title: Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity.
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.
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.|Department of Pathology, University Hospital of Muenster, Muenster, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Grünewald
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vollbrecht
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Meinrath
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Cologne, Germany.
authors.forename: Moritz F
authors.initials: MF
authors.lastname: Meyer
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Drebber
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Quaas
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Cologne, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Beutner
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Cologne, Germany.
authors.forename: Karl-Bernd
authors.initials: KB
authors.lastname: Hüttenbrink
authors.affiliation: Department of Pathology, University Hospital of Muenster, Muenster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.|Department of Pathology, University Hospital of Muenster, Muenster, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Cologne, Germany.|Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Muenster, Muenster, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Stenner
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010307:Parotid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010641:Phenotype; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor
keywords: HRAS; PIK3CA; carcinogenesis; individualized therapy; salivary gland cancer