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Published on: March 30, 2019

Expression of the p16INK4A/Cdkn2a gene is prevalently downregulated in human pheochromocytoma tumor specimens

Peter Muscarella1, Mark Bloomston, Alexander R Brewer

  • 1Department of Surgery, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.

Gene Expression
|December 30, 2008
PubMed

Insights

Reduced expression of the p16INK4A/Cdkn2a gene (p16) is common in pheochromocytomas. Inactivating genetic abnormalities, including deletions, methylation, and mutations, are the primary cause of this p16 downregulation in tumor development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hereditary syndromes are linked to pheochromocytoma.
  • Secondary molecular events in pheochromocytoma tumorigenesis are understudied.
  • The role of the p16INK4A/Cdkn2a (p16) gene in pheochromocytoma is not well understood.

Purpose of the Study:

  • To investigate the expression and molecular alterations of the p16 gene in pheochromocytoma.
  • To determine the frequency and mechanisms of p16 downregulation in pheochromocytoma development.

Main Methods:

  • Tissue microarray and immunohistochemistry were used to assess p16 expression in 31 pheochromocytoma specimens and 7 normal controls.
  • Quantitative real-time PCR, methylation-specific PCR, and direct DNA sequencing were employed to analyze genetic alterations of the p16 gene.

Main Results:

  • p16 was downregulated in 96.8% of pheochromocytoma specimens, contrasting with high expression in 71.6% of normal controls.
  • Genetic alterations, including deletions (29.0%), aberrant CpG methylation (35.5%), and a point mutation affecting CDK4-inhibitory activity, were identified in the p16 gene.
  • The overall frequency of p16 genetic alterations was 67.7%.

Conclusions:

  • Reduced p16 expression is a frequent event in human pheochromocytomas.
  • Inactivating genetic abnormalities of the p16 gene are the main drivers of its downregulation in pheochromocytoma.
  • These findings highlight the significance of p16 alterations in pheochromocytoma tumorigenesis.

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