Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression

Abstract

Adenoid cystic carcinomas can occasionally undergo dedifferentiation, a phenomenon also referred to as high-grade transformation. However, cases of adenoid cystic carcinomas have been described showing transformation to adenocarcinomas that are not poorly differentiated, indicating that high-grade transformation may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form, which may encompass a wide spectrum of carcinomas in terms of aggressiveness. The aim of this study was to gain more insight in the biology of this pathological phenomenon by means of genetic profiling of both histological components. Using microarray comparative genomic hybridization, we compared the genome-wide DNA copy-number changes of the conventional and transformed area of eight adenoid cystic carcinomas with high-grade transformation, comprising four with transformation into moderately differentiated adenocarcinomas and four into poorly differentiated carcinomas. In general, the poorly differentiated carcinoma cases showed a higher total number of copy-number changes than the moderately differentiated adenocarcinoma cases, and this correlated with a worse clinical course. Special attention was given to chromosomal translocation and protein expression of MYB, recently being considered to be an early and major oncogenic event in adenoid cystic carcinomas. Our data showed that the process of high-grade transformation is not always accompanied by an accumulation of genetic alterations; both conventional and transformed components harbored unique genetic alterations, which indicate a parallel progression. Our data further demonstrated that the MYB/NFIB translocation is not necessarily an early event or fundamental for the progression to adenoid cystic carcinoma with high-grade transformation.

Primary cutaneous adenoid cystic carcinoma with MYB aberrations: report of three cases and comprehensive review of the literature

“…The importance that MYB activation, either through gene alterations or MYB‐NFIB fusions, has in ACC oncogenesis has been underscored by recent whole‐exome sequencing studies of head and neck ACCs, which showed an otherwise ‘quiet’ mutational landscape with very few genetic aberrations. These findings indicate that activating MYB aberrations are probably driving these tumors …”

MYB expression: Potential role in separating adenoid cystic carcinoma (ACC) from pleomorphic adenoma (PA)

“…However, RT‐PCR cannot detect cases of gene fusion without transcript formation since translocation of other genetic sequences to the noncoding flanking sites of the MYB gene may lead to aberrant fusion and atypical MYB transcriptional activation . The implementation of next generation sequencing may circumvent these issues based on its ability to detect MYB and/or NFIB gene rearrangement or variant gene fusions although it may overlook cases of ACC with copy number gains or gene insertions/deletions . The availability and implementation of these studies in most laboratories may be limited by cost, increased turn‐around time, and technical challenge.…”

“…7 The implementation of next generation sequencing may circumvent these issues based on its ability to detect MYB and/or NFIB gene rearrangement or variant gene fusions although it may overlook cases of ACC with copy number gains or gene insertions/deletions. 20 The availability and implementation of these studies in most laboratories may be limited by cost, increased turn-around time, and technical challenge. Recent whole genome sequencing studies have revealed novel driver mutations involving the MYB homologue, MYBL1, identifying a novel MYBL1-NFIB fusion as a result of translocation of 8q and 9p in t(6;9)-negative and t(6;9)-positive with MYB-NFIB fusion negative ACC.…”

MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma

“…MYB is associated with the development of tumours, including leukaemia, pancreatic cancer, breast cancer and prostate cancer (16)(17)(18). However, whether MYB is associated with the development and metastasis of SACC is not clear (19).…”