The purpose of this research study is to learn more about variants in the TP53 gene both associated with Li-Fraumeni Syndrome (LFS), a hereditary cancer risk condition, and TP53 variants found in the blood for other reasons (e.g. ACE/CHIP and mosaicism).
Individuals with a TP53 pathogenic or likely pathogenic variant identified in blood or saliva,
Individuals with variants of uncertain significance in TP53 may be eligible at the PI's discretion,
Blood relatives of individuals with a TP53 variant, who may be presumed obligate carriers or healthy controls,
Individuals who meet Classic or Chompret LFS criteria whether or not they have a TP53 gene variant,
Individuals who decline to sign consent
Individuals who are unable to give consent or assent and are without a designated healthcare proxy
Adults and children with a TP53 gene variant identified in blood or saliva
Family-based
Other
Data and Specimen Collection
Genetic* Provide research team and access to relevant medical records * Answer short questionnaires periodically * Consider consenting to other optional parts of the research such as: * Providing up to 3 tubes (15ml) of blood at or near the time of consent, as approved by treating physician (optional). * Provide a saliva sample (optional). * Provide eyebrow hairs for analysis of DNA from the bulb (15-20 eyebrow plucks) (optional). * Provide permission for obtainment of stored tissue specimens from cancer or pre-cancer surgeries or biopsies from the pathology departments where they have been stored (optional). * Consider inviting relatives to join the study (optional).
Repository of specimens and data
Examine accuracy of family history and the extent to which families meet various published Li-Fraumeni family criteria or assess for de-novo mutations using descriptive statistics. Exact binomial confidence limits for percents will be calculated at 95% coverage. Tests of difference between \>2 groups for binary variables will use the Fisher exact test.
Estimation of Cancer Risks in TP53 mutation carriers
Estimate the frequency in ExAc as a population rate and calculate a standardized risk ratio as the ratio of the prevalence of mutations in a given cancer type compared to that in ExAc. P-values and 95% confidence intervals will be calculated assuming the observed number of mutations follows a Poisson distribution with mean equal to the expected value calculated from the ExAC observed frequency.
Modified segregation analysis
For each dataset, the following analyses will be performed using MENDEL: a) the relative risk (RR) across age groups is assumed to be constant; b) the RR is assumed to be a continuous, piece wise linear function of age which was constant before age 40 years and after age 60 years, and linear between ages 40 and 60 years
Estimation of risk for the more commonly occurring cancers associated with inherited TP53 mutations
P-values and 95% confidence intervals will be calculated
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Dana-Farber Cancer Institute
Lead sponsor
National Cancer Institute (NCI)
Collaborator
City of Hope Medical Center
Collaborator
Baylor College of Medicine
Collaborator
