Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma

Abstract

Adenoid cystic carcinoma (ACC) of the head and neck is a malignant tumor with poor long-term prognosis. Besides the recently identified MYB-NFIB fusion oncogene generated by a t(6;9) translocation, little is known about other genetic alterations in ACC. Using high-resolution, array-based comparative genomic hybridization, and massively paired-end sequencing, we explored genomic alterations in 40 frozen ACCs. Eighty-six percent of the tumors expressed MYB-NFIB fusion transcripts and 97% overexpressed MYB mRNA, indicating that MYB activation is a hallmark of ACC. Thirty-five recurrent copy number alterations (CNAs) were detected, including losses involving 12q, 6q, 9p, 11q, 14q, 1p, and 5q and gains involving 1q, 9p, and 22q. Grade III tumors had on average a significantly higher number of CNAs/tumor compared to Grade I and II tumors (P = 0.007). Losses of 1p, 6q, and 15q were associated with high-grade tumors, whereas losses of 14q were exclusively seen in Grade I tumors. The t(6;9) rearrangements were associated with a complex pattern of breakpoints, deletions, insertions, inversions, and for 9p also gains. Analyses of fusion-negative ACCs using high-resolution arrays and massively paired-end sequencing revealed that MYB may also be deregulated by other mechanisms in addition to gene fusion. Our studies also identified several down-regulated candidate tumor suppressor genes (CTNNBIP1, CASP9, PRDM2, and SFN) in 1p36.33-p35.3 that may be of clinical significance in high-grade tumors. Further, studies of these and other potential target genes may lead to the identification of novel driver genes in ACC.

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

“…However, finding a compound that specifically inhibits the MYB transcriptional function presents a formidable challenge. On the other hand, some of the proposed downstream effectors of MYB may be more “druggable.” These include cell proliferation proteins ( MYC , CD53 , FGF2 , VEGFA , and KIT ), cell cycle proteins ( CCNB1 , CDC2 , and MAD1L1 ), apoptosis‐related markers ( API5 , BCL2 , BIRC3 , HSPA8 , and SET ), and cellular adhesion molecules ( CD34 ) 28. In addition, the tumor DNA studies suggest that agents that inhibit signaling through the Notch, protein kinase A, or FGF‐insulin‐like growth factor‐PI3K pathways or block the epigenetic effects of chromatin remodeling may also be active in ACC 24, 25…”

“…However, the most intriguing alteration is a translocation between chromosomes 6q and 9p [(6;9)(q22–23;p23–24)]. Persson et al27, 28 were the first to report that this rearrangement juxtaposes the genes for the MYB and nuclear factor I/B (NFIB) transcription factors. This translocation seems to be specific for ACC, found in up to 86% of these tumors,24, 27, 28 and may be helpful in differentiating these tumors from other forms of carcinoma, such as pleomorphic adenoma 29, 30.…”

“…Persson et al27, 28 were the first to report that this rearrangement juxtaposes the genes for the MYB and nuclear factor I/B (NFIB) transcription factors. This translocation seems to be specific for ACC, found in up to 86% of these tumors,24, 27, 28 and may be helpful in differentiating these tumors from other forms of carcinoma, such as pleomorphic adenoma 29, 30. 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.…”

“…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…”

K5/K14-positive cells contribute to salivary gland-like breast tumors with myoepithelial differentiation

“…89 In contrast, salivary gland adenoid cystic carcinomas have multiple recurrent copy number alterations some of which are associated with a poor prognosis. 90,91 Dedifferentiation and progression to high-grade lesions (no specific type grade 3, malignant myoepithelial, or of mixed epithelial-myoepithelial type) have been described both in salivary gland and breast tumors. 59,71,[92][93][94][95][96][97] It has been suggested that new genetic alterations gradually accumulate in subclones of these tumors leading to clonal evolution and disease progression.…”