Background Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by very high lifetime cancer risk and early age at diagnosis of a wide cancer spectrum. Precise estimates for first and subsequent cancers risk are lacking. Methods The NCI’s LFS Study includes families meeting diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or ≥3 cancers. We estimated cumulative risk and annual hazards for first and second cancer among TP53 mutation carriers (TP53+) using MATLAB. Results We evaluated 286 TP53+ individuals from 107 families. Cumulative cancer incidence was 50% by age 31 among TP53+ females and 46 among males, and nearly 100% by age 70 for both. Cancer risk was highest after age 20 for females, mostly due to breast cancer, while among males risk was higher in childhood and later adulthood. Among females, the cumulative incidence by age 70 for breast cancer, soft tissue sarcoma (STS), brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence was 22%, 19%, and 11% for STS, brain cancer, and osteosarcoma. 49% of those with one cancer developed at least another cancer after a median of 10 years. Average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. Conclusions Cumulative cancer risk in TP53+ individuals was high and varied by gender, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management.

These data suggest clinical utility of baseline WBMRI in TP53 germline mutation carriers and may form an integral part of baseline clinical risk management in this high-risk population.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome and telomere biology disorder characterized by dysplastic nails, reticular skin pigmentation and oral leucoplakia. Androgens are a standard therapeutic option for bone marrow failure in those patients with DC who are unable to undergo haematopoietic stem cell transplantation, but there are no systematic data on its use in those patients. We evaluated haematological response and side effects of androgen therapy in 16 patients with DC in our observational cohort study. Untreated DC patients served as controls. Seventy percent of treated DC patients had a haematological response with red blood cell and/or platelet transfusion independence. The expected age-related decline in telomere length was noted in androgen-treated patients. All treated DC patients had at least one significant lipid abnormality. Additional treatment-related findings included a significant decrease in thyroid binding globulin, accelerated growth in pre-pubertal children and splenic peliosis in two patients. Liver enzymes were elevated in both androgen-treated and untreated patients, suggesting underlying liver involvement in DC. This study suggests that androgen therapy can be effectively used to treat bone marrow failure in DC, but that side effects need to be closely monitored.