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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.
PMID
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Authors

Mayor MeshTerms

Gene Silencing

Keywords

PTPRD

bisulfite pyrosequencing

cell lines

epigenetics

head and neck cancer

laryngeal cancer

microRNA

mutation screen

tumor suppressor gene

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28345455
OWN - NLM
STAT- MEDLINE
DA  - 20170327
DCOM- 20170407
LR  - 20170407
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 3
DP  - 2017 Mar
TI  - Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal
      squamous cell carcinoma.
PG  - 1010428317691427
LID - 10.1177/1010428317691427 [doi]
AB  - 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.
FAU - Szaumkessel, Marcin
AU  - Szaumkessel M
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Wojciechowska, Sonia
AU  - Wojciechowska S
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Janiszewska, Joanna
AU  - Janiszewska J
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Zemke, Natalia
AU  - Zemke N
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Byzia, Ewa
AU  - Byzia E
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Kiwerska, Katarzyna
AU  - Kiwerska K
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Kostrzewska-Poczekaj, Magdalena
AU  - Kostrzewska-Poczekaj M
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Ustaszewski, Adam
AU  - Ustaszewski A
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Jarmuz-Szymczak, Malgorzata
AU  - Jarmuz-Szymczak M
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Grenman, Reidar
AU  - Grenman R
AD  - 2 Department of Otorhinolaryngology-Head and Neck Surgery, Turku University
      Hospital and University of Turku, Turku, Finland.
AD  - 3 Department of Medical Biochemistry and Genetics, University of Turku, Turku,
      Finland.
FAU - Wierzbicka, Malgorzata
AU  - Wierzbicka M
AD  - 4 Department of Otolaryngology and Laryngological Oncology, K. Marcinkowski
      University of Medical Sciences, Poznan, Poland.
FAU - Bartochowska, Anna
AU  - Bartochowska A
AD  - 4 Department of Otolaryngology and Laryngological Oncology, K. Marcinkowski
      University of Medical Sciences, Poznan, Poland.
FAU - Szyfter, Krzysztof
AU  - Szyfter K
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
AD  - 5 Department of Phoniatrics and Audiology, K. Marcinkowski University of Medical 
      Sciences, Poznan, Poland.
FAU - Giefing, Maciej
AU  - Giefing M
AD  - 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
AD  - 4 Department of Otolaryngology and Laryngological Oncology, K. Marcinkowski
      University of Medical Sciences, Poznan, Poland.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - EC 3.1.3.48 (PTPRD protein, human)
RN  - EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 2)
RN  - Carcinoma, squamous cell of head and neck
SB  - IM
MH  - Base Sequence
MH  - Carcinoma, Squamous Cell/*genetics/pathology
MH  - Cell Line, Tumor
MH  - DNA Methylation/*genetics
MH  - Female
MH  - Gene Deletion
MH  - *Gene Silencing
MH  - Head and Neck Neoplasms/*genetics/pathology
MH  - Humans
MH  - Laryngeal Neoplasms/*genetics/pathology
MH  - Male
MH  - Mucous Membrane/cytology
MH  - Promoter Regions, Genetic/*genetics
MH  - Receptor-Like Protein Tyrosine Phosphatases, Class 2/*genetics
MH  - Sequence Analysis, DNA
OTO - NOTNLM
OT  - PTPRD
OT  - bisulfite pyrosequencing
OT  - cell lines
OT  - epigenetics
OT  - head and neck cancer
OT  - laryngeal cancer
OT  - microRNA
OT  - mutation screen
OT  - tumor suppressor gene
EDAT- 2017/03/28 06:00
MHDA- 2017/04/08 06:00
CRDT- 2017/03/28 06:00
AID - 10.1177/1010428317691427 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Mar;39(3):1010428317691427. doi: 10.1177/1010428317691427.

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