Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer
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Updated: May 6, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
T Takahashi1, D D'Amico, I Chiba
1National Cancer Institute, Navy Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20814.
Abstract:
The p53 gene initially was thought to be an oncogene, but recent evidence suggests that wild-type p53 can function as a tumor suppressor gene in lung, colon, and breast cancer as well as less common malignancies. This study reports the first identification of intronic point mutations as a mechanism for inactivation of the p53 tumor suppressor gene. Abnormally sized p53 mRNAs found in a small cell and a non-small cell lung cancer cell line were characterized by sequence analysis of cDNA/PCR products, the RNase protection assay and immunoprecipitation. These mRNAs were found to represent aberrant splicing leading to the production of abnormal or no p53 protein. Sequence analysis of genomic DNA revealed that a point mutation at the splice acceptor site in the third intron or the splice donor site in the seventh intron accounts for the abnormal mRNA splicing. In one patient the same intronic point mutation was found in the tumor cell line derived from a bone marrow metastasis and in multiple liver metastases but not in normal DNA, indicating that it occurred as a somatic event before the development of these metastases. These findings further support the role of inactivation of the p53 gene in the pathogenesis of lung cancer and indicate the role of intronic point mutation in this process.
Insights
This study identifies intronic point mutations as a novel mechanism for inactivating the p53 tumor suppressor gene. These mutations cause aberrant splicing, leading to abnormal p53 protein and supporting its role in lung cancer development.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The p53 gene, initially considered an oncogene, is now recognized as a crucial tumor suppressor.
- Wild-type p53 plays a role in suppressing various cancers, including lung, colon, and breast malignancies.
Purpose of the Study:
- To report the first identification of intronic point mutations causing p53 tumor suppressor gene inactivation.
- To investigate the mechanism of p53 gene inactivation in lung cancer.
Main Methods:
- Characterization of abnormally sized p53 messenger RNAs (mRNAs) using sequence analysis of complementary DNA (cDNA)/polymerase chain reaction (PCR) products, RNase protection assay, and immunoprecipitation.
- Sequence analysis of genomic DNA to identify mutations.
- Analysis of tumor samples from different metastatic sites and normal DNA.
Main Results:
- Abnormal p53 mRNAs in lung cancer cell lines resulted from aberrant splicing.
- Intronic point mutations at splice acceptor (intron 3) or splice donor (intron 7) sites were identified as the cause of aberrant splicing.
- A specific intronic point mutation was found in tumor cells from multiple metastases but not in normal DNA, indicating a somatic origin before metastasis.
Conclusions:
- Intronic point mutations represent a newly identified mechanism for p53 tumor suppressor gene inactivation.
- These findings reinforce the significance of p53 gene inactivation in the pathogenesis of lung cancer.
- The study highlights the role of intronic point mutations in the process of p53 inactivation in cancer.
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