Patient case: 62-year-old female with mucosal melanoma; genetic feature: KIT (L576P), KIT amplification

Clinical trial: Clinical and Genetic Studies of Li-Fraumeni Syndrome

Summary: Background:
  - Li-Fraumeni syndrome (LFS) is a genetic condition that increases the risk for some types of cancer. LFS may lead to cancer of the bone or connective tissue, breast, and brain. It may also increase the risk for certain types of leukemia and other cancers. The only known cause of LFS is a change (called a mutation ) in a gene known as TP53. However, not all people with LFS have a TP53 mutation. Researchers want to study other possible genetic causes of LFS, and factors that may increase or decrease cancer risk in people with the syndrome.
  Objectives:
  -  To learn more about the types of cancers that occur in individuals with LFS.
  -  To study the role of the TP53 gene in the development of cancer.
  -  To look for other possible genes that cause LFS
  -  To study the effect of LFS diagnosis on families.
  -  To determine if environmental factors or other genes can change a person s cancer risk associated with LFS.
  Eligibility:
  -  Individuals with a family or personal medical history of cancers consistent with LFS.
  -  Individuals with a family or personal medical history of cancers that does not meet the diagnosis of LFS, but the history is suggestive for LFS (meets the diagnosis for the so-called Li-Fraumeni like syndrome)
  -  Individuals with certain rare cancers
  -  Individuals with a family or personal history of a TP53 gene mutation, with or without related cancer(s).
  Design:
  -  Participants will fill out a medical history questionnaire and a family history questionnaire.
  -  Blood samples will be collected for DNA and for storage. Cheek cell samples may be collected if blood cannot be obtained for DNA. Participants can choose to have or not have cancer screening with blood tests, imaging studies, and other exams.
  -  Participants will complete questionnaires about their worries about cancer, stress levels, and coping strategies. Diet and physical activity questionnaires will also be given. Other psychological tests may be given as needed.
  -  Participants will be monitored for several years, with regular followup visits to the National Institutes of Health, if indicated. Any changes in health or cancer status will be recorded.

Detailed description: 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.

Eligibility: -  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.

Relevance to patient case: not relevant