Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome

NCT00406445 | Completed

• 2 other identifiers: 07003007-H-0030
• Study Type: observational
• Target: 82
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Mitochondrial Disorders; Li-Fraumeni Syndrome; Carriers of p53 Mutation

Keywords

p53 Mutation; Li-Fraumeni Syndrome; Aerobic Metabolism; Magnetic Resonance Spectroscopy

Outcome Measures

Primary Outcomes (1)

• Non-invasively measure aerobic exercise capacity and metabolism

  Because an interim analysis has confirmed our hypothesis, the aim of the primary endpoint has been achieved.

  ongoing

Secondary Outcomes (2)

• Non-invasively measure markers of mitochondrial function by magneticresonance spectroscopy (MRS) in response to transient ischemic stress

  ongoing

• Measure oxygen consumption, protein and RNA levels of p53-regulated mitochondrial genes using blood cells and other tissue samples if available.

  ongoing

Study Arms (5)

carrier LFS family members

96 carrier LFS family members

non-carrier LFS family members or normal

60 non-carrier LFS family members or normal

non-carrier mitochondrial disorder family members or normal controls

20 non-carrier mitochondrial disorder family members or normal controls

normal controls for MR spectroscopy study

30 normal controls for MR spectroscopy study

subjects with mitochondrial disorders

20 subjects with mitochondrial disorders

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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

You may qualify if:

• At least 18 years of age and able to give informed consent
• In overall good physical and mental health;
• Able to exercise on a treadmill (if participating in the treadmill exercise portion).
• Able to perform hand or leg exercises (if participating in the MRS portion)
• Able to undserstand and sign consent
• Have been diagnosed with the Li-Fraumeni Syndrome or have a family member with the Li-Fraumeni Syndrome or have been diagnosed with mitochondrial disorder or be a healthy volunteer

You may not qualify if:

• Cancer patients undergoing or requiring systemic treatment

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Arena R, Myers J, Abella J, Peberdy MA. Influence of heart failure etiology on the prognostic value of peak oxygen consumption and minute ventilation/carbon dioxide production slope. Chest. 2005 Oct;128(4):2812-7. doi: 10.1378/chest.128.4.2812.

  PMID: 16236959 BACKGROUND

• Brown BW, Costello TJ, Hwang SJ, Strong LC. Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet. 2005 Dec;118(3-4):489-98. doi: 10.1007/s00439-005-0016-x. Epub 2005 Nov 12.

  PMID: 16284780 BACKGROUND

• Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981 Dec;68(6):1456-67. doi: 10.1172/jci110398.

  PMID: 7033284 BACKGROUND

• Wang PY, Li J, Walcott FL, Kang JG, Starost MF, Talagala SL, Zhuang J, Park JH, Huffstutler RD, Bryla CM, Mai PL, Pollak M, Annunziata CM, Savage SA, Fojo AT, Hwang PM. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J Clin Invest. 2017 Jan 3;127(1):132-136. doi: 10.1172/JCI88668. Epub 2016 Nov 21.

  PMID: 27869650 DERIVED

• Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU, Strong LC, Talagala SL, Balaban RS, Kang JG, Hwang PM. Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med. 2013 Mar 14;368(11):1027-32. doi: 10.1056/NEJMoa1214091.

  PMID: 23484829 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Mitochondrial Diseases; Li-Fraumeni Syndrome

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Neoplastic Syndromes, Hereditary; Neoplasms; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders

Study Officials

• Paul M Hwang, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2006
• First Posted: December 4, 2006
• Study Start: January 23, 2007
• Primary Completion: March 22, 2021
• Study Completion: March 22, 2021
• Last Updated: November 22, 2021

Record last verified: 2021-11

Locations

US (1)