MYB-NFIB fusion

Adenoid cystic carcinoma arising in the external auditory canal is rare, and even rarer are cases with sebaceous differentiation mimicking sebaceous carcinoma. This case with clinical, radiologic, gross, and histologic images exemplifies an unusual occurrence of adenoid cystic carcinoma in the external auditory canal with sebaceous differentiation, confirmed by MYB::NFIB fusion.

Our study demonstrates that in patients with breast AdCC, overexpression of NOTCH1 ≥20% is associated with larger tumour size and aggressive clinical outcomes. Importantly, NOTCH1 inhibitors may have potential therapeutic effect in patients with breast AdCC.

AdCC-BGs constitute a convergent phenotype, whereby activation of MYB or MYBL1 can be driven by the MYB::NFIB fusion gene or MYBL1 rearrangements. Our observations further support the notion that AdCCs, irrespective of organ site, constitute a genotypic-phenotypic correlation. Assessment of MYB or MYBL1 rearrangements may be used as an ancillary marker for the diagnosis of AdCC-BGs.

There were no MYBL1 or NFIB rearrangements and no MYB::NFIB fusions. Our findings corroborate that the histologic, immunohistochemical, and oncogenic background is similar between ACCs of the lower female genital tract and ACCs elsewhere, although the canonical MYB::NFIB fusion seems to be a less common finding in this location.

Our study highlights the variety of molecular alterations associated with lacrimal system tumours and emphasises the importance of molecular testing in these tumours, which can reveal potentially targetable mutations. Our results also reinforce the hypothesis of a common physiopathology of all ACCs, regardless of their primary location.

Immunohistochemical antibodies have emerged that identify the underlying genetic alterations in these tumors and serve as useful diagnostic tools. This review will provide an update on the molecular features and diagnostic immunohistochemical markers that have become increasingly popular to aid in diagnosing these uncommon triple-negative breast tumors.

The data highlight the histopathologic spectrum of basaloid carcinomas including SB-AdCC and reveal shared genetics and MYB activation, which can be diagnostically useful. Aggressive behavior and poor treatment responses emphasize a need for additional treatment approaches.

This case highlights a rare presentation of primary adenoid cystic carcinoma of the lung treated with curative robot assisted surgical resection.

Bioinformatic, RNA-seq, and immunohistochemical (IHC) analyses of primary tissues and metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of the RA system in diagnosis and treatment.

We hypothesize that loss of the 3'-part of MYB results from an unbalanced t(6;9) leading to an MYB-NFIB fusion with concomitant loss of the segment distal to the MYB breakpoint in 6q23.3. Our study provides new knowledge about the prevalence and clinical significance of MYB/MYBL1 alterations and indicates the presence of genes with tumor suppressive functions in 6q23.3-qter that contribute to poor prognosis and short overall survival in ACC.

In vitro and in vivo studies have been conducted to understand the biological consequences of MYB-NFIB translocation, and such findings could contribute to improving the current inefficient therapeutic options for disseminated ACC. This review provides a discussion on relevant evidence in the context of ACC MYB-NFIB translocations to determine the current state of knowledge and discuss future directions.

We conclude that HPV and HPyV have no major role in AdCC. However, based on our data, we also suggest that HMSC should be considered as a basaloid variant of squamous cell carcinoma, and not its own entity, until better characterized.

In vivo tumor formation analysis indicated the capacity of MYB-NFIB fusion cells to grow as implanted tumors, although there were no fusion-mediated growth advantages. This expression system may be useful not only in studies to determine the functional aspects of MYB-NFIB fusion but also in evaluating effective drug response in vitro and in vivo settings.

Examples of the most significant recurrent gene fusions to date include (1) ESR1::CCDC170 gene fusions in luminal B and endocrine-resistant breast cancer that exert oncogenic function via modulating the HER2/HER3/SRC Proto-Oncogene (SRC) complex, (2) ESR1 exon 6 fusions in metastatic disease that drive estrogen-independent estrogen-receptor transcriptional activity, (3) BCL2L14::ETV6 fusions in a more aggressive form of the triple-negative subtype that prime epithelial-mesenchymal transition and endow paclitaxel resistance, (4) the ETV6::NTRK3 fusion in secretory breast carcinoma that constitutively activates NTRK3 kinase, (5) the oncogenic MYB-NFIB fusion as a genetic driver underpinning adenoid cystic carcinomas of the breast that activates MYB Proto-Oncogene (MYB) pathway, and (6) the NOTCH/microtubule-associated serine-threonine (MAST) kinase gene fusions that activate NOTCH and MAST signaling...Thus, these gene fusions could be utilized as genetic biomarkers to identify patients that require more intensive treatment and surveillance. In addition, kinase fusions are currently being evaluated in breast cancer clinical trials and on-going mechanistic investigation is exposing therapeutic vulnerabilities in patients with fusion positive disease.

This includes CRTC1-MAML2 and CRTC-MAML2 in mucoepidermoid carcinoma, MYBNFIB and MYBL1-NFIB fusions in adenoid cystic carcinoma, PLAG1 and HMGA2 in pleomorphic adenoma, ETV6-NTRK3 in secretory carcinoma, NR4A3 rearrangements in acinic cell carcinoma, PRKD1 mutations in polymorphous adenocarcinoma and EWSR1-ATF1 in clear cell carcinoma. This review is a lens for progress made till date in the molecular pathology of salivary gland tumours with a special focus on their role as diagnostic tools and implications on clinical management of the patient as prognostic and predictive markers.

Six novel gene fusions other than MYB/MYBL1-NFIB were identified. The detection of novel fusion genes and investigation of the molecular mechanism will contribute to the development of novel molecular targeted therapies for this disease.

However, this finding is sensible given that the MYB-NFIB fusion is not present in all ACC PDX models. Through our work, investigators will have a better understanding of the advantages and limitations of the utilization of the ACC PDX as a model for ACC research.

ACC is a genetically heterogenous disease with an immune-excluded microenvironment . NOTCH1 mutations were associated with worse, while MYB:NFIB fusion was not associated with prognosis . Our study shows that M2 macrophages and MYC are potential novel therapeutic targets in ACC.

Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.

In this study, we displayed the morphologically and genetic featured PDXs which recapitulated the heterogeneity of original ACC tumors, indicating that the models could be used as a platform for drug screening for therapy response. The feasibility of combination treatment approaches for dual targets were confirmed, providing new regimens for personalized therapies in ACC.

Further, chemotherapy (carboplatin/paclitaxel) was conducted on the PDX model. All three PDX models had histopathological features similar to those of the original tumors, and retained the MYB-NFIB fusion gene. We successfully established PDX models of adenoid cystic carcinoma, including an HGT model, which was characterized by detailed clinical and genomic information. Tumors that show HGT characteristics may be drug-sensitive, and can be used in the development of personalized cancer treatments.