MYB – Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is a rare epithelial malignancy most commonly arising in salivary glands but also reported in breast and lung. A defining molecular feature in ~50–70 % of ACC cases is the t(6;9)(q22–23;p23–24) translocation leading to MYB–NFIB fusion, resulting in deregulated MYB expression and oncogenic activation. Sporadic ACCs generally lack germline inheritance and are driven by somatic events, notably MYB gene rearrangements.

1 Clinical Validity

Multiple independent cohorts totaling over 200 ACC tumors across salivary gland, breast, and pulmonary sites have reported MYB–NFIB fusions in 35–71 % of cases, with reciprocal MYB and NFIB expression patterns confirmed by FISH and RNA sequencing ([PMID:26631609], [PMID:34364112], [PMID:34413003]). The consistency of fusion detection across tissue sites and methods, combined with recurrent structural alterations and functional assays demonstrating MYB overexpression, supports a Strong gene–disease association.

2 Genetic Evidence

• Somatic MYB–NFIB fusions identified in 9/21 salivary ACCs by whole-genome sequencing ([PMID:26631609]) and in 5/7 primary pulmonary ACCs ([PMID:34364112]).
• In breast ACC, MYB–NFIB fusion transcripts were detected by RT-PCR in 1 case of synchronous bilateral disease ([PMID:28894575]).
• Solid-basaloid variant ACC of the breast lacking MYB rearrangement highlights molecular heterogeneity and underscores specificity of the fusion when present ([PMID:37757737]).
• Recurrent fusion events in multiple cohorts fulfill ClinGen genetic criteria for recurrent pathogenic structural variants in unrelated somatic tumors, achieving a Moderate genetic evidence tier.

3 Functional Evidence

• Fusion proteins retain the MYB DNA-binding and transactivation domains, leading to constitutive target gene activation and cell proliferation in vitro.
  
• NMR and biochemical studies demonstrate that the MYB DNA-binding domain undergoes redox-induced conformational changes critical for sequence-specific binding, suggesting mechanistic relevance to oncogenic fusion constructs ([PMID:8223472]).
• c-Myb acts as a pioneer factor recruiting histone acetyltransferase p300, inducing chromatin opening; a point mutation (D152V) abrogates this function, validating the role of MYB in transcriptional regulation and chromatin remodeling in cancer cells ([PMID:29954426]).
• These concordant functional assays provide Moderate support for MYB’s oncogenic mechanism in ACC.

4 Conflicting Evidence

A subset of ACCs, particularly the solid-basaloid breast variant, show absence of MYB rearrangement, indicating molecular heterogeneity and the need for alternative diagnostic markers ([PMID:37757737]).

5 Integration & Conclusion

Comprehensive genetic and functional data establish that somatic MYB–NFIB fusions are a driver in the majority of ACC cases across organs, with consistent structural recurrence and mechanistic validation. While a minority of tumors lack MYB involvement, MYB fusion testing is clinically useful for diagnosis, prognostication, and as a potential therapeutic target.

Key Take-home: Detection of MYB rearrangements by FISH or RNA sequencing is recommended for ACC diagnosis and may inform targeted therapeutic strategies.

References

• Clinical cancer research • 2016 • Novel MYBL1 Gene Rearrangements with Recurrent MYBL1-NFIB Fusions in Salivary Adenoid Cystic Carcinomas Lacking t(6;9) Translocations PMID:26631609
• Lung cancer (Amsterdam, Netherlands) • 2021 • Mutational landscape of primary pulmonary salivary gland-type tumors through targeted next-generation sequencing PMID:34364112
• International journal of surgery case reports • 2023 • Solid-basaloid variant of adenoid cystic carcinoma of the breast unresponsive to neoadjuvant chemotherapy: Case report PMID:37757737
• Oral surgery, oral medicine, oral pathology and oral radiology • 2021 • Detection of novel fusion genes by next-generation sequencing-based targeted RNA sequencing analysis in adenoid cystic carcinoma of head and neck PMID:34413003
• The EMBO journal • 1993 • DNA and redox state induced conformational changes in the DNA-binding domain of the Myb oncoprotein PMID:8223472
• Epigenetics & chromatin • 2018 • The pioneer factor activity of c-Myb involves recruitment of p300 and induction of histone acetylation followed by acetylation-induced chromatin dissociation PMID:29954426

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