Somatic mutations of the Parkinson's disease–associated gene PARK2 in glioblastoma and other human malignancies

Abstract

Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease1, 2, 3. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.

Elevated TRAF2/6 expression in Parkinson's disease is caused by the loss of Parkin E3 ligase activity

“…However, deletion of Parkin has also been reported in human cancer tissues. 13,14 These findings are inconsistent with our first premise. To resolve these conflicting data, we proposed the hypothesis that Parkin would be linked to inflammation, which can promote cell death and can also induce cancer.…”

“…This function explains frequent Parkin mutations found in human cancers. 13,14 Because cancer cells originate from replaceable epithelial cells, chronic inflammation can trigger cell proliferation, which will contribute to the progression of the cancer. Thus, Parkindeficient cells will be more sensitive to inflammation.…”

“…Recently, based on the frequent deletion or mutation in human colon cancer, Parkin has been suggested as a haploinsufficient tumor suppressor gene. 13,14 As chronic inflammation is tightly related with colon cancer as well as PD, 15,16 we examined the biological role of Parkin in the cytokine-induced inflammation response.…”

Advancing a clinically relevant perspective of the clonal nature of cancer

“…Recent reports have identified somatic mutations of NUMB in breast carcinoma and of PARK2 in GBM, colon, and lung cancers (42,43). Thus, our detection of homozygous deletions provides evidence that their tumor suppressor function extends to PA and identifies a series of genes that are selectively disrupted in PA (e.g., SMAD2, SMAD3, JARID2) and PC (e.g., AIM1, NEDD9, FOXO3A).…”

Gene Therapy of Some Genetic Diseases by Transferring Normal Human Genomic DNA into Somatic Cells and Stem Cells from Patients

“…This possible gene therapy method also might be used to cure other diseases such as Alzheimer's disease Sherrington et al, 1995), Parkinson's disease (Terzi & Zachariou, 2008;Veeriah et al, 2010), X-chronic granulomatous disease (CGD) Kang et al, 2010), type I (insulin-dependent) (Efrat, 1998) and type II (noninsulin-dependent) (Freeman et al, 1999) diabetes.…”