Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

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.

Oncocytic Lipoadenoma of the Salivary Gland: A Clinicopathologic Analysis of 7 Cases and Review of the Literature

“…The protein influences an array of cellular processes through regulation of gene transcription [38]. In addition to oncocytic lipoadenoma, HMGA2 gene rearrangements have also been recognized in a number of other neoplasms, including soft tissue lipomas and a subset of salivary gland pleomorphic adenomas [39,40]. Further molecular analyses may yield more definitive evidence as to the significance of HMGA2 gene disruption in the development of oncocytic lipoadenoma.…”

Fine-Needle Aspiration Biopsy of Salivary Gland Lesions

“…19,20 Of note, the PLAG1 and HMGA2 fusions are present only in PA and carcinoma ex pleomorphic adenoma (CA-ex-PA) and have not been encountered in any other types of salivary gland neoplasms. 21 Compared to PA, subsets of Ca-ex-PA also show amplification of human homolog of mouse double minute 2 gene, mutations of tumor protein p53 gene (TP53), and amplification of human epidermal growth factor receptor 2 gene (HER2/neu) as molecular markers of malignant transformation. 22 Changes in the expression levels of Ki-67, cyclin E, and p63 are also proposed to differentiate PA from Ca-ex-PA. 23 …”

“…25 For pathologic practice, the MYB-NF1B fusion and/or MYB activation may be identified by reverse transcription-polymerase chain reaction analysis of fusion transcripts, fluorescence in situ hybridization analysis using probes for MYB and NF1B, or by immunohistochemical staining of MYB proteins. 21 …”

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumors of the Salivary Gland

“…However, of note, the understanding of the molecular pathogenesis of salivary gland neoplasia has expanded rapidly, and several key defining alterations have made their way into clinical settings. The paradigm of defining translocations and gene fusions seen particularly in monomorphic salivary gland tumors [2] features heavily in the 4th edition given its importance to key tumor types such as adenoid cystic carcinoma, mucoepidermoid carcinoma, (mammary analogue) secretory carcinoma, and even pleomorphic adenoma. Other molecular alterations that are important diagnostically are summarized when relevant.…”