Analysis Of Myb Oncogene In Transformed Adenoid Cystic Carcinomas Reveals Distinct Pathways Of Tumor Progression

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.946692702Cheuk, W., Chan, J.K., Ngan, R.K., Dedifferentiation in adenoid cystic carcinoma of salivary gland: An uncommon complication associated with an accelerated clinical course (1999) Am J Surg Pathol, 23, pp. 465-472Moles, M.A., Avila, I.R., Archilla, A.R., Dedifferentiation occurring in adenoid cystic carcinoma of the tongue (1999) Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 88, pp. 177-180Chau, Y., Hongyo, T., Aozasa, K., Dedifferentiation of adenoid cystic carcinoma: Report of a case implicating p53 gene mutation (2001) Hum Pathol, 32, pp. 1403-1407Nagao, T., Gaffey, T.A., Serizawa, H., Dedifferentiated adenoid cystic carcinoma: A clinicopathologic study of 6 cases (2003) Mod Pathol, 16, pp. 1265-1272Ide, F., Mishima, K., Saito, I., Small foci of high-grade carcinoma cells in adenoid cystic carcinoma represent an incipient phase of dedifferentiation (2003) Histopathology, 43, pp. 604-606Brackrock, S., Krüll, A., Röser, K., Neutron therapy, prognostic factors and dedifferentiation of adenoid cystic carcinomas (ACC) of salivary glands (2005) Anticancer Res, 25, pp. 1321-1326Hayashido, Y., Yoshioka, H., Tanaka, N., Dedifferentiation in adenoid cystic carcinoma of submaxillary gland: A case of report (2005) Oral Oncol Extra, 41, pp. 84-88Sato, K., Ueda, Y., Sakurai, A., Adenoid cystic carcinoma of the maxillary sinus with gradual histologic transformation to high- grade adenocarcinoma: A comparative report with dedifferentiated carcinoma (2006) Virchows Archiv, 448, pp. 204-208Seethala, R.R., Hunt, J.L., Baloch, Z.W., Adenoid cystic carcinoma with high-grade transformation: A report of 11 cases and a review of the literature (2007) Am J Surg Pathol, 31, pp. 1683-1694Skálová, A., Sima, R., Vanecek, T., Acinic cell carcinoma with highgrade transformation: A report of 9 cases with immunohistochemical study and analysis of TP53 and HER-2/neu genes (2009) Am J Surg Pathol, 33, pp. 1137-1145Roy, P., Bullock, M.J., Perez-Ordoñez, B., Epithelial-myoepithelial carcinoma with high grade transformation (2010) Am J Surg Pathol, 34, pp. 1258-1265Costa, A.F., Altemani, A., Hermsen, M., Current concepts on dedifferentiation/ high-grade transformation in salivary gland tumors (2011) Patholog Res Int, 17, pp. 1-9Nagao, T., Dedifferentiation and high-grade transformation in salivary gland carcinomas (2013) Head Neck Pathol, 7 (SUPPL. 1), pp. S37-S47Bonfitto, V.L., Demasi, A.P., Costa, A.F., High-grade transformation of adenoid cystic carcinomas: A study of the expression of GLUT1 glucose transporter and of mitochondrial antigen (2010) J Clin Pathol, 63, pp. 615-619Costa, A.F., Altemani, A., Vékony, H., Genetic profile of adenoid cystic carcinomas (ACC) with high-grade transformation versus solid type (2011) Cell Oncol, 34, pp. 369-379El-Naggar, A.K., Huvos, A.G., Adenoid Cystic Carcinoma, pp. 2005221-2005222. , Barnes L, Evenson JW, Reichart P, Sidransky D (eds) World Health Organization Classification of Head and Neck Tumours, LyonSeethala, R.R., Cieply, K., Barnes, E.L., Progressive genetic alterations of adenoid cystic carcinoma with high-grade transformation (2011) Arch Pathol Lab Med, 135, pp. 123-130Ho, A.S., Kannan, K., Roy, D.M., The mutational landscape of adenoid cystic carcinoma (2013) Nat Genet, 45, pp. 791-798Stephens, P.J., Davies, H.R., Mitani, Y., Whole exoma sequencing of adenoid cystic carcinoma (2013) J Clin Invest, 123, pp. 2965-2968Frierson Jr., H.F., Moskaluk, C.A., Mutation signature of adenoid cystic carcinoma: Evidence for transcriptional and epigenetic reprogramming (2013) J Clin Invest, 123, pp. 2783-2785Persson, M., Andrén, Y., Mark, J., Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck (2009) Proc Natl Acad Sci USA, 106, pp. 18740-18744Mitani, Y., Li, J., Rao, P.H., Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability, and clinicopathologic significance (2010) Clin Cancer Res, 16, pp. 4722-4731West, R.B., Kong, C., Clarke, N., MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinicopathologic correlation (2011) Am J Surg Pathol, 35, pp. 92-99Fehr, A., Kovács, A., Löning, T., The MYB-NFIB gene fusion-A novel genetic link between adenoid cystic carcinoma and dermal cylindroma (2011) J Pathol, 224, pp. 322-327Brill II, L.B., Kanner, W.A., Fehr, A., Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms (2011) Mod Pathol, 24, pp. 1169-1176Szanto, M.A., Luna, M.E., Tortoledo, M.E., Histologic grading of adenoid cystic carcinoma of the salivary glands (1984) Cancer, 54, pp. 1062-1069Wenning, B.M., Neoplasmas of the Salivary Glands, pp. 628-631. , Wening BM Heffess CS) (eds Atlas of head and neck pathology China 2008Prince, M.E., Ubell, M.L., Castro, J., Tissue-preserving approach to extracting DNA from paraffin-embedded specimens using tissue microarray technology (2007) Head Neck, 29, pp. 465-471Buffart, T.E., Israelli, D., Tijssen, M., Across array comparative genomic hybridization: A strategy to reduce reference channel hybridizations (2008) Genes Chromosomes Cancer, 47, pp. 994-1004Helczynska, K., Kronblad, A., Jögi, A., Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ (2003) Cancer Res, 63, pp. 1441-1444Coindre, J.M., Pédeutour, F., Aurias, A., Well-differentiated and dedifferentiated liposarcomas (2010) Virchows Arch, 456, pp. 167-179Jögi, A., Oøra, I., Nilsson, H., Hypoxia-induced differentiation in neuroblastoma cells (2003) Cancer Lett, 197, pp. 145-150Jopling, C., Boue, S., Izpisua Belmonte, J.C., Dedifferentiation, transdifferentation and reprogramming: Three routes to regeneration (2011) Nat Rev Mol Cell Biol, 12, pp. 79-89Vécony, H., Leemans, C.R., Ylstra, B., Salivary gland carcinosarcoma: Oligonucleotide array CGH reveals similar genomic profiles in epithelial and mesenchymal components (2009) Oral Oncol, 45, pp. 259-265Horvai, A.E., Devries, S., Roy, R., Similarity in genetic alterations between paired well-differentiated and dedifferentiated components of dedifferentiated liposarcoma (2009) Mod Pathol, 22, pp. 1477-1488Ricke, R.M., Van Ree, J.H., Van Deursen, J.M., Whole chromosome instability and cancer: A complex relationship (2008) Trends Genet, 24, pp. 457-466Mitani, Y., Rao, P.H., Futreal, P.A., Novel chromosomal rearrangements and break points at the t(6;9) in salivary adenoid cystic carcinoma: Association with MYB-NFIB chimeric fusion MYB expression, and clinical outcome (2011) Clin Cancer Res, 17, pp. 7003-7014Persson, M., Andrén, Y., Moskaluk, C.A., Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma (2012) Genes Chromosomes Cancer, 51, pp. 805-817Mukai, H.Y., Motohashi, H., Ohneda, O., Transgene insertion in proximity to the c-myb gene disrupts erythroid-megakaryocytic lineage bifurcation (2006) Mol Cell Biol, 26, pp. 7953-7965Ramsay, R.G., Gonda, T.J., MYB function in normal and cancer cells (2008) Nat Rev Cancer, 8, pp. 523-534Altemani, A., Costa, A.F., Montalli, V.A., Signet-ring cell change in adenoid cystic carcinoma: A clinicopathological and immunohistochemical study of four cases (2013) Histopathology, 62, pp. 531-54