Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma

N Engl J Med. 1992 May 14;326(20):1301-8. doi: 10.1056/NEJM199205143262001.


Background: Recent studies have identified germline mutations of the p53 tumor-suppressor gene in families with the Li-Fraumeni syndrome, a rare inherited disorder characterized by a high risk of sarcomas of bone and soft tissue, breast cancer, and other tumors. In this report, we address the possibility that some sporadic sarcomas may be associated with new germline mutations of the p53 gene, which would not be manifested as familial cancer unless the patient survived to reproduce.

Methods: We studied DNA from peripheral leukocytes of 196 patients with sarcoma and from 200 controls. Of the 196 patients with sarcoma, 15 were selected because they had had multiple primary cancers or had a family history of cancer. The entire coding sequence and splice junctions of the p53 gene were analyzed for mutations.

Results: Eight germline mutations were found, three in patients with no known family history of cancer and five in patients with an unusual personal or family history of cancer. Four mutations caused amino acid substitutions, and four caused stop codons. These mutations were not present in any of the 200 controls.

Conclusions: New germline mutations of the p53 gene are rare among patients with "sporadic" sarcoma but may be common in patients with sarcoma whose background includes either multiple primary cancers or a family history of cancer. Diverse mutations of this gene were associated with an increased likelihood of cancer; hence, the entire gene should be considered a target for heritable mutation. It appears that the group of patients with cancer who carry germline mutations of the p53 gene is more diverse than is suggested by the clinical definition of the Li-Fraumeni syndrome. The identification of carriers could be of substantial clinical importance.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Base Sequence
  • Child
  • Codon
  • Cross-Sectional Studies
  • Female
  • Genes, p53*
  • Heterozygote
  • Humans
  • Infant
  • Japan / epidemiology
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Neoplastic Syndromes, Hereditary / epidemiology
  • Neoplastic Syndromes, Hereditary / genetics
  • Osteosarcoma / genetics
  • Polymorphism, Genetic
  • Sarcoma / epidemiology
  • Sarcoma / genetics*
  • United States / epidemiology


  • Codon