Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome
Condition: Mitochondrial Disorders; Li-Fraumeni Syndrome; Carriers of p53 Mutation
MeSH terms: Li-Fraumeni Syndrome; Mitochondrial Diseases; Syndrome
Study type: Observational

Summary: 
      This study will examine metabolic and biological factors in people with Li-Fraumeni syndrome,
      a rare hereditary disorder that greatly increases a person's susceptibility to cancer.
      Patients have a mutation in the p53 tumor suppressor gene, which normally helps control cell
      growth. This gene may control metabolism as well as cancer susceptibility, and the study
      findings may help improve our understanding of not only cancer but also other conditions,
      such as cardiovascular function.

      Healthy normal volunteers and patients with the Li-Fraumeni syndrome and their family members
      may be eligible for this study. Candidates must be at least 18 years of age, in overall good
      health and cancer-free within 1 year of entering the study. Participants undergo the
      following procedures:

        -  Blood tests for routine lab values and for research purposes.

        -  ECG and echocardiogram (heart ultrasound) to evaluate heart structure and function.

        -  Resting and exercise metabolic stress testing: The subject first relaxes in a chair
           wearing the facemask and then exercises on a stationary bicycle or treadmill while
           wearing the mask. This test uses the facemask to measure oxygen usage by the body to
           determine metabolic fitness. Electrodes are placed on the body to monitor the heart in
           an identical manner to a standard exercise stress test.

        -  Magnetic resonance imaging of metabolism: The subject lies on a bed that slides into a
           large magnet (the MRI scanner) for up to 60 minutes. During scanning, the arm or leg
           muscles are stressed by inflating a blood pressure cuff and by exercising the limb for
           several minutes. Subjects may be asked to squeeze a rubber ball or exercise with a foot
           pedal. Immediately afterwards, the pressure in the cuff is released and remains deflated
           for 10 to 15 minutes. No more than three 5-minute episodes of blood flow stoppage are
           performed.

        -  Standard MRI scan of exercised limb to determine muscle volume.

        -  Brachial artery reactivity test to measure blood vessel function: Before the exercise
           stress testing, subjects lie on a stretcher while the brachial artery (artery in the
           forearm) is imaged using a noninvasive ultrasound method. Artery size and blood flow
           velocity are measured before and after inflating a blood pressure cuff on the forearm.
           Vessel size and flow velocity measurements are repeated after 15 minutes and again after
           administration of nitroglycerin under the tongue.

        -  Oral glucose tolerance testing to test for diabetes: To assess sugar metabolism,
           subjects drink a sugar solution. Blood samples are collected before drinking the
           solution and 1 and 2 hours after drinking the solution.

        -  Muscle biopsy (optional according to subject preference): Subjects may be given small
           amounts of sedation for the procedure. A small area of skin over a leg muscle is numbed
           and a small amount of muscle tissue is surgically removed.
    

Detailed description: 
      We have previously reported that TP53 (encoding p53 protein), one of the most frequently
      mutated genes in human cancers, dose dependently modulates the balance between the
      utilization of oxidative and glycolytic pathways for energy generation in human colon cancer
      cells and mouse liver mitochondria. Though morphologically similar to their wild-type
      littermates, mice deficient in p53 display a gene dose-dependent decrease in aerobic exercise
      capacity, implying that p53 has functions beyond its well characterized cell cycle
      activities. These current findings have broad implications in fields ranging from cancer and
      aging research to cardiovascular physiology.

      In the Li-Fraumeni familial cancer syndrome (LFS), affected individuals harbor a germline
      mutation in TP53, hence they are heterozygous with reduced wild-type p53 activity. We
      hypothesize that the heterozygous individuals will display alterations in aerobic capacity
      and metabolism that previously has been unappreciated. This IRB proposal translates our
      experimental observation to human subjects in collaboration with extramural groups studying
      this rare familial syndrome. The results may not only help clarify why mutations of p53 gene
      are so common in cancers by potentially conferring metabolic advantages in tumorigenesis, but
      they may also give us an opportunity to understand a fundamental regulatory mechanism in
      cellular energy generation relevant to other processes.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        96 carrier LFS family members 60 non-carrier LFS family members or normal 30 normal
        controls for MR spectroscopy study 20 subjects with mitochondrial disorders 20 non-carrier
        mitochondrial disorder family members or normal controls
      
Keywords: p53 Mutation; Li-Fraumeni Syndrome; Aerobic Metabolism; Magnetic Resonance Spectroscopy