MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB–NFIB fusion gene

Abstract

Breast adenoid cystic carcinoma (AdCC), a rare type of triple-negative breast cancer, has been shown to be driven by MYB pathway activation, most often underpinned by the MYB-NFIB fusion gene. Alternative genetic mechanisms, such as MYBL1 rearrangements, have been reported in MYB-NFIB-negative salivary gland AdCCs. Here we report on the molecular characterization by massively parallel sequencing of four breast AdCCs lacking the MYB-NFIB fusion gene. In two cases, we identified MYBL1 rearrangements (MYBL1-ACTN1 and MYBL1-NFIB), which were associated with MYBL1 overexpression. A third AdCC harboured a high-level MYB amplification, which resulted in MYB overexpression at the mRNA and protein levels. RNA-sequencing and whole-genome sequencing revealed no definite alternative driver in the fourth AdCC studied, despite high levels of MYB expression and the activation of pathways similar to those activated in MYB-NFIB-positive AdCCs. In this case, a deletion encompassing the last intron and part of exon 15 of MYB, including the binding site of ERG-1, a transcription factor that may downregulate MYB, and the exon 15 splice site, was detected. In conclusion, we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression. These observations emphasize that breast AdCCs probably constitute a convergent phenotype, whereby activation of MYB and MYBL1 and their downstream targets can be driven by the MYB-NFIB fusion gene, MYBL1 rearrangements, MYB amplification, or other yet to be identified mechanisms. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

NFIB promotes cell growth, aggressiveness, metastasis and EMT of gastric cancer through the Akt/Stat3 signaling pathway

“…Nuclear factors and their receptors are indispensable in the development of tumor growth, metastasis and epithelial-mesenchymal transition (EMT) in several types of cancers (8). Nuclear factor I/B (NFIB) is a recently discovered member of the nuclear factor family (which includes NFI-A, B and X) and emerging evidence has shown that NFIB, besides functioning during normal somatic development, is also involved in the generation and progression of various types of cancer, including small-cell lung cancer, melanoma and breast cancer, through different molecular mechanisms such as forming the oncogenic NFIB-MYB gene fusion or increasing the chromatin accessibilities of its downstream targets (9)(10)(11). Nevertheless, research on the functions and involvement of NFIB on the development of GC has not been reported yet.…”

MYB rearrangement and immunohistochemical expression in adenomyoepithelioma of the breast: a comparison with adenoid cystic carcinoma

“…Our results are in line with this study and support the use of MYB IHC as a useful adjunct to establishing the diagnosis of adenoid cystic carcinoma in the breast as well as non‐breast sites. Recent genetic investigations demonstrate that alternative mechanisms for MYB pathway activation including MYB amplification or rearrangement of MYBL1 (a closely related gene with similar function) may be present in a considerable number of ACC cases that lack the classic MYB–NFIB translocation . These provide a logical potential explanation for the observations that MYB expression by immunohistochemistry may be more sensitive for ACC of the breast compared to FISH.…”

Molecular features of adenoid cystic carcinoma with an emphasis on microRNAexpression

“…Salivary gland ACC is driven by the MYB-NFIB gene fusion in the majority of cases, which has also been demonstrated in breast and lacrimal gland ACC, although much fewer cases have been examined (28,29,33,34,161,207). Recently, the identification of the MYBL1-NFIB gene fusion was shown to account for a subset of salivary gland and breast ACC without MYB-NFIB or the expression of MYB protein, whereas MYBL1 is yet to be shown to be involved in lacrimal gland ACC (21,30). We identified a spectrum of genetic abnormalities in salivary gland ACC, including MYB amplification (5 0 ), isolated MYB rearrangement (MYB-X), MYB-NFIB, MYBL1-NFIB, and isolated NFIB rearrangement (NFIB-X).…”