Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein

T. Frebourg, J. Kassel, K. T. Lam, M. A. Gryka, N. Barbier, T. I. Andersen, A. L. Borresen, S. H. Friend

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Abstract

Germ-line mutations in the p53 tumor suppressor gene have been observed in patients with Li-Fraumeni syndrome, brain tumors, second malignancies, and breast cancers. It is unclear whether all of these mutations have inactivated p53 and thereby provide an increased risk for cancer. Therefore, it is necessary to establish the biological significance of these germ-line mutations by the functional and structural analysis of the resulting mutant p53 proteins. We analyzed the ability of seven germ-line mutant proteins observed in patients with Li-Fraumeni syndrome, second primary neoplasms, or familial breast cancer to block the growth of malignant cells and compared the structural properties of the mutant proteins to that of the wild-type protein. Six of seven missense mutations disrupted the growth inhibitory properties and structure of the wild-type protein. One germ-line mutation retained the features of the wild-type p53. Genetic analysis of the breast cancer family in which this mutation was observed indicated that this germ- line mutation was not associated with the development of cancer. These results demonstrate that germ-line p53 mutations observed in patients with Li-Fraumeni syndrome and with second malignancies have inactivated the p53 tumor suppressor gene. The inability of the germ-line p53 mutants to block the growth of malignant cells can explain why patients with these germ-line mutations have an increased risk for cancer. The observation of a functionally silent germ-line mutation indicates that, before associating a germ-line tumor suppressor gene mutation with cancer risk, it is prudent to consider its functional significance.

Original languageEnglish (US)
Pages (from-to)6413-6417
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number14
DOIs
StatePublished - Jul 31 1992

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Germ-Line Mutation
Tumor Suppressor Genes
Second Primary Neoplasms
Li-Fraumeni Syndrome
Mutant Proteins
Neoplasms
Germ Cells
Proteins
Growth
Breast Neoplasms
Genetic Suppression
Mutation
Aptitude
Missense Mutation
Brain Neoplasms
Observation

ASJC Scopus subject areas

  • General

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Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. / Frebourg, T.; Kassel, J.; Lam, K. T.; Gryka, M. A.; Barbier, N.; Andersen, T. I.; Borresen, A. L.; Friend, S. H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 14, 31.07.1992, p. 6413-6417.

Research output: Contribution to journalArticle

Frebourg, T. ; Kassel, J. ; Lam, K. T. ; Gryka, M. A. ; Barbier, N. ; Andersen, T. I. ; Borresen, A. L. ; Friend, S. H. / Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. In: Proceedings of the National Academy of Sciences of the United States of America. 1992 ; Vol. 89, No. 14. pp. 6413-6417.
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