Oncotarget

Research Papers:

Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland

Simon Andreasen _, Tina Klitmøller Agander, Kristine Bjørndal, Daiva Erentaite, Steffen Heegaard, Stine R. Larsen, Linea Cecilie Melchior, Qihua Tan, Benedicte Parm Ulhøi, Irene Wessel and Preben Homøe

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Oncotarget. 2018; 9:19675-19687. https://doi.org/10.18632/oncotarget.24800

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Abstract

Simon Andreasen1,2, Tina Klitmøller Agander3, Kristine Bjørndal4, Daiva Erentaite5, Steffen Heegaard3,6, Stine R. Larsen7, Linea Cecilie Melchior3, Qihua Tan8, Benedicte Parm Ulhøi9, Irene Wessel2 and Preben Homøe1

1Department of Otorhinolaryngology and Maxillofacial Surgery, Zealand University Hospital, Køge, Denmark

2Department of Otorhinolaryngology Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen, Denmark

3Department of Pathology, Rigshospitalet, Copenhagen, Denmark

4Department of Otorhinolaryngology, Head and Neck Surgery, Odense University Hospital, Odense, Denmark

5Department of Pathology, Aalborg University Hospital, Aalborg, Denmark

6Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen, Denmark

7Department of Pathology, Odense University Hospital, Odense, Denmark

8Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

9Department of Pathology, Aarhus University Hospital, Aarhus, Denmark

Correspondence to:

Simon Andreasen, email: [email protected]

Keywords: adenoid cystic carcinoma; salivary gland; metastases; MYB; microRNA

Received: September 29, 2017     Accepted: March 04, 2018     Published: April 13, 2018

ABSTRACT

Adenoid cystic carcinoma (ACC) is among the most common salivary gland malignancies, and is notorious for its unpredictable clinical course with frequent local recurrences and metastatic spread. However, the molecular mechanisms for metastatic spread are poorly understood. This malignancy is known to frequently harbor gene fusions involving MYB, MYBL1, and NFIB, and to have a low mutational burden. Most studies have focused on primary tumors to understand the biology of ACC, but this has not revealed a genetic cause for metastatic dissemination in the majority of cases. Hence, other molecular mechanisms are likely to be involved. Here, we characterize the genetic and microRNA expressional landscape of primary ACC and corresponding metastatic lesions from 11 patients. FISH demonstrated preservation of MYB aberrations between primary tumors and metastases, and targeted next-generation sequencing identified mutations exclusive for the metastatic lesions in 3/11 cases (27.3%). Global microRNA profiling identified several differentially expressed miRNAs between primary ACC and metastases as compared to normal salivary gland tissue. Interestingly, individual tumor pairs differed in miRNA profile, but there was no general difference between primary ACCs and metastases. Collectively, we show that MYB and NFIB aberrations are consistently preserved in ACC metastatic lesions, and that additional mutations included in the 50-gene hotspot panel used are infrequently acquired by the metastatic lesions. In contrast, tumor pairs differ in microRNA expression and our data suggest that they are heterogeneous according to their microRNA profile. This adds an additional layer to the complex process of ACC metastatic spread.


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