Hereditary Leiomyomatosis Renal Cell Cancer - Study of the Genetic Cause and the Predisposition to Renal Cancer

• ClinicalTrials.gov Identifier: NCT00050752
• Recruitment Status: Recruiting
• First Posted: December 18, 2002
• Last Update Posted: December 29, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

This study will investigate what causes hereditary leiomyomatosis renal (kidney) cell cancer, or HLRCC, and how the disease is related to the development of kidney tumors. Leiomyomas are benign (non-cancerous) tumors arising from smooth muscle. HLRCC can cause various health problems. Some people develop red bumps on their skin that can be painful at times. Some women with HLRCC can develop leiomyomas of the uterus. In some families, people with HLRCC develop kidney tumors. This study will try to determine:

• What gene changes (mutations) cause HLRCC
• What kind of kidney tumors develop in HLRCC and how they grow
• What the chance is that a person with HLRCC will develop a kidney tumor

People with known or suspected HLRCC (and their family members of any age) may be eligible for this study. This includes people in families in which one or more members has skin leiomyoma and kidney cancer; skin leiomyoma and uterine leiomyoma; multiple skin leiomyomas; kidney cancer and uterine leiomyomas, or kidney cancer consistent with HLRCC, including, but not limited to, collecting duct or papillary, type II. Candidates will be screened with a physical examination, family history, and, for affected family members, a review of medical records, including pathology slides and computed tomography (CT) or magnetic resonance imaging (MRI) scans.

Participants will undergo tests and procedures that may include the following:

• Review of medical records, x-rays, and tissue slides
• Physical examination and family history
• Skin examination
• Gynecological examination for women
• Interviews with a cancer doctor, cancer nurses, kidney surgeon, and genetic counselor

• Blood tests for:

  1. Genetic research to identify the gene responsible for HLRCC
  2. Evaluation of liver, kidney, heart, pancreas, and thyroid function
  3. Complete blood count and clotting profile
  4. Pregnancy test for pre-menopausal women
  5. PSA test for prostate cancer in men over age 40
• CT or MRI scans (for participants 15 years of age and older only)
• Skin biopsy (surgical removal of a small sample of skin tissue)
• Cheek swab or mouth rinse to collect cells for genetic analysis
• Medical photographs of lesions
• Questionnaire

When the tests are completed, participants will discuss the results with a doctor and possibly a genetic nurse or genetic counselor. The genetic findings will not be revealed to participants because their meaning and implications may not yet be understood. Participants may be asked to return to NIH from every 3 months to every 3 years, depending on their condition, for follow-up examinations and tests.

Condition or disease
Renal Tumor Histology; Cutaneous Leiomyoma; Kidney Cancer

Detailed Description:

Background:

• Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare autosomal dominantly inherited disorder which confers susceptibility to develop cutaneous and uterine leiomyomas and renal cell carcinoma.
• HLRCC is caused by mutations in the Krebs cycle enzyme, fumarate hydratase localized on chromosome 1q42.3-q43.

Objectives:

• Define the risk of developing renal cancer, cutaneous leiomyoma and uterine leiomyoma in this hereditary cancer syndrome
• Define the types and characteristics (including patterns of growth) of renal cancer associated with HLRCC.
• Determine the incidence and characteristics of HLRCC-associated fumarate hydratase gene mutations.
• Determine genotype/phenotype correlations.
• Determine if other genes caused HLRCC.

Eligibility:

-An individual from a family in which one or more biological family members have:

• Cutaneous leiomyoma and kidney cancer.
• Cutaneous leiomyoma and uterine leiomyoma.
• Multiple cutaneous leiomyoma.
• Kidney cancer and uterine leiomyomata.
• Renal tumor histology consistent with HLRCC including, but not limited to: Collecting Duct and/or Papillary, Type II.

Design:

• These rare biological families will be recruited to genetically confirm diagnosis, determine size and location of renal tumors, size at presentation, growth rate and metastatic potential of renal tumors.
• Genetic testing will be offered to gain appreciation of the effect of mutations on the relative activity of various germline and somatic mutations.
• We will determine if there is a relationship between mutation and disease phenotype.

Study Design

• Study Type: Observational
• Estimated Enrollment: 950 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Hereditary Leiomyomatosis Renal Cell Cancer (HLRCC): Identification of the Disease Gene, and Characterization of the Predisposition to Renal Cancer
• Actual Study Start Date: February 24, 2003

Groups and Cohorts

Group/Cohort
1 / Patients; Patients with known or suspected Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC)
2 / Family Members; Family members (related by blood) of patients who have or are suspected of having Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC)
3 / Non-Biologic Family Members; Spouses enrolled primarily for linkage analysis (Spouses have been removed from the inclusion criteria for this study. This closed cohort is for spouses previously enrolled on study.)

Outcome Measures

Primary Outcome Measures :

1. Determine the incidence and characteristics of HLRCC-associated fumarate hydratase gene mutations. [ Time Frame: on-going ]
   Molecular genetic differences between normal and tumorigenic fumarate hydratase (fumerase) mutations.
2. Determine the clinical manifestations of HLRCC [ Time Frame: on-going ]
   Collection of blood, urine and/or benign and malignant tissue.
3. Determine if other genes cause HLRCC. [ Time Frame: on-going ]
   Molecular genetic differences between normal and tumorigenic cells.
4. Determine genotype/phenotype correlations. [ Time Frame: on-going ]
   Detection and expression analysis of gene(s).
5. Define the types and characteristics (including patterns of growth) of renal cancer associated with HLRCC. [ Time Frame: on-going ]
   Detection and expression analysis of gene(s).
6. Define the risk of developing renal cancer, cutaneous leiomyoma and uterine leiomyoma in this hereditary cancer syndrome. [ Time Frame: on-going ]
   Collection of blood, urine and/or benign and malignant tissue.

Eligibility Criteria

• Ages Eligible for Study: 2 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

An individual (including patient) from a family in which one or more family member have: cutaneous leiomyoma and kidney cancer, cutaneous leiomyoma and uterine leiomyoma, multiple cutaneous leiomyoma, kidney cancer and uterine leiomyomata, renal tumor histology consistent with HLRCC including, but not limited to: Collecting Duct and/or Papillary, Type II.

Criteria

• INCLUSION CRITERIA:

Patients suspected or known to have phenotype or genotype suggestive of Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC), such as:

• Cutaneous leiomyoma and kidney cancer
• Cutaneous leiomyoma and uterine leiomyoma
• Multiple cutaneous leiomyoma
• Kidney cancer and uterine leiomyomata
• Renal tumor histology consistent with HRLRCC including, but not limited to: Collecting Duct and/or Papillary, Type II
• All patients and parents/guardians, for children younger than 18 years of age, must sign an informed consent document indicating their understanding of the investigational nature and the risks of this study before any protocol related studies are performed. Patients under the age of 18 but who are age 13 or older will be asked to sign an assent document prior to participation.
• Participants must be >= 2 years of age.
• A relative (related by blood) of a patient with a confirmed or suspected diagnosis of HLRCC.

EXCLUSION CRITERIA:

None

Contacts and Locations

Contacts

Contact: Deborah A Nielsen, R.N.; (240) 760-6247; deborah.nielsen@nih.gov

Contact: W. Marston Linehan, M.D.; (240) 858-3700; linehanm@mail.nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: W. Marston Linehan, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Linehan WM, Lerman MI, Zbar B. Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA. 1995 Feb 15;273(7):564-70. No abstract available.

Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317-20. doi: 10.1126/science.8493574.

Zbar B, Tory K, Merino M, Schmidt L, Glenn G, Choyke P, Walther MM, Lerman M, Linehan WM. Hereditary papillary renal cell carcinoma. J Urol. 1994 Mar;151(3):561-6. doi: 10.1016/s0022-5347(17)35015-2.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00050752
• Obsolete Identifiers: NCT00055627
• Other Study ID Numbers: 030066; 03-C-0066
• First Posted: December 18, 2002
• Last Update Posted: December 29, 2022
• Last Verified: December 23, 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Renal Cancer; Hereditary Leiomyomatosis; Uterine Fibroid; Cutaneous Leiomyoma; Natural History

Additional relevant MeSH terms:

Carcinoma, Renal Cell; Kidney Neoplasms; Leiomyoma; Myofibroma; Leiomyomatosis; Disease Susceptibility; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Connective Tissue Diseases; Disease Attributes; Pathologic Processes