Clinical and Genetic Studies of Li-Fraumeni Syndrome

BACKGROUND:

- Li-Fraumeni syndrome (LFS) is a dominantly-inherited cancer predisposition syndrome
associated with a lifetime risk of approximately 90% by age 60 of numerous cancer types,
most notably bone and soft-tissue sarcomas, breast cancer, brain tumors, leukemia, and
adrenal cortical carcinoma

- Classic LFS is defined by 1) A proband with a sarcoma diagnosed before 45 years of age,
and 2) a first-degree relative with any cancer under 45 years of age, and 3) a first- or
second-degree relative with any cancer diagnosed under 45 years of age or a sarcoma at
any age. Li-Fraumeni-like syndrome (LFL), a more inclusive diagnostic criteria, shares
some of the features of LFS but that do not meet the strict LFS diagnostic criteria

- TP53 was identified as the underlying cause of LFS in 1990. A TP53 mutation is
identified in approximately 70% of classic LFS and 40% of LFL

- Although screening LFS patients for certain cancers can lead to early detection, a
favorable impact on quality of life or overall survival as a result of such screening
has not been shown. Currently, there is no standard recommended screening protocol in
either adults or children with LFS

OBJECTIVES:

- To evaluate and define the clinical spectrum and quantify cumulative cancer risk in
individuals with LFS and LFL

- To develop a cancer screening program for individuals with LFS and LFL

- To identify genetic determinants, environmental factors, and gene-environment
interactions that potentially modify cancer risk in these high-risk individuals

- To explore the plausibility of lifestyle risk-reducing interventions

- Evaluate the psychological and social functioning effects of LFS on the individuals and
the family

- To create an annotated biospecimen repository of LFS-related materials for translational

Research

ELIGIBILITY:

- A family or personal medical history of cancers consistent with the diagnosis of LFS or
LFL; or,

- A personal history of a germline TP53 mutation; or,

- A first- or second- degree relative of a TP53 mutation carrier, regardless of mutation
status; or,

- A personal history of three or more LFS-related primary cancers; or,

- A personal history of adrenal cortical carcinoma or choroid plexus carcinoma at any age

DESIGN:

- Long-term prospective cohort study to collect data from as many individuals with LFS as
permissible in order to precisely evaluate the main aims

- Medical/pathology records are reviewed to ascertain the family history and verify a
diagnosis of LFS. Questionnaires are administered to gather etiologic risk factor data.

- Participants are offered the option of undergoing a screening protocol and are followed
prospectively. Biospecimens are collected to investigate cancer etiology and mechanisms
of carcinogenesis.

- Clinical genetic testing is offered as appropriate after education and counseling.
Genetic testing is optional, and not required for other protocol aspects.

- We do not offer anti-cancer therapy; consultations for treatment recommendations of
cancer diagnosed while on study will be offered if available.

- INCLUSION CRITERIA:

- On referral, persons of all ages will be considered for inclusion in the study because
of either:

- A family or personal medical history of neoplasia consistent with the diagnosis of LFS
or LFL; or,

- A personal history of a germline TP53 mutation; or,

- A first- or second- degree relative of a TP53 mutation carrier, regardless of mutation
status; or,

- A personal history of three or more LFS-related primary cancers; or,

- A personal history of adrenal cortical carcinoma or choroid plexus carcinoma at any
age, regardless of family history

Personal and family medical history must be verified through questionnaires, interviews,
review of medical records and/or review of pathology slides.

There are 72 families who have previously enrolled in the pilot study under protocol
78-C-0039. As the eligibility criteria remain the same, these families will be eligible for
this protocol and will be invited to sign the new consent.

- Ability of subject or Legally Authorized Representative (LAR) to understand and the
willingness to sign a written informed consent document.

-Pregnant women-

--Pregnant women are eligible for enrollment on the data collection component of this
study.

EXCLUSION CRITERIA:

- Referred individuals and families whose reported diagnoses cannot be verified

- Medical or psychiatric disorder which, in the opinion of the Principal Investigator,
would preclude the ability to participate in clinical research

- Women who are pregnant will not be eligible for the cancer screening protocol. Women
participating in the cancer screening protocol will discontinue this component if they
become pregnant while on study.