIG3. LRIG expression has proven to be of prognostic value in different types of human cancers, including breast cancer, early stage invasive squamous cervical cancer, cutaneous squamous cell carcinoma, oligodendroglioma, and astrocytoma. LRIF1 functions as a tumor suppressor gene, while little is known about the functions of LRIG2 and LRIG3.2727 Muller S, Lindquist D, Kanter L, Flores-Staino C, Henriksson R, Hedman H, et al. Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma. Int J Oncol. 2013;42:247-52.
WIF1 is Wnt inhibitory factor 1 gene. The protein encoded by this gene functions to inhibit WNT proteins, which are extracellular signaling molecules that play a role in embryonic development. This gene acts as tumor suppressor gene, and has been found to be epigenetically silenced in various cancers.2828 Lambiv WL, Vassallo I, Delorenzi M, Shay T, Diserens AC, Misra A, et al. The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence. Neuro Oncol. 2011;13:736-47.
Conclusion
In conclusion, we identified unique genomic profiles of copy number alterations among three cases of CXPA from RPA, and differences can be explained due to histopathological subtypes and invasiveness degrees. However, recurrent gains at 3q and 8q, and amplifications at 12q14.3 and 12q15 here detected can be the promotional factors in the recurrence of the disease.
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FundingProcess FAPESP: 2011/23204-5 and Process FAPESP: 2011/23366-5.
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☆
Please cite this article as: Mariano FV, Giovanetti K, Saccomani LF, Del Negro A, Kowalskic LP, Krepischi AC, et al. Carcinoma ex-pleomorphic adenoma derived from recurrent pleomorphic adenoma shows important difference by array CGH compared to recurrent pleomorphic adenoma without malignant transformation. Braz J Otorhinolaryngol. 2016;82:687-94.
References
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1Eveson JW, Reichart P, Sidransky D. Pleomorphic adenoma. World health Organization Classification of Tumors. Pathology & Genetics: head and neck tumours. Lyon: IARC Press; 2005. p. 254-8.
-
2Zbären P, Tschumi I, Nuyens M, Stauffer E. Recurrent pleomorphic adenoma of the parotid gland. Am J Surg. 2005;189:203-7.
-
3Laccourreye H, Laccourreye O, Cauchois R, Jouffre V, Menard M, Brasnu D. Total conservative parotidectomy for primary benign pleomorphic adenoma of the parotid gland: a 25-year experience with 229 patients. Laryngoscope. 1994;104:1487-94.
-
4Leonetti JP, Marzo SJ, Petruzzelli GJ, Herr B. Recurrent pleomorphic adenoma of the parotid gland. Otolaryngol Head Neck Surg. 2005;133:319-22.
-
5Laskawi R, Schott T, Schroder M. Recurrent pleomorphic adenomas of the parotid gland: clinical evaluation and long-term follow-up. Br J Oral Maxillofac Surg. 1998;36:48-51.
-
6Eneroth CM, Zetterberg A. Malignancy in pleomorphic adenoma. A clinical and micro-spectrophotometric study. Acta Otolaryngol. 1974;77:426-32.
-
7Phillips PP, Olsen KD. Recurrent pleomorphic adenoma of the parotid gland: report of 126 cases and a review of the literature. Ann Otol Rhinol Laryngol. 1995;104:100-4.
-
8Gupta A, Manipadam MT, Michael R. Myoepithelial carcinoma arising in recurrent pleomorphic adenoma in maxillary sinus. J Oral Maxillofac Pathol. 2013;17:427-30.
-
9Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GL, Mudie JL, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27-40.
-
10Forment JV, Kaidi A, Jackson SP. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer. 2012;12:663-70.
-
11Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
-
12Bradley P. Recurrent salivary gland pleomorphic adenoma: etiology, management, and results. Curr Opin Otol Head Neck Surg. 2001;9:100-8.
-
13Persson F, Andrén Y, Winnes M, Wedell B, Nordkvist A, Gudnadottir G, et al. High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosom Cancer. 2009;48:69-82.
-
14Matsuyama A, Hisaoka M, Nagao Y, Hashimoto H. Aberrant PLAG1 expression in pleomorphic adenomas of the salivary gland: a molecular genetic and immunohistochemical study. Virchows Arch. 2011;458:583-92.
-
15Bahrami A, Dalton JD, Shivakumar B, Krane JF. PLAG1 alteration in carcinoma ex pleomorphic adenoma: immunohistochemical and fluorescence in situ hybridization studies of 22 cases. Head Neck Pathol. 2012;6:328-35.
-
16Abe N, Watanabe T, Masaki T, Mori T, Sugiyama M, Uchimura H, et al. Pancreatic duct cell carcinomas express high levels of high mobility group I(Y) proteins. Cancer Res. 2000;60:3117-22.
-
17Miyazawa J, Mitoro A, Kawashiri S, Chada KK, Imai K. Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res. 2004;64:2024-9.
-
18Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, et al. HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog. 2007;46:503-11.
-
19Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K, Mori M. Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family. Clin Cancer Res. 2008;14:2334-40.
-
20Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer. 2007;7:899-910.
-
21Zhao Y, Yu H, Hu W. The regulation of MDM2 oncogene and its impact on human cancers. Acta Biochim Biophys Sin. 2014;46:180-9.
-
22Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453-9.
-
23Stec I, van Ommen GJ, den Dunnen JT. WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. Genomics. 2001;76:5-8.
-
24Tonon G, Wong KK, Maulik G, Brennan C, Feng B, Zhang Y, et al. High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci U S A. 2005;102:9625-30.
-
25Lee Y, Dominy JE, Choi YJ, Jurczak M, Tolliday N, Camporez JP, et al. Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature. 2014;510:547-51.
-
26Malumbres M, Barbacid M. Cell cycle. CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153-66.
-
27Muller S, Lindquist D, Kanter L, Flores-Staino C, Henriksson R, Hedman H, et al. Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma. Int J Oncol. 2013;42:247-52.
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Publication Dates
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Publication in this collection
Nov-Dec 2016
History
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Received
11 Oct 2015 -
Accepted
08 Dec 2015