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