Penetrance Estimates Over Time to First and Second Primary Cancer Diagnosis in Families with Li-Fraumeni Syndrome: A Single Institution Perspective

Cancer Res. 2020 Jan 15;80(2):347-353. doi: 10.1158/0008-5472.CAN-19-0725. Epub 2019 Nov 12.


Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging because of limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center [MDACC, Houston, TX; number of families = 189; single primary cancer (SPC) = 771; and MPC = 87]. Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC = 102 and MPC = 58). These findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second primary cancer. In addition, TP53 mutation carriers had a HR of 1.65 (95% confidence interval, 1.1-2.5) for developing a second primary cancer versus SPC. The area under the ROC (AUC) curve for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for first and second primary cancer for TP53 germline mutation carriers and demonstrate its accuracy for cancer risk assessment. SIGNIFICANCE: These findings present an open-source R package LFSPRO that could be used for genetic counseling and health management of individuals with LFS as it estimates the risk of both first and second primary cancer diagnosis.See related article by Shin et al., p. 354.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Computational Biology
  • Datasets as Topic
  • Female
  • Follow-Up Studies
  • Genetic Counseling / methods
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Li-Fraumeni Syndrome / diagnosis
  • Li-Fraumeni Syndrome / genetics*
  • Male
  • Middle Aged
  • Models, Genetic*
  • Mutation Rate
  • Neoplasms, Second Primary / diagnosis
  • Neoplasms, Second Primary / epidemiology
  • Neoplasms, Second Primary / genetics*
  • Penetrance*
  • Predictive Value of Tests
  • Risk Assessment / methods
  • Software
  • Time Factors
  • Tumor Suppressor Protein p53 / genetics
  • Young Adult


  • TP53 protein, human
  • Tumor Suppressor Protein p53