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p53 mutations in primary human lung tumors and their metastases
M B Reichel1, H Ohgaki, I Petersen
1Institute of Neuropathology, University of Zürich, Switzerland.
Abstract:
In a total of 26 primary human lung tumors and 60 metastases derived from them, exons 5-8 of the p53 tumor suppressor gene were analyzed by single-strand conformation polymorphism and subsequent direct DNA sequencing of amplified DNA. Mutational inactivation of the p53 gene was identified in four of five squamous cell carcinomas, three of nine adenocarcinomas, and two of nine small-cell carcinomas, the overall incidence being 35%. Point mutations occurred at a similar incidence in exons 5-8, with a preference for G-->T transversions. In seven of nine cases (78%), mutations were identical in the primary tumor and all of its metastases, indicating that in lung tumors, p53 mutations usually precede metastasis and that hematogenic and lymphogenic dissemination of tumor cells to other tissues is not associated with a selection against p53 inactivation. In one case, a kidney metastasis had the same mutation as the primary squamous cell carcinoma, whereas a liver metastasis had no mutation, indicating heterogeneity of the primary lung neoplasm and selective metastasis of mutated and nonmutated tumor cells to kidney and liver, respectively. Only in one liver metastasis was a mutation identified that was neither present in the primary lung tumor nor in a kidney metastasis, suggesting that occasionally p53 mutations occur after metastatic spread.
Insights
p53 gene mutations are common in lung tumors and typically occur before metastasis. These p53 alterations usually persist in metastases, indicating they are an early event in lung cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 tumor suppressor gene plays a critical role in preventing cancer.
- Understanding p53 gene mutations in lung cancer is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the incidence and timing of p53 gene mutations in primary human lung tumors and their metastases.
- To determine if p53 mutations precede or follow metastatic spread in lung cancer.
Main Methods:
- Analysis of exons 5-8 of the p53 gene using single-strand conformation polymorphism (SSCP) and direct DNA sequencing.
- Examination of 26 primary lung tumors and 60 matched metastases.
Main Results:
- p53 gene mutations were found in 35% of analyzed lung tumors, with varying incidence across different histological types (squamous cell carcinoma, adenocarcinoma, small-cell carcinoma).
- G to T transversions were the predominant mutation type.
- In 78% of cases, p53 mutations were consistent between primary tumors and metastases, suggesting mutations usually occur before metastasis.
- Tumor heterogeneity and late-onset mutations were observed in a minority of cases.
Conclusions:
- p53 gene inactivation is a frequent event in lung tumorigenesis and typically occurs early, preceding metastatic dissemination.
- The presence of p53 mutations in metastases suggests that these alterations do not hinder tumor cell spread.
- While generally an early event, p53 mutations can occasionally arise after metastatic spread, contributing to tumor heterogeneity.