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Alterations of the WNT7A gene in clear cell renal cell carcinomas

Aleksandr G Kondratov1, Sergiy M Kvasha, Liubov A Stoliar

  • 1Department of Molecular Oncogenetics, Institute of Molecular Biology and Genetics, National Academy of Science, Kyiv, Ukraine. o.g.kondratov@imbg.org.ua

Plos One
|October 12, 2012
PubMed

Insights

The WNT7A gene, a tumor suppressor, is frequently silenced by hypermethylation in clear cell renal cell carcinomas (RCC). This inactivation correlates with tumor progression and WNT7A demonstrates tumor suppressor functions in RCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • WNT7A is a known tumor suppressor gene in non-small cell lung carcinomas (NSCLC).
  • WNT gene family members are crucial in cell signaling and cancer development.
  • CpG-island hypermethylation frequently inactivates tumor suppressor genes in human cancers.

Purpose of the Study:

  • To investigate the role of WNT7A gene inactivation in clear cell renal cell carcinoma (RCC).
  • To determine the frequency and correlation of WNT7A hypermethylation with clinicopathological features in RCC.
  • To confirm the tumor suppressor function of WNT7A in RCC.

Main Methods:

  • Methyl-specific PCR (MSP) and bisulfite sequencing to detect WNT7A hypermethylation.
  • Analysis of correlations between WNT7A hypermethylation and tumor stage/Fuhrman nuclear grade.
  • 5-aza-2'-deoxycytidine treatment to restore WNT7A expression and functional assays (colony formation, proliferation) to assess tumor suppressor activity.

Main Results:

  • WNT7A hypermethylation was detected in 66% of clear cell RCCs and correlated with advanced tumor stage and higher Fuhrman nuclear grade.
  • Bisulfite sequencing confirmed intensive 5'-CpG island hypermethylation of WNT7A.
  • WNT7A gene expression was down-regulated in 88% of clear cell RCCs, with restoration observed after 5-aza-2'-deoxycytidine treatment.
  • Loss of heterozygosity (LOH) was frequent on chromosome 3p25.
  • WNT7A demonstrated tumor suppressor function in RCC cell lines.

Conclusions:

  • The WNT7A gene is frequently inactivated by genetic and epigenetic alterations in clear cell RCC.
  • WNT7A hypermethylation is a significant event in RCC pathogenesis, correlating with disease progression.
  • WNT7A acts as a tumor suppressor in clear cell renal cell carcinoma.

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