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Loss-of-function mutations in PPAR gamma associated with human colon cancer
P Sarraf1, E Mueller, W M Smith
1Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
The gamma isoform of the peroxisome proliferator-activated receptor, PPAR gamma, regulates adipocyte differentiation and has recently been shown to be expressed in neoplasia of the colon and other tissues. We have found four somatic PPAR gamma mutations among 55 sporadic colon cancers: one nonsense, one frameshift, and two missense mutations. Each greatly impaired the function of the protein. c.472delA results in deletion of the entire ligand binding domain. Q286P and K319X retain a total or partial ligand binding domain but lose the ability to activate transcription through a failure to bind to ligands. R288H showed a normal response to synthetic ligands but greatly decreased transcription and binding when exposed to natural ligands. These data indicate that colon cancer in humans is associated with loss-of-function mutations in PPAR gamma.
Insights
Loss-of-function mutations in peroxisome proliferator-activated receptor gamma (PPAR gamma) are associated with human colon cancer. Four distinct mutations were identified, each significantly impairing PPAR gamma
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Peroxisome proliferator-activated receptor gamma (PPAR gamma) regulates adipocyte differentiation.
- PPAR gamma is expressed in colon neoplasia.
Purpose of the Study:
- To investigate the role of PPAR gamma mutations in sporadic colon cancer.
Main Methods:
- Somatic mutation analysis of PPAR gamma in 55 sporadic colon cancer samples.
- Functional assays to assess the impact of identified mutations on PPAR gamma activity.
Main Results:
- Four somatic PPAR gamma mutations (one nonsense, one frameshift, two missense) were identified in 55 colon cancers.
- Mutations included c.472delA (deleting ligand binding domain), Q286P and K319X (impaired ligand binding and transcription activation), and R288H (decreased transcription and binding to natural ligands).
- All identified mutations significantly impaired PPAR gamma function.
Conclusions:
- Colon cancer in humans is associated with loss-of-function mutations in PPAR gamma.
- These findings highlight the importance of PPAR gamma in colon carcinogenesis.