Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity

Abstract

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Inga Grünewald1, 2, Claudia Vollbrecht1, Jeannine Meinrath1, Moritz F. Meyer3, Lukas C. Heukamp1, Uta Drebber1, Alexander Quaas1, Dirk Beutner3, Karl-Bernd Hüttenbrink3, Eva Wardelmann2, Wolfgang Hartmann1, 2, Reinhard Büttner1, 4, Margarete Odenthal1, 4, *, Markus Stenner3, 5, * 1Institute of Pathology, University Hospital of Cologne, Cologne, Germany 2Department of Pathology, University Hospital of Muenster, Muenster, Germany 3Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Cologne, Germany 4Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 5Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Muenster, Muenster, Germany *These authors have contributed equally to this work Correspondence to: Inga Grünewald, e-mail: inga.gruenewald@ukmuenster.de Keywords: salivary gland cancer, individualized therapy, PIK3CA, HRAS, carcinogenesis Received: January 21, 2015 Accepted: May 14, 2015 Published: May 25, 2015 ABSTRACT Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations. Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes. Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4. In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.