PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice.
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.
Poulogiannis
George
G
Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
McIntyre
Rebecca E
RE
Dimitriadi
Maria
M
Apps
John R
JR
Wilson
Catherine H
CH
Ichimura
Koichi
K
Luo
Feijun
F
Cantley
Lewis C
LC
Wyllie
Andrew H
AH
Adams
David J
DJ
Arends
Mark J
MJ
D011125:Adenomatous Polyposis Coli / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003043:Cocarcinogenesis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D009154:Mutation; D032681:Spectral Karyotyping; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics*
D017931:DNA Primers; D004273:DNA, Neoplasm; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein