Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms

TLDR

Familial cancer syndromes, especially Li‑Fraumeni syndrome, illustrate how tumor suppressor genes contribute to diverse childhood and adult tumors, but the syndrome’s rarity and high mortality have limited formal linkage studies. The study aimed to identify the most plausible candidate gene—p53—and to assess the frequency of germ‑line p53 mutations in additional Li‑Fraumeni families and other cancer patients. All five analyzed Li‑Fraumeni families carried germ‑line p53 mutations, yet the mutant protein levels were insufficient to cause a trans‑dominant loss‑of‑function effect on wild‑type p53.

Abstract

Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.