Low VHL mRNA expression is associated with more aggressive tumor features of papillary thyroid carcinoma

Boban Stanojevic; Vladimir Saenko; Lidija Todorovic; Nina Petrovic; Dragan Nikolic; Vladan Zivaljevic; Ivan Paunovic; Masahiro Nakashima; Shunichi Yamashita; Radan Dzodic

doi:10.1371/journal.pone.0114511

Low VHL mRNA expression is associated with more aggressive tumor features of papillary thyroid carcinoma

PLoS One. 2014 Dec 9;9(12):e114511. doi: 10.1371/journal.pone.0114511. eCollection 2014.

Authors

Affiliations

¹ Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan; Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.
² Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
³ Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.
⁴ School of Medicine, University of Belgrade, Belgrade, Serbia.
⁵ School of Medicine, University of Belgrade, Belgrade, Serbia; Center for Endocrine Surgery, Clinic for Endocrinology, Clinical Center of Serbia, Belgrade, Serbia.
⁶ School of Medicine, University of Belgrade, Belgrade, Serbia; Department of Surgical Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.

Abstract

Alterations of the von Hippel-Lindau (VHL) tumor suppressor gene can cause different hereditary tumors associated with VHL syndrome, but the potential role of the VHL gene in papillary thyroid carcinoma (PTC) has not been characterized. This study set out to investigate the relationship of VHL expression level with clinicopathological features of PTC in an ethnically and geographically homogenous group of 264 patients from Serbia, for the first time. Multivariate logistic regression analysis showed a strong correlation between low level of VHL expression and advanced clinical stage (OR = 5.78, 95% CI 3.17-10.53, P<0.0001), classical papillary morphology of the tumor (OR = 2.92, 95% CI 1.33-6.44, P = 0.008) and multifocality (OR = 1.96, 95% CI 1.06-3.62, P = 0.031). In disease-free survival analysis, low VHL expression had marginal significance (P = 0.0502 by the log-rank test) but did not appear to be an independent predictor of the risk for chance of faster recurrence in a proportion hazards model. No somatic mutations or evidence of VHL downregulation via promoter hypermethylation in PTC were found. The results indicate that the decrease of VHL expression associates with tumor progression but the mechanism of downregulation remains to be elucidated.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Carcinoma / pathology*
Carcinoma, Papillary
Child
DNA Methylation
DNA Mutational Analysis
Disease-Free Survival
Female
Gene Expression Regulation, Neoplastic
Humans
Logistic Models
Male
Middle Aged
Multivariate Analysis
RNA, Messenger / metabolism*
Thyroid Cancer, Papillary
Thyroid Neoplasms / pathology*
Von Hippel-Lindau Tumor Suppressor Protein / genetics*

Substances

RNA, Messenger
Von Hippel-Lindau Tumor Suppressor Protein
VHL protein, human

Grants and funding

This work was supported in part by Nagasaki University Global COE Program; Ministry of Education, Science and Technological Development of the Republic of Serbia, Contracts No. 173049 and 145094D. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.