Germline Mutations of the p53 Tumor-Suppressor Gene in Children and Young Adults with Second Malignant Neoplasms

Acquired mutations in the p53 tumor-suppressor gene have been detected in several human cancers, including colon, breast, and lung cancer. Inherited mutations (transmitted through the germline) of this gene can underlie the Li—Fraumeni syndrome, a rare familial association of breast cancer in young women, childhood sarcomas, and other malignant neoplasms. We investigated the possibility that p53 mutations in the germline are associated with second primary cancers that arise in children and young adults who would not be considered as belonging to Li—Fraumeni families. Genomic DNA was extracted from the blood leukocytes of 59 children and young adults with a second primary cancer. The polymerase chain reaction, in combination with denaturant-gel electrophoresis and sequencing, was used to identify p53 gene mutations. Mutations of p53 that changed the predicted amino acid sequence were identified in leukocyte DNA from 4 of the 59 patients (6.8 percent). In three cases, the mutations were identical to ones previously found in the p53 gene. The fourth mutation was the first germline mutation to be identified in exon 9, at codon 325. Analysis of leukocyte DNA from close relatives of three of the patients indicated that the mutations were inherited, but cancer had developed in only one parent at the start of the study. These findings identify an important subgroup of young patients with cancer who carry germline mutations in the p53 tumor-suppressor gene but whose family histories are not indicative of the Li—Fraumeni syndrome. The early detection of such mutations would be useful not only in treating these patients, but also in identifying family members who may be at high risk for the development of tumors. (N Engl J Med 1992;326: 1309–15.), THE p53 tumor-suppressor gene, located on the short arm of human chromosome 17,^{1 , 2} encodes a 53-kd nuclear phosphoprotein involved in the control of cellular proliferation.^{3 4 5 6 7} Acquired mutations in p53 are the most common tumor-specific genetic changes observed to date, having been identified in most major cancer types.^{8 , 9} In addition, germline mutations in p53 were recently identified in families with the Li—Fraumeni syndrome, a rare familial cancer syndrome characterized by an unusually high incidence of sarcomas, premenopausal breast cancers, and other diverse neoplasms, particularly brain tumors, leukemias, and adrenocortical carcinomas.^{10 11 12 13 14 15} Families with Li—Fraumeni syndrome have been described as including a proband…