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 <i>MYB-NFIB</i> gene fusion or, more rarely, an <i>MYBL1</i> 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 <i>MYB/MYBL1</i> alterations by FISH and immunohistochemistry. Alterations of <i>MYB</i> or <i>MYBL1</i> were found in 78% of the cases, of which 62% had <i>MYB</i> alterations and 16% had <i>MYBL1</i> rearrangements. Overexpression of MYB/MYBL1 oncoproteins was detected in 93% of the cases. <i>MYB</i> 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 <i>MYB</i> 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 <i>MYB</i> results from an unbalanced t(6;9) leading to an <i>MYB-NFIB</i> fusion with concomitant loss of the segment distal to the <i>MYB</i> breakpoint in 6q23.3. Our study provides new knowledge about the prevalence and clinical significance of <i>MYB/MYBL1</i> 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.