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

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

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).

Study Overview

• Status: Recruiting
• Conditions: TP53 Gene Mutation; Li-Fraumeni Syndrome; Hereditary Cancer Syndrome; Mosaicism; Clonal Hematopoiesis
• Intervention / Treatment: Genetic: Data and Specimen Collection

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 Type: Observational
• Enrollment (Estimated): 1500

Contacts and Locations

• Study Contact: Name: Judy E Garber, MD, MPH; Phone Number: 617-632-5770; Email: jegarber@partners.org
• Study Contact Backup: Name: Sophie Cahill, BS; Phone Number: 617-632-4795; Email: Sophie_Cahill@DFCI.HARVARD.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: JUNNE KAMIHARA, MD; Phone Number: 888-733-4662; Email: jkamihara@partners.org
      • Principal Investigator: JUNNE KAMIHARA, MD
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Brigham and Women's Hospital
      • Principal Investigator: Judy Garber, MD, MPH
      • Contact: Judy Garber, MD, MPH; Phone Number: 617-632-2282; Email: jegarber@partners.org
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Judy E. Garber
      • Principal Investigator: Judy Garber, MD, MPH
      • Contact: Judy E. Garber, MD, MPH; Phone Number: 617-763-8821; Email: judy_garber@dfci.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults and children with a TP53 gene variant identified in blood or saliva

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Other

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Variant in the TP53 Gene in blood or saliva; 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

Genetic: Data and Specimen Collection; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 years or Study closure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 years or Study closure
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	5 years or Study closure
Estimation of risk for the more commonly occurring cancers associated with inherited TP53 mutations	P-values and 95% confidence intervals will be calculated	5 years or Study closure

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: National Cancer Institute (NCI); Baylor College of Medicine; City of Hope Medical Center
• Investigators: Principal Investigator: Judy E Garber, MD, MPH, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• de Andrade KC, Lee EE, Tookmanian EM, Kesserwan CA, Manfredi JJ, Hatton JN, Loukissas JK, Zavadil J, Zhou L, Olivier M, Frone MN, Shahzada O, Longabaugh WJR, Kratz CP, Malkin D, Hainaut P, Savage SA. The TP53 Database: transition from the International Agency for Research on Cancer to the US National Cancer Institute. Cell Death Differ. 2022 May;29(5):1071-1073. doi: 10.1038/s41418-022-00976-3. Epub 2022 Mar 29. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2020
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: August 25, 2020
• First Submitted That Met QC Criteria: September 4, 2020
• First Posted (Actual): September 9, 2020

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Mosaicism; Li-Fraumeni Syndrome; TP53 Gene Mutation (Variant); Hereditary Cancer Syndrome; Clonal Hematopoiesis
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Neoplasms; Disease; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Syndrome; Neoplastic Syndromes, Hereditary; Li-Fraumeni Syndrome
• Other Study ID Numbers: 20-226; R01CA242218 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No