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.

Fig. 1

A translocation-generated network of oncogenic gene fusions in salivary gland tumors. The multiple translocation target genes MYB, HMGA2, and PLAG1 are indicated in red. ACC adenoid cystic carcinoma, MEC mucoepidermoid carcinoma, HCCC hyalinizing clear cell carcinoma, MASC mammary analogue secretory carcinoma, Pl. Ad. pleomorphic adenoma

Fig. 2

a Schematic illustration of the MYB and NFIB genes as well as the MYB–NFIB fusion oncogene (coding exons are shown i darker red and bluecolors) and the resulting fusion oncoprotein. Translocation breakpoints are shown by vertical arrows and binding sites for negatively regulating miRNAs in the 3′-UTR of MYB are indicated. DBD DNA binding domain, TAD transactivation domain, NRD negative regulatory domain. b and c FISH analysis of MYB rearrangements in adenoid cystic carcinoma using a dual-color MYB break-apart probe consisting of a centromeric (green) and a telomeric (red) probe covering the MYB locus and its flanking sequences. Interphase nuclei from a MYB–NFIB fusion-positive tumor (b), showing an intact signal (fused red/green signals) and a split signal (separated red and green signals), indicating a breakpoint within the MYB gene. Panel c shows interphase nuclei from a tumor with 1–2 intact red/green signals as well as 1–2 green signals indicating a selective gain of the MYB gene

Fig. 3

Schematic illustration of two alternative mechanisms of activation of MYB in fusion-negative adenoid cystic carcinomas, that is insertions of a segment from 9p23–p22. 3, including the 3′-part of NFIB, immediately centromeric to the MYB locus or t(6;9) translocations with breakpoints 10–100 kb distal to MYB. In both cases, the proximity of the 3′-part of NFIB and its flanking sequences to MYB leads to transcriptional activation of an apparently intact MYB gene