Rearrangements, Expression, and Clinical Significance of MYB and MYBL1 in Adenoid Cystic Carcinoma: A Multi-Institutional Study

Abstract

Adenoid cystic carcinoma (ACC) is an aggressive head and neck malignancy characterized by a t (6;9) translocation resulting in an MYB–NFIB gene fusion or, more rarely, an MYBL1 fusion. The true frequency and clinical significance of these alterations are still unclear. Here, we have used tissue microarrays and analyzed 391 ACCs and 647 non-ACC salivary neoplasms to study the prevalence, expression, and clinical significance of MYB/MYBL1 alterations by FISH and immunohistochemistry. Alterations of MYB or MYBL1 were found in 78% of the cases, of which 62% had MYB alterations and 16% had MYBL1 rearrangements. Overexpression of MYB/MYBL1 oncoproteins was detected in 93% of the cases. MYB split signal, seen in 39% of the cases, was specific for ACC and not encountered in non-ACC salivary tumors. Loss of the 3′-part of MYB was enriched in grade 3 tumors and was a significant independent prognostic biomarker for overall survival in multivariate analyses. 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.

Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers

“…Our findings suggest that PARK2 is also a tumor suppressor in ACC that is associated with poor prognosis in a subset of tumors. This observation is further supported by our recent study showing that losses of sequences distal to the MYB locus in 6q23.3 preferentially occur in grade 3 tumors and are associated with poor OS in ACC [24]. Integrated transcriptomic and copy number profiling revealed several previously unrecognized events associated with ACC tumorigenesis.…”

“…FISH analysis of TMAs was done to study CNAs involving 1p36 represented by the marker genes CHD5 (1p36.31; CHD5/1q44 subtelomeric deletion probe from Cytocell, Cambridge, UK), KLHDC7A (1p36.13; KLHDC7A/CEN1 probe from Abnova, Taipei, Taiwan), Novel drivers and prognostic biomarkers in adenoid cystic carcinoma 257 and PARK2 (6q26) (PARK2 FISH probe from Empire Genomics (Buffalo, NY, USA) and a subtelomeric 6qter probe from Leica Biosystems, Nussloch, Germany), as previously described [24,27]. The protocols for pretreatment, hybridization, and posthybridization washes were as recommended by the manufacturers.…”

“…In contrast to the near‐universal MYB/MYBL1 activation in ACC, the frequency of other mutations in individual genes is low [2,13,16–24]. Nonetheless, certain mutations seem to cluster in specific pathways such as NOTCH and IGF/FGF signaling as well as in genes involved in chromatin remodeling.…”

Synthetic oleanane triterpenoids suppress MYB oncogene activity and sensitize T-cell acute lymphoblastic leukemia cells to chemotherapy

“…Targeting the MYB oncogene in a clinical setting will require information about the MYB activation status. Since the mechanism of activation of MYB varies in T-ALL, analysis of the expression of MYB by RT-PCR, RNA-seq or immunohistochemistry are the preferable methods to determine whether the gene is activated or not ( 57 ). T-ALL patients with overexpression of MYB are thus candidates for MYB inhibitory treatments, whereas those with low or undetectable MYB levels are not.…”

The evolving landscape of salivary gland tumors

“…Later work demonstrated that the rearrangement facilitates interaction of the MYB promoter with super‐enhancers to drive MYB overexpression 146 . A large, multi‐institutional study recently reported alterations in the MYB locus in 62.1% of ADCC tumors, with 39.1% of all tumors harboring MYB rearrangements, 16.1% with 3′ loss of the gene, and 3.1% with a gain of an intact MYB allele 147 . High MYB protein expression can also be found among rearrangement‐negative ADCCs, 142,145,148 suggesting that alternative mechanisms of MYB overexpression likely exist.…”