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

Hereditary Leiomyomatosis Renal Cell Cancer (HLRCC): Identification of the Disease Gene, and Characterization of the Predisposition to Renal Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Kidney Cancer; Renal Tumor Histology; Cutaneous Leiomyoma

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 Type: Observational
• Enrollment (Estimated): 950

Contacts and Locations

• Study Contact: Name: Deborah A Nielsen, R.N.; Phone Number: (240) 760-6247; Email: deborah.nielsen@nih.gov
• Study Contact Backup: Name: W. Marston Linehan, M.D.; Phone Number: (240) 858-3700; Email: linehanm@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• 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.

Description

• 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

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.)

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

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

Publications and helpful links

General 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2003

Study Registration Dates

• First Submitted: December 17, 2002
• First Submitted That Met QC Criteria: December 17, 2002
• First Posted (Estimated): December 18, 2002

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 26, 2024

More Information

Terms related to this study

• Keywords: Natural History; Renal Cancer; Uterine Fibroid; Hereditary Leiomyomatosis; Cutaneous Leiomyoma
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Connective Tissue Diseases; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Neoplasms; Carcinoma, Renal Cell; Disease Susceptibility; Leiomyoma; Myofibroma; Leiomyomatosis
• Other Study ID Numbers: 030066; 03-C-0066

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No