Comprehensive Analysis of the MYB-NFIB Gene Fusion in Salivary Adenoid Cystic Carcinoma: Incidence, Variability, and Clinicopathologic Significance

Abstract

Purpose The objective of this study was to determine the incidence of the MYB-MFIB fusion in salivary adenoid cystic carcinoma (ACC), to establish the clinicopathological significance of the fusion and to analyze the expression of MYB in ACCs in the context of the MYB-NFIB fusion. Experimental Design We performed an extensive analysis involving 123 cancers of the salivary gland, including primary and metastatic ACCs, and non-ACC salivary carcinomas. MYB-NFIB fusions were identified by reverse transcription-PCR (RT-PCR) and sequencing of the RT-PCR products, and confirmed by fluorescence in situ hybridization. MYB RNA expression was determined by quantitative RT-PCR and protein expression was analyzed by immunohistochemistry. Results The MYB-NFIB fusion was detected in 28% primary and 35% metastatic ACCs, but not in any of the non-ACC salivary carcinomas analyzed. Different exons in both MYB and NFIB genes were involved in the fusions, resulting in expression of multiple chimeric variants. Notably, MYB was overexpressed in the vast majority of the ACCs, although MYB expression was significantly higher in tumors carrying the MYB-NFIB fusion. The presence of the MYB-NFIB fusion was significantly associated (p = 0.03) with patients older than 50 years of age. No correlation with other clinicopathological markers, factors and survival was found. Conclusions We conclude that the MYB-NFIB fusion characterizes a subset of ACCs and contributes to MYB overexpression. Additional mechanisms may be involved in MYB overexpression in ACCs lacking the MYB-NFIB fusion. These findings suggest that MYB may be a specific novel target for tumor intervention in patients with ACC.

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…”

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].…”

“…2b. One research group showed evidence that some ACC tumors that did not contain a translocated MYB gene had elevated levels of wild-type MYB transcript and protein through an unknown mechanism [32]. While, as previously noted, the majority of ACC will show strong MYB immunoreactivity, this stain cannot be used to exclude the diagnosis of ACC, as some tumors (up to a third of cases) that otherwise meet the histologic diagnosis of ACC may show weak or negative MYB staining [34,36,37].…”