Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms

Abstract

Recent studies have shown that the recurrent t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma results in a novel fusion of the MYB proto-oncogene with the transcription factor gene NFIB. To determine the frequency of this finding, we used RT-PCR assays of the MYB and MYB-NFIB fusion transcripts, and immunohistochemistry for the MYB protein, to study adenoid cystic carcinomas and other epithelial tumors of the salivary glands, and head and neck region. MYB-NFIB fusion transcript was detected in 25 of 29 (86%) frozen adenoid cystic carcinoma tumor samples, and in 14 of 32 (44%) formalin-fixed paraffin-embedded adenoid cystic carcinoma tumor specimens. In contrast, the MYB-NFIB fusion was not expressed in non-adenoid cystic carcinoma neoplasms of the head and neck, confirming the high specificity of the MYB-NFIB fusion. Adenoid cystic carcinomas from various anatomic sites, including salivary gland, sinonasal cavity, tracheobronchial tree, larynx, breast, and vulva were repeatedly fusion-positive, indicating that adenoid cystic carcinomas located in different anatomic sites not only have important morphologic features in common, but also probably evolve through activation of the same molecular pathways. Studies of the expression of MYB revealed that 89% of the tumors, including both fusion-positive and fusion-negative cases, overexpressed MYB RNA. Similarly, 82% of adenoid cystic carcinomas stained positive for MYB protein, compared with 14% of non-adenoid cystic carcinoma neoplasms, indicating that MYB immunostaining may be useful for the diagnosis of adenoid cystic carcinoma, but that neoplasms sometimes in the differential diagnosis are also labeled. The latter are, however, fusion-negative. In summary, our studies show that MYB activation through gene fusion or other mechanisms is a major oncogenic event in adenoid cystic carcinoma occurring at various anatomic sites. In addition to being a diagnostically useful biomarker for adenoid cystic carcinoma, MYB and its downstream effectors are also novel potential therapeutic targets.

Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials

“…One consequence of the rearrangement is the overexpression of a fusion transcript (perhaps related to absence of a 3′ negative regulatory element found in the normal MYB mRNA) as well as a largely intact MYB oncoprotein. This leads to deregulation of expression of the MYB target genes, which, in turn, promotes tumorigenesis 28, 31, 32, 33. Alterations of NFIB may also be of significance because mutations that seem to target this gene have been described in some ACCs 24…”

“…For those patients who relapse after surgery, 1 older study indicated that the response rate to salvage radiation may be as high as 94%, but long‐term control was achieved in only 10% of the patients 56. Also, radiation is a standard treatment for palliation of brain and bone metastases 31. Of note, modern radiation techniques, such as intensity‐modulated radiation therapy, proton beam, and neutron beam therapies seem to be at least equally effective against ACC 57, 58, 59…”

Morphology in Conjunction with Immunohistochemistry is Sufficient for the Diagnosis of Mammary Analogue Secretory Carcinoma

“…There are a handful of salivary gland tumors that have been demonstrated to have recurring cytogenetic abnormalities including adenoid cystic carcinomas [t(6;9) (MYB-NFIB)] [8][9][10], mucoepidermoid carcinomas [t(11:19) (MECT1-MAML2)] [11,12], pleomorphic adenomas (PLAG1 and HMGA2 rearrangements) [13][14][15][16][17], and hyalinizing clear cell carcinoma [t(12;22) (EWSR1-ATF)] [18,19]. In the majority of these tumors, the morphology is distinctive enough to allow for a diagnosis and molecular confirmation is typically not necessary.…”

Adenoid Cystic Carcinoma: Clinical and Molecular Features

“…Though there is some disagreement in the literature regarding the percent of ACC tumors harboring this molecular alteration, most subsequent studies have shown that the majority of ACC have a disrupted MYB gene and/ or evidence of a MYB-NFIB fusion RNA transcript [32][33][34][35][36]. One of the largest independent cohorts separate from the Stenman group came from a study at Stanford University, where 37 cases of ACC were studied by fluorescence in situ hybridization (FISH) of the MYB and NFIB loci, with 65 % of cases showing abnormalities of these loci [34].…”