Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers

Germ-line p53 mutations are associated with dominantly inherited Li-Fraumen i syndrome (LFS), which features early-onset sarcomas of bone and soft tiss ues, carcinomas of the breast and adrenal cortex, brain tumors, and acute l eukemias. However, carriers of germ-line p53 mutations may also be at incre ased risk of other cancers. To clarify the tumor spectrum associated with i nherited p53 mutations, we examined cancer occurrences among our series of 45 families, plus 140 other affected cases and kindreds reported in the lit erature. The analyses included all cancers in patients with a germ-line p53 mutation and their first-degree relatives with nearly 50% likelihood of be ing a carrier. Data were abstracted on tumor types and ages at diagnosis in eligible family members, and duplicate reports were excluded. Among 738 ev aluable cancers, 569 (77%) were the six tumor types (breast and adrenocorti cal carcinomas, sarcomas of the bone and soft tissues, brain tumors, and le ukemias) associated with LFS, The remaining 169 (23%) cancers included dive rse carcinomas of the lung and gastrointestinal tract, lymphomas, and other neoplasms that occurred at much earlier ages than expected in the general population. Unusually early ages at diagnosis are characteristic of heredit ary cancers and suggest that carriers of germ-line p53 mutations are at inc reased risk of a wide range of neoplasms. Future studies addressing age-spe cific penetrance and site-specific cancer risks can increase the utility of LFS as a model for understanding the role of p53 alterations in carcinogen esis and for designing diagnostic and preventive interventions for the broa d array of neoplasms in this syndrome.