Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer.
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.
Takahashi
T
T
National Cancer Institute, Navy Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20814.
D'Amico
D
D
Chiba
I
I
Buchhagen
D L
DL
Minna
J D
JD
D000595:Amino Acid Sequence; D001483:Base Sequence; D018288:Carcinoma, Small Cell / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005796:Genes; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53
D004273:DNA, Neoplasm; D015513:Oncogene Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004247:DNA