title: Genomic aberrations of MDM2, MDM4, FGFR1 and FGFR3 are associated with poor outcome in patients with salivary gland cancer.
abstract: Fibroblast growth factor receptor 1 and 3 (FGFR1, FGFR3) impact on tissue homoeostasis, embryonic development and carcinogenesis. Murine double minute protein 4 (MDM4) and mouse double minute 2 homologue (MDM2) are regulators of p53-protein and may be the origin of an apoptosis overpowering cascade. A collective of 266 carcinomas of salivary glands were investigated for MDM2, MDM4, FGFR1 and FGFR3 aberrations by fluorescence in situ hybridization (FISH). The results were matched with clinicopathological parameters and with expression of PTEN and p53. MDM2 gene amplification (n = 9) and chromosomal aberrations (trisomy, n = 47; high polysomy, n = 7) are linked to high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.001), advanced tumour size (P = 0.013) and stage (P < 0.001), gender (P = 0.002) and age (P = 0.001). MDM4 gene amplification (n = 19) and chromosomal aberrations (trisomy, n = 34; high polysomy, n = 31) are correlated to high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.008), advanced tumour size (P = 0.039), stage (P = 0.004) and loss of PTEN (P < 0.001). Only, high-grade malignancy (P < 0.001), lymph node metastasis (P = 0.036) and advanced tumour stage (P = 0.025) are associated with FGFR3 amplification (n = 1) or chromosomal aberrations (low polysomy, n = 61; high polysomy, n = 55) but not with MDM4 alterations. FGFR1 amplifications (n = 5) and chromosomal aberrations (trisomy, n = 38; high polysomy, n = 30) are associated with high-grade malignancy (P < 0.001), advanced tumour size (P = 0.026) and stage (P = 0.004), gender (P = 0.016) and age (P = 0.023). Aberrations of MDM2, MDM4, FGFR1 and FGFR3 correlate with aggressive tumour growth and nodal metastasis. MDM2 (P < 0.001), MDM4 (P = 0.005) and FGFR3 (P = 0.006) alterations are associated with worse overall survival of patients with salivary gland cancer.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ach
authors.affiliation: Institute of Pathology, Kaufbeuren, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarz-Furlan
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ach
authors.affiliation: Department of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Center of Tumor Registry, University of Regensburg, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gerken
authors.affiliation: Department of Otorhinolaryngology, University of Regensburg, Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rohrmeier
authors.affiliation: Department of Otorhinolaryngology, Hospital of Augsburg, Augsburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zenk
authors.affiliation: Department of Otorhinolaryngology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Iro
authors.affiliation: Department of Gynecology and Obstetrics, University of Regensburg, Regensburg, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ettl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018797:Cell Cycle Proteins; D002648:Child; D002869:Chromosome Aberrations; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C496348:FGFR1 protein, human; C496365:FGFR3 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: FGFR1; FGFR3; MDM2; MDM4; prognosis; salivary gland cancer