PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice
- 9 August 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (34), 15145-15150
- https://doi.org/10.1073/pnas.1009941107
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.This publication has 50 references indexed in Scilit:
- Signatures of mutation and selection in the cancer genomeNature, 2010
- PINK1-dependent recruitment of Parkin to mitochondria in mitophagyProceedings of the National Academy of Sciences of the United States of America, 2009
- Prognostic relevance of DNA copy number changes in colorectal cancerThe Journal of Pathology, 2009
- Mutated K‐rasAsp12 promotes tumourigenesis in ApcMin mice more in the large than the small intestines, with synergistic effects between K‐ras and Wnt pathwaysInternational Journal of Experimental Pathology, 2009
- Integrative approach for prioritizing cancer genes in sporadic colon cancerGenes, Chromosomes and Cancer, 2009
- An expression module of WIPF1-coexpressed genes identifies patients with favorable prognosis in three tumor typesJournal of Molecular Medicine, 2009
- 1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomasOncogene, 2007
- Tumor immunoediting and immunosculpting pathways to cancer progressionSeminars in Cancer Biology, 2007
- A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K–Akt signallingNature, 2006
- Activation of the DNA damage checkpoint and genomic instability in human precancerous lesionsNature, 2005