Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer

Takashi Takahashi, Domenico D'Amico, Itsuo Chiba, Dorothy L. Buchhagen, John D. Minna

Research output: Contribution to journalArticle

110 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)363-369
Number of pages7
JournalJournal of Clinical Investigation
Volume86
Issue number1
StatePublished - Jul 1990

Fingerprint

Point Mutation
Lung Neoplasms
RNA Splice Sites
p53 Genes
Neoplasm Metastasis
Tumor Suppressor Genes
Introns
Messenger RNA
Ribonucleases
Tumor Cell Line
DNA Sequence Analysis
Oncogenes
Immunoprecipitation
Non-Small Cell Lung Carcinoma
Colonic Neoplasms
Sequence Analysis
Complementary DNA
Bone Marrow
Breast Neoplasms
Cell Line

Keywords

  • Abnormal splicing
  • Recessive oncogene
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer. / Takahashi, Takashi; D'Amico, Domenico; Chiba, Itsuo; Buchhagen, Dorothy L.; Minna, John D.

In: Journal of Clinical Investigation, Vol. 86, No. 1, 07.1990, p. 363-369.

Research output: Contribution to journalArticle

Takahashi, Takashi ; D'Amico, Domenico ; Chiba, Itsuo ; Buchhagen, Dorothy L. ; Minna, John D. / Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer. In: Journal of Clinical Investigation. 1990 ; Vol. 86, No. 1. pp. 363-369.
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