title: Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal squamous cell carcinoma.
abstract: Cellular processes like differentiation, mitotic cycle, and cell growth are regulated by tyrosine kinases with known oncogenic potential and tyrosine phosphatases that downmodulate the first. Therefore, tyrosine phosphatases are recurrent targets of gene alterations in human carcinomas. We and others suggested recently a tumor suppressor function of the PTPRD tyrosine phosphatase and reported homozygous deletions of the PTPRD locus in laryngeal squamous cell carcinoma. In this study, we investigated other gene-inactivating mechanisms potentially targeting PTPRD, including loss-of-function mutations and also epigenetic alterations like promoter DNA hypermethylation. We sequenced the PTPRD gene in eight laryngeal squamous cell carcinoma cell lines but did not identify any inactivating mutations. In contrast, by bisulfite pyrosequencing of the gene promoter region, we identified significantly higher levels of methylation (p = 0.001 and p = 0.0002, respectively) in 9/14 (64%) laryngeal squamous cell carcinoma cell lines and 37/79 (47%) of primary laryngeal squamous cell carcinoma tumors as compared to normal epithelium of the upper aerodigestive tract. There was also a strong correlation (p = 0.0001) between methylation and transcriptional silencing for the PTPRD gene observed in a cohort of 497 head and neck tumors from The Cancer Genome Atlas dataset suggesting that DNA methylation is the main mechanism of PTPRD silencing in these tumors. In summary, our data provide further evidence of the high incidence of PTPRD inactivation in laryngeal squamous cell carcinoma. We suggest that deletions and loss-of-function mutations are responsible for PTPRD loss only in a fraction of cases, whereas DNA methylation is the dominating mechanism of PTPRD inactivation.
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Szaumkessel
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Wojciechowska
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Janiszewska
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Zemke
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Byzia
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kiwerska
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kostrzewska-Poczekaj
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Ustaszewski
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Jarmuz-Szymczak
authors.affiliation: 2 Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Hospital and University of Turku, Turku, Finland.|3 Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.affiliation: 4 Department of Otolaryngology and Laryngological Oncology, K. Marcinkowski University of Medical Sciences, Poznan, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wierzbicka
authors.affiliation: 4 Department of Otolaryngology and Laryngological Oncology, K. Marcinkowski University of Medical Sciences, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Bartochowska
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.|5 Department of Phoniatrics and Audiology, K. Marcinkowski University of Medical Sciences, Poznan, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szyfter
authors.affiliation: 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.|4 Department of Otolaryngology and Laryngological Oncology, K. Marcinkowski University of Medical Sciences, Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Giefing
mesh_terms: D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D009092:Mucous Membrane / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: PTPRD; bisulfite pyrosequencing; cell lines; epigenetics; head and neck cancer; laryngeal cancer; microRNA; mutation screen; tumor suppressor gene