title: Aberrations of MET are associated with copy number gain of EGFR and loss of PTEN and predict poor outcome in patients with salivary gland cancer.
abstract: Hepatocyte growth factor receptor (MET) is a key driver of oncogenic transformation. Copy number gain and amplification of MET positively enhance tumour growth, invasiveness and metastasis in different cancer types. In the present study, 266 carcinomas of the major and minor salivary glands were investigated for genomic MET status by fluorescence in situ hybridization and for protein expression by immunohistochemistry. Results were matched with clinicopathological parameters, long-term survival and the status of epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN). Low polysomy (n = 42), high polysomy (n = 27), amplification (n = 2) and deletion (n = 18) were found as aberrations of genomic MET in certain subtypes. MET aberrations were associated with increased patient age (>70 years, p = 0.003), male gender (p = 0.01), increased tumour size (p = 0.002), lymph node metastases (p < 0.001), high-grade malignancy (p < 0.001) and unfavourable overall survival (p < 0.001). Both copy number gain (p < 0.001) and deletion (p = 0.031) of MET correlated with copy number gain of EGFR. Tumours with genomic loss of PTEN (n = 48) concurrently presented aberration of genomic MET (p < 0.001). MET gene status significantly correlated with protein status (p = 0.038). In conclusion, gain but also loss of genomic MET activity correlates with aggressive tumour growth, nodal metastasis and worse overall survival in salivary gland cancer. Moreover, aberrations of MET are associated with EGFR and PTEN signalling and might possess relevance for targeted therapies of salivary gland carcinomas in the future.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany. tobias.ach@ukr.de
authors.forename: Tobias
authors.initials: T
authors.lastname: Ach
authors.forename: Katharina
authors.initials: K
authors.lastname: Zeitler
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarz-Furlan
authors.forename: Katharina
authors.initials: K
authors.lastname: Baader
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.forename: Christian
authors.initials: C
authors.lastname: Rohrmeier
authors.forename: Johannes
authors.initials: J
authors.lastname: Zenk
authors.forename: Martin
authors.initials: M
authors.lastname: Gosau
authors.forename: Torsten E
authors.initials: TE
authors.lastname: Reichert
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
authors.forename: Tobias
authors.initials: T
authors.lastname: Ettl
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000032:analysis; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012468:Salivary Gland Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human