Advertisement

Head and Neck Pathology

, Volume 7, Supplement 1, pp 12–19 | Cite as

Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

  • Göran StenmanEmail author
Invited Review: An Update on Salivary Gland Pathology

Abstract

Salivary gland tumors constitute a heterogeneous group of uncommon diseases that pose significant diagnostic and therapeutic challenges. However, the recent discovery of a translocation-generated gene fusion network in salivary gland carcinomas as well in benign salivary gland tumors opens up new avenues for improved diagnosis, prognostication, and development of specific targeted therapies. The gene fusions encode novel fusion oncoproteins or ectopically expressed normal or truncated oncoproteins. The major targets of the translocations are transcriptional coactivators, tyrosine kinase receptors, and transcription factors involved in growth factor signaling and cell cycle regulation. Notably, several of these targets or pathways activated by these targets are druggable. Examples of clinically significant gene fusions in salivary gland cancers are the MYB–NFIB fusion specific for adenoid cystic carcinoma, the CRTC1–MAML2 fusion typical of low/intermediate-grade mucoepidermoid carcinoma, and the recently identified ETV6–NTRK3 fusion in mammary analogue secretory carcinoma. Similarly, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas. Continued studies of the molecular consequences of these fusion oncoproteins and their down-stream targets will ultimately lead to the identification of novel driver genes in salivary gland neoplasms and will also form the basis for the development of new therapeutic strategies for salivary gland cancers and, perhaps, other neoplasms.

Keywords

Fusion oncogenes Salivary gland neoplasms Adenoid cystic carcinoma Mucoepidermoid carcinoma Biomarker Targeted therapy MYB–NFIB CRTC1–MAML2 ETV6–NTRK3 

Notes

Acknowledgments

I thank Marta Persson for excellent help with the illustrations. Work presented in this review was supported by the Swedish Cancer Society, IngaBritt and Arne Lundberg Research Foundation, the Adenoid Cystic Carcinoma Research Foundation, and BioCARE—a National Strategic Cancer Research program at University of Gothenburg.

References

  1. 1.
    Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7:233–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Mitelman F, Johansson B, Mertens F, editors. Mitelman database of chromosome aberrations and gene fusions in cancer: http://cgap.nci.nih.gov/Chromosomes/Mitelman, 2013.
  3. 3.
    Asp J, Persson F, Kost-Alimova M, Stenman G. CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas. Genes Chromosomes Cancer. 2006;45:820–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, Menon A, Jing X, Cao Q, Han B, Yu J, Wang L, Montie JE, Rubin MA, Pienta KJ, Roulston D, Shah RB, Varambally S, Mehra R, Chinnaiyan AM. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007;448:595–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Persson F, Winnes M, Andrén Y, Wedell B, Dahlenfors R, Asp J, Mark J, Enlund F, Stenman G. High-resolution array CGH analysis of salivary gland tumors reveals fusion and amplification of the FGFR1 and PLAG1 genes in ring chromosomes. Oncogene. 2008;27:3072–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Persson F, Andrén Y, Winnes M, Wedell B, Nordkvist A, Gudnadottir G, Dahlenfors R, Sjögren H, Mark J, Stenman G. High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosomes Cancer. 2009;48:69–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Stenman G, Andersson MK, Andrén Y. New tricks from an old oncogene: gene fusions and copy number alterations of MYB in human cancer. Cell Cycle. 2010;9:2986–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Persson M, Andrén Y, Moskaluk CA, Frierson HF Jr, Cooke SL, Futreal PA, Kling T, Nelander S, Nordkvist A, Persson F, Stenman G. Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma. Genes Chromosomes Cancer. 2012;51:805–17.PubMedCrossRefGoogle Scholar
  10. 10.
    Li Z, Tognon CE, Godinho FJ, Yasaitis L, Hock H, Herschkowitz JI, Lannon CL, Cho E, Kim SJ, Bronson RT, Perou CM, Sorensen PH, Orkin SH. ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex. Cancer Cell. 2007;12:542–58.PubMedCrossRefGoogle Scholar
  11. 11.
    Stenman G. Fusion oncogenes and tumor type specificity—insights from salivary gland tumors. Semin Cancer Biol. 2005;15:224–35.PubMedCrossRefGoogle Scholar
  12. 12.
    Åman P. Fusion oncogenes in tumor development. Semin Cancer Biol. 2005;15:236–43.PubMedCrossRefGoogle Scholar
  13. 13.
    Helman LJ, Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer. 2003;3:685–94.PubMedCrossRefGoogle Scholar
  14. 14.
    Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood. 2008;112:4808–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World health organization classification of tumours. Pathology and genetics of head and neck tumours. Lyon: IARC Press; 2005. Pp. 209–74.Google Scholar
  16. 16.
    Nordkvist A, Mark J, Gustafsson H, Bang G, Stenman G. Non-random chromosome rearrangements in adenoid cystic carcinoma of the salivary glands. Genes Chromosomes Cancer. 1994;1994(10):115–21.CrossRefGoogle Scholar
  17. 17.
    Persson M, Andrén Y, Mark J, Horlings HM, Persson F, Stenman G. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci USA. 2009;106:18740–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Oh IH, Reddy EP. The myb gene family in cell growth, differentiation and apoptosis. Oncogene. 1999;18:3017–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Ramsay RG, Gonda TJ. MYB function in normal and cancer cells. Nat Rev Cancer. 2008;8:523–34.PubMedCrossRefGoogle Scholar
  20. 20.
    Mitani Y, Li J, Rao PH, Zhao YJ, Bell D, Lippman SM, Weber RS, Caulin C, El-Naggar AK. Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: incidence, variability, and clinicopathologic significance. Clin Cancer Res. 2010;16:4722–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Mitani Y, Rao PH, Futreal PA, Roberts DB, Stephens PI, Zhao YI, Zhang L, Mitani M, Weber RS, Lippman SM, Caulin C, El-Naggar AK. 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. Clin Cancer Res. 2011;17:7003–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM, Dik WA, Langerak AW, Montpellier B, Nadel B, Walrafen P, Delattre O, Aurias A, Leblanc T, Dombret H, Gewirtz AM, Baruchel A, Sigaux F, Soulier J. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood. 2007;110:1251–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Brill LB, Kanner WA, Fehr A, Andrén Y, Moskaluk CA, Löning T, Stenman G, Frierson HF Jr. Analysis of MYB Expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms. Mod Pathol. 2011;24:1169–76.PubMedCrossRefGoogle Scholar
  24. 24.
    West RB, Kong C, Clarke N, Gilks T, Lipsick JS, Cao H, Kwok S, Montgomery KD, Varma S, Le QT. MYB expression and translocation in adenoid cystic carcinoma and other salivary gland tumors with clinicopathological correlation. Am J Surg Pathol. 2011;35:92–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Fehr A, Kovács A, Löning T, Frierson H Jr, van den Oord J, Stenman G. The MYB-NFIB gene fusion—a novel genetic link between adenoid cystic carcinoma and dermal cylindroma. J Pathol. 2011;224:322–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Behboudi A, Winnes M, Gorunova L, van den Oord JJ, Mertens F, Enlund F, Stenman G. Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)-associated TORC1-MAML2 gene fusion. Genes Chromosomes Cancer. 2005;43:202–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Möller E, Stenman G, Mandahl N, Hamberg H, Mölne L, van den Oord JJ, Brosjö O, Mertens F, Panagopoulos I. POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. J Pathol. 2008;215:78–86.PubMedCrossRefGoogle Scholar
  28. 28.
    Winnes M, Mölne L, Suurküla M, Andrén Y, Persson F, Enlund F, Stenman G. Frequent fusion of the CRTC1 and MAML2 genes in clear cell variants of cutaneous hidradenomas. Genes Chromosomes Cancer. 2007;46:559–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Behboudi A, Enlund F, Winnes M, Andrén Y, Nordkvist A, Leivo I, Flaberg E, Szekely L, Mäkitie A, Grenman R, Mark J, Stenman G. Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer. 2006;45:470–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Nordkvist A, Gustafsson H, Juberg-Ode M, Stenman G. Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma. Cancer Genet Cytogenet. 1994;74:77–83.PubMedCrossRefGoogle Scholar
  31. 31.
    Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O’Neil K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet. 2003;33:208–13.PubMedCrossRefGoogle Scholar
  32. 32.
    Enlund F, Behboudi A, Andren Y, Öberg C, Lendahl U, Mark J, Stenman G. Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin’s tumors. Exp Cell Res. 2004;292:21–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Tirado Y, Williams MD, Hanna EY, Kaye FJ, Batsakis JG, El-Naggar AK. CRTC1/MAML2 fusion transcript in high-grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin′s tumors: implications for histogenesis and biologic behavior. Genes Chromosomes Cancer. 2007;46:708–15.PubMedCrossRefGoogle Scholar
  34. 34.
    Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia L, Hogenesch JB, Montminy M. TORCs: transducers of regulated CREB activity. Mol Cell. 2003;12:413–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Iourgenko V, Zhang W, Mickanin C, Daly I, Jiang C, Hexham JM, Orth AP, Miraglia L, Meltzer J, Garza D, Chirn GW, McWhinnie E, Cohen D, Skelton J, Terry R, Yu Y, Bodian D, Buxton FP, Zhu J, Song C, Labow MA. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc Natl Acad Sci USA. 2003;100:12147–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M. Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling. J Biol Chem. 2002;277:50612–20.PubMedCrossRefGoogle Scholar
  37. 37.
    Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol Cell Biol. 2002;22:7688–700.PubMedCrossRefGoogle Scholar
  38. 38.
    Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD. Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation. EMBO J. 2005;24:2391–402.PubMedCrossRefGoogle Scholar
  39. 39.
    Coxon A, Rozenblum E, Park YS, Joshi N, Tsurutani J, Dennis PA, Kirsch IR, Kaye FJ. Mect1-Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes. Cancer Res. 2005;65:7137–44.PubMedCrossRefGoogle Scholar
  40. 40.
    Jee KJ, Persson M, Heikinheimo K, Passador-Santos F, Aro K, Knuutila S, Odell EW, Mäkitie A, Sundelin K, Stenman G, Leivo I. Genomic profiles and CRTC1-MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma. Mod Pathol. 2012; Sep 28:154. doi: 10.1038/modpathol.
  41. 41.
    Winnes M, Enlund F, Mark J, Stenman G. The MECT1-MAML2 gene fusion and benign Warthin′s tumour: is the MECT1-MAML2 gene fusion specific to mucoepidermoid carcinoma? J Mol Diagn. 2006;8:394–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Fehr A, Röser K, Belge G, Löning T, Bullerdiek J. A closer look at Warthin tumors and the t(11;19). Cancer Genet Cytogenet. 2008;180:135–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Yamaguchi S, Yamazaki Y, Ishikawa Y, Kawaguchi N, Mukai H, Nakamura T. EWSR1 is fused to POU5F1 in a bone tumour with translocation t(6;22)(p21;q12). Genes Chromosomes Cancer. 2005;43:217–22.PubMedCrossRefGoogle Scholar
  44. 44.
    Antonescu CR, Zhang L, Chang NE, Pawel BR, Travis W, Katabi N, Edelman M, Rosenberg AE, Nielsen GP, Dal Cin P, Fletcher CD. EWSR1-ATF1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosomes Cancer. 2010;49:1114–24.PubMedCrossRefGoogle Scholar
  45. 45.
    Antonescu CR, Katabi N, Zhang L, Sung YS, Seethala RR, Jordan RC, Perez-Ordoñez B, Have C, Asa SL, Leong IT, Bradley G, Klieb H, Weinreb I. EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing cler-cell sarcoma of salivary gland. Genes Chromosomes Cancer. 2011;50:559–70.PubMedCrossRefGoogle Scholar
  46. 46.
    Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993;4:341–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Rossi S, Szuhai K, Ijszenga M, Tanke HJ, Zanatta L, Sciot R, Fletcher CD. Dei Tos AP, Hogendoorn PC. EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin Cancer Res. 2007;13:7322–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Flucke U, Mentzel T, Verdijk MA, Slootweg PJ, Creytens DH, Suurmeijer AJ, Tops BB. EWSR1-ATF1 chimeric transcript in a myoepithelial tumor of soft tissue: a case report. Hum Pathol. 2012;43:764–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Skálová A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, Starek I, Geierova M, Simpson RH, Passador-Santos F, Ryska A, Leivo I, Kinkor Z, Michal M. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34:599–608.PubMedGoogle Scholar
  50. 50.
    Fehr A, Löning T, Stenman G. Mammary analogue secretory carcinoma of the salivary glands with ETV6-NTRK3 gene fusion. Am J Surg Pathol. 2011;35:1600–2.PubMedCrossRefGoogle Scholar
  51. 51.
    Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2:367–76.PubMedCrossRefGoogle Scholar
  52. 52.
    Lannon CL, Sorensen PH. ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin Cancer Biol. 2005;15:215–23.PubMedCrossRefGoogle Scholar
  53. 53.
    Wai DH, Knezevich SR, Lucas T, Jansen B, Kay RJ, Sorensen PH. The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene. 2000;19:906–15.PubMedCrossRefGoogle Scholar
  54. 54.
    Kazakov DV, Hantschke M, Vanecek T, Kacerovska D, Michal M. Mammary-type secretory carcinoma of the skin. Am J Surg Pathol. 2010;34:1226–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Kas K, Voz ML, Röijer E, Åström AK, Meyen E, Stenman G, Van de Ven WJ. Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nat Genet. 1997;15:170–4.PubMedCrossRefGoogle Scholar
  56. 56.
    Geurts JM, Schoenmakers EF, Röijer E, Åström AK, Stenman G, van de Ven WJ. Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas. Oncogene. 1998;16:865–72.PubMedCrossRefGoogle Scholar
  57. 57.
    Voz ML, Mathys J, Hensen K, Pendeville H, Van Valckenborgh I, Van Huffel C, Chavez M, Van Damme B, De Moor B, Moreau Y, Van de Ven WJ. Microarray screening for target genes of the proto-oncogene PLAG1. Oncogene. 2004;23:179–91.PubMedCrossRefGoogle Scholar
  58. 58.
    Tessari MA, Gostissa M, Altamura S, Sgarra R, Rustighi A, Salvagno C, Caretti G, Imbriano C, Mantovani R, Del Sal G, Giancotti V, Manfioletti G. Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2. Mol Cell Biol. 2003;23:9104–16.PubMedCrossRefGoogle Scholar
  59. 59.
    De Martino I, Visone R, Wierinckx A, Palmieri D, Ferraro A, Cappabianca P, Chiappetta G, Forzati F, Lombardi G, Colao A, Trouillas J, Fedele M, Fusco A. HMGA proteins up-regulate CCNB2 gene in mouse and human pituitary adenomas. Cancer Res. 2009;69:1844–50.PubMedCrossRefGoogle Scholar
  60. 60.
    Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science. 2007;315:1576–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Bell D, N Myers J, Rao PH, El-Naggar AK. t(3;8) as the sole chromosomal abnormality in a myoepithelial carcinoma ex pleomorphic adenoma: a putative progression event. Head Neck. 2012; Jan 27. doi: 10.1002/hed.22926. .

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Pathology, Sahlgrenska Cancer CenterUniversity of GothenburgGöteborgSweden

Personalised recommendations