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Updated: Jul 3, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Tumorigenesis and neurodegeneration: two sides of the same coin?
1Department of Pathology, Massachusetts General Hospital, Gray-Jackson 249, MGH, 55 Fruit St Boston, MA 02114-2696, USA. jstaropoli@partners.org
Abstract:
Dysregulation of genes that control cell-cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post-mitotic neurons under certain conditions. The gene for ataxia-telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss-of-function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss-of-function mutations in which account for about half of cases of early-onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re-expression sensitizes derivative cell lines to inhibitors of cell-cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long-held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders.
Insights
Gene dysregulation impacts both cancer and neurodegeneration. Defects in cell-cycle control and DNA repair, seen in ataxia-telangiectasia mutated (ATM) and parkin mutations, link these diseases, offering new therapeutic avenues.
Area of Science:
- Genetics
- Neuroscience
- Oncology
Background:
- Cell-cycle and DNA repair gene dysregulation is key in cancer.
- These genetic defects also contribute to neurodegenerative conditions.
- The dual role of genes like ATM and parkin highlights this overlap.
Purpose of the Study:
- To explore the shared molecular pathways between cancer and neurodegeneration.
- To investigate how genes controlling cell-cycle progression and DNA repair influence both disease types.
- To identify potential therapeutic strategies targeting these common pathways.
Main Methods:
- Review of genetic studies on ataxia-telangiectasia mutated (ATM), amyloid precursor protein, and parkin.
- Analysis of gene function in tumorigenesis and neuronal degeneration.
- Examination of gene expression and mutation data in cancer and neurological disorders.
Main Results:
- Loss-of-function mutations in ATM cause cerebellar degeneration and increase cancer risk.
- Amyloid precursor protein dosage in Down syndrome is linked to Alzheimer-type dementia and leukemia.
- Parkin, implicated in Parkinson's disease, acts as a tumor suppressor, with its loss associated with various cancers.
Conclusions:
- Shared molecular pathways link cancer and neurodegeneration, challenging traditional views of cell differentiation.
- Understanding these overlaps can lead to novel therapeutic approaches for both cancer and neurological disorders.
- Genes like ATM and parkin exemplify the intricate relationship between tumorigenesis and neuronal health.
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