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RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis

MJAM Clausen, LJ Melchers, MF Mastik, L Slagter-Menkema, HJM Groen, BFAM van der Laan, Wim Van Criekinge UGent, Tim De Meyer UGent, Simon Denil, B van der Vegt, et al. (2016) EPIGENETICS. 11(9). p.653-663
abstract
Oral and oropharyngeal squamous cell carcinoma (OOSCC) have a low survival rate, mainly due to metastasis to the regional lymph nodes. For optimal treatment of these metastases, a neck dissection is required; however, inaccurate detection methods results in under- and over-treatment. New DNA prognostic methylation biomarkers might improve lymph node metastases detection. To identify epigenetically regulated genes associated with lymph node metastases, genome-wide methylation analysis was performed on 6 OOSCC with (pN+) and 6 OOSCC without (pN0) lymph node metastases and combined with a gene expression signature predictive for pN+ status in OOSCC. Selected genes were validated using an independent OOSCC cohort by immunohistochemistry and pyrosequencing, and on data retrieved from The Cancer Genome Atlas. A two-step statistical selection of differentially methylated sequences revealed 14 genes with increased methylation status and mRNA downregulation in pN+ OOSCC. RAB25, a known tumor suppressor gene, was the highest-ranking gene in the discovery set. In the validation sets, both RAB25 mRNA (P = 0.015) and protein levels (P = 0.012) were lower in pN+ OOSCC. RAB25 mRNA levels were negatively correlated with RAB25 methylation levels (P < 0.001) but RAB25 protein expression was not. Our data revealed that promoter methylation is a mechanism resulting in downregulation of RAB25 expression in pN+ OOSCC and decreased expression is associated with lymph node metastasis. Detection of RAB25 methylation might contribute to lymph node metastasis diagnosis and serve as a potential new therapeutic target in OOSCC.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
NECK-CANCER, DIFFERENTIAL EXPRESSION, PROMOTER METHYLATION, BREAST-CANCER, HEAD, GENE, IDENTIFICATION, VALIDATION, MICROARRAY, PREDICTION, DNA methylation, epigenetic regulation, head and neck cancer, metastasis, MethylCap-Seq, oral squamous cell carcinoma
journal title
EPIGENETICS
Epigenetics
volume
11
issue
9
pages
653 - 663
Web of Science type
Article
Web of Science id
000385563400003
JCR category
GENETICS & HEREDITY
JCR impact factor
4.394 (2016)
JCR rank
34/166 (2016)
JCR quartile
1 (2016)
ISSN
1559-2294
DOI
10.1080/15592294.2016.1205176
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
8516974
handle
http://hdl.handle.net/1854/LU-8516974
date created
2017-04-05 06:07:33
date last changed
2017-06-09 08:33:32
@article{8516974,
  abstract     = {Oral and oropharyngeal squamous cell carcinoma (OOSCC) have a low survival rate, mainly due to metastasis to the regional lymph nodes. For optimal treatment of these metastases, a neck dissection is required; however, inaccurate detection methods results in under- and over-treatment. New DNA prognostic methylation biomarkers might improve lymph node metastases detection. To identify epigenetically regulated genes associated with lymph node metastases, genome-wide methylation analysis was performed on 6 OOSCC with (pN+) and 6 OOSCC without (pN0) lymph node metastases and combined with a gene expression signature predictive for pN+ status in OOSCC. Selected genes were validated using an independent OOSCC cohort by immunohistochemistry and pyrosequencing, and on data retrieved from The Cancer Genome Atlas. A two-step statistical selection of differentially methylated sequences revealed 14 genes with increased methylation status and mRNA downregulation in pN+ OOSCC. RAB25, a known tumor suppressor gene, was the highest-ranking gene in the discovery set. In the validation sets, both RAB25 mRNA (P = 0.015) and protein levels (P = 0.012) were lower in pN+ OOSCC. RAB25 mRNA levels were negatively correlated with RAB25 methylation levels (P {\textlangle} 0.001) but RAB25 protein expression was not. Our data revealed that promoter methylation is a mechanism resulting in downregulation of RAB25 expression in pN+ OOSCC and decreased expression is associated with lymph node metastasis. Detection of RAB25 methylation might contribute to lymph node metastasis diagnosis and serve as a potential new therapeutic target in OOSCC.},
  author       = {Clausen, MJAM and Melchers, LJ and Mastik, MF and Slagter-Menkema, L and Groen, HJM and van der Laan, BFAM and Van Criekinge, Wim and De Meyer, Tim and Denil, Simon and van der Vegt, B and Wisman, GBA and Roodenburg, JLN and Schuuring, E},
  issn         = {1559-2294},
  journal      = {EPIGENETICS},
  keyword      = {NECK-CANCER,DIFFERENTIAL EXPRESSION,PROMOTER METHYLATION,BREAST-CANCER,HEAD,GENE,IDENTIFICATION,VALIDATION,MICROARRAY,PREDICTION,DNA methylation,epigenetic regulation,head and neck cancer,metastasis,MethylCap-Seq,oral squamous cell carcinoma},
  language     = {eng},
  number       = {9},
  pages        = {653--663},
  title        = {RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis},
  url          = {http://dx.doi.org/10.1080/15592294.2016.1205176},
  volume       = {11},
  year         = {2016},
}

Chicago
Clausen, MJAM, LJ Melchers, MF Mastik, L Slagter-Menkema, HJM Groen, BFAM van der Laan, Wim Van Criekinge, et al. 2016. “RAB25 Expression Is Epigenetically Downregulated in Oral and Oropharyngeal Squamous Cell Carcinoma with Lymph Node Metastasis.” Epigenetics 11 (9): 653–663.
APA
Clausen, M., Melchers, L., Mastik, M., Slagter-Menkema, L., Groen, H., van der Laan, B., Van Criekinge, W., et al. (2016). RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis. EPIGENETICS, 11(9), 653–663.
Vancouver
1.
Clausen M, Melchers L, Mastik M, Slagter-Menkema L, Groen H, van der Laan B, et al. RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis. EPIGENETICS. 2016;11(9):653–63.
MLA
Clausen, MJAM, LJ Melchers, MF Mastik, et al. “RAB25 Expression Is Epigenetically Downregulated in Oral and Oropharyngeal Squamous Cell Carcinoma with Lymph Node Metastasis.” EPIGENETICS 11.9 (2016): 653–663. Print.