Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress

Recruiting

• Conditions: Li-Fraumeni Syndrome; Clonal Hematopoiesis; Hereditary Cancer Syndrome; TP53 Gene Mutation; Mosaicism
• Interventions: Genetic: Data and Specimen Collection

• Registration Number: NCT04541654
• Lead Sponsor: Dana-Farber Cancer Institute

Brief Summary

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).

Detailed Description

This research study looks to enroll as many people with LFS or TP53 gene variants as possible in order to:

* Better estimate cancer risks in individuals with TP53 variants or LFS, which is a rare condition.

* Learn the range of cancer risks linked to TP53 variants to help individuals and families to improve our ability to counsel patients and families about cancer risks more accurately.

* Improve opportunities for cancer prevention, early detection, and treatment.

* Learn more about the meaning of TP53 variants in the blood that are not inherited (e.g. ACE/CHIP and mosaicism).

Study procedures will include:

* Collecting information from the participant's medical record and short questionnaires.

* Collecting blood, saliva, eyebrow hair and tumor tissue samples (optional).

* Sharing study information with family members (optional).

It is expected that about 1500 people will take part in this research study. Participants will be in this study until it closes or the participant withdraws consent.

The National Cancer Institute is providing funding for part of this study and is considered a study sponsor. They will require that some of the genetic information be made available to the research community without personal identifying information.

Study Timeline

• Study First Submitted: 2020-08-25
• Study First Submitted QC: 2020-09-04
• Study First Posted: 2020-09-09
• Study Start: 2020-09-15
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-18
• Last Update Posted: 2024-03-20
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1500

Inclusion Criteria

• 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 may enroll their deceased relatives in the study.
• Individuals with a known TP53 variant that is not LFS, but rather ACE, CHIP, or mosaicism.
• Individuals participating in other LFS studies can still enroll in LiFT UP. Investigators may be collaborators.

Exclusion Criteria

• Individuals who decline to sign consent
• Individuals who are unable to give consent or assent and are without a designated healthcare proxy

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Variant in the TP53 Gene in blood or saliva	Data and Specimen Collection	Variant in the TP53 gene found on a blood or saliva test, have a relative with a variant in the TP53 gene, or because participant meets genetic testing criteria for Li-Fraumeni Syndrome (LFS) based on personal or family cancer history

Primary Outcome Measures

Name	Time	Method
Repository of specimens and data	5 years or Study closure	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.

Secondary Outcome Measures

Name	Time	Method
Estimation of Cancer Risks in TP53 mutation carriers	5 years or Study closure	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	5 years or Study closure	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	5 years or Study closure	P-values and 95% confidence intervals will be calculated

Trial Locations

Locations (3)

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Judy E. Garber; 🇺🇸 Boston, Massachusetts, United States