Editors' ChoiceGenetics and Cancer

Where to PARK?

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Science Translational Medicine  16 Dec 2009:
Vol. 1, Issue 11, pp. 11ec41
DOI: 10.1126/scitranslmed.3000710

Mutations in PARK2 have been linked to the familial form of Parkinson’s disease (PD), yet how PARK2 changes leads to PD is not entirely clear. Now, Veeriah and colleagues show that in addition to its role in PD, PARK2 may be a tumor suppressor. Chromosomal region 6q25.2-27 harbors PARK2 and is frequently deleted in individuals with brain, colon, or lung cancers. By using comparative genome hybridization of 216 glioblastoma (GBM) and 98 colon cancer samples, the authors demonstrate that 85% of GBM and 100% of colon cancers with loss of genetic material at 6q showed loss of PARK2 protein.

Exome sequencing of PARK2 in 242 human cancers revealed somatic mutations that occur in the same domains as the germline PD mutations. Interestingly, these alterations were mainly heterozygous, implicating PARK2 as a haploinsufficient tumor suppressor. Reconstitution of cancer cell lines that lack PARK2 with normal PARK2 sequences inhibited colony formation and decreased tumor growth in mouse cancer models, whereas reconstitution with the cancer-specific PARK2 mutants did not. In cells, cancer-specific PARK2 mutants abrogated the normal ubiquitin E3 ligase function of PARK2 and resulted in impaired mitosis, establishing a possible mechanism for the loss-of-function mutations.

These results highlight cell-specific contexts of somatically acquired mutations and their role in complex diseases and may offer potential targets for customized therapeutic intervention.

S. Veeriah et al., Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat. Gen. 29 November 2009 (10.1038/ng.491). [Abstract]

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