PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice Academic Article uri icon

Overview

MeSH Major

  • Adenomatous Polyposis Coli
  • Colorectal Neoplasms
  • Gene Deletion
  • Gene Dosage
  • Genes, APC
  • Ubiquitin-Protein Ligases

abstract

  • In 100 primary colorectal carcinomas, we demonstrate by array comparative genomic hybridization (aCGH) that 33% show DNA copy number (DCN) loss involving PARK2, the gene encoding PARKIN, the E3 ubiquitin ligase whose deficiency is responsible for a form of autosomal recessive juvenile parkinsonism. PARK2 is located on chromosome 6 (at 6q25-27), a chromosome with one of the lowest overall frequencies of DNA copy number alterations recorded in colorectal cancers. The PARK2 deletions are mostly focal (31% approximately 0.5 Mb on average), heterozygous, and show maximum incidence in exons 3 and 4. As PARK2 lies within FRA6E, a large common fragile site, it has been argued that the observed DCN losses in PARK2 in cancer may represent merely the result of enforced replication of locally vulnerable DNA. However, we show that deficiency in expression of PARK2 is significantly associated with adenomatous polyposis coli (APC) deficiency in human colorectal cancer. Evidence of some PARK2 mutations and promoter hypermethylation is described. PARK2 overexpression inhibits cell proliferation in vitro. Moreover, interbreeding of Park2 heterozygous knockout mice with Apc(Min) mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity. We conclude that PARK2 is a tumor suppressor gene whose haploinsufficiency cooperates with mutant APC in colorectal carcinogenesis.

publication date

  • August 24, 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2930574

Digital Object Identifier (DOI)

  • 10.1073/pnas.1009941107

PubMed ID

  • 20696900

Additional Document Info

start page

  • 15145

end page

  • 50

volume

  • 107

number

  • 34