Patient case: 38-year-old male with melanoma; genetic feature: BRAF (K601E)

Clinical trial: Clinical Manifestations and Molecular Bases of Heritable Urologic Malignant Disorders

Summary: We will investigate the clinical manifestations and molecular genetic defects of heritable urologic malignant disorders. Families with urologic malignancy with known or suspected genetic basis will be enrolled. Affected individuals or individuals suspected of having a germline urologic malignant disorder will undergo periodic clinical assessment and genetic analyses for the purpose of: 1) definition and characterization of phenotype, 2) determination of the natural history of the disorder, and 3) genotype/phenotype correlation. Genetic linkage studies may be performed in situations in which the genetic basis of the disorder has not been elucidated.

Detailed description: Background:
  -  Disorders under investigation are: Autosomal dominant inherited urologic malignant disorders including: von Hippel- Lindau (VHL), hereditary papillary renal cancer (HPRC), Birt Hogg Dube (BHD) and hereditary leiomyomatosis and renal cell acarcinoma (HLRCC) as well as familial renal cancer.
  -  Studies have led to the identification and characterization of the VHL, HPRC, BHD and HLRCC genes.
  -  The genetic etiology of the most common type of inherited kidney cancer, familial renal cancer (FRC), remains to be determined.
  Objectives:
  -  To characterize the natural and clinical histories of inherited urologic malignant disorders.
  -  To determine the genetic etiology of hereditary urologic malignant disorders in which the gene defect is unknown, by linkage analysis, positional cloning and evaluation of candidate genes.
  -  To correlate specific mutations and their associated protein domains with disease phenotypic expression based on parameters including presenting age, clinical manifestations, histopathology and rate of recurrence.
  -  To identify and describe as yet unknown or uncharacterized inherited urologic malignant disorders.
  Eligibility:
  -  Individuals and family members with a suspected or an established diagnosis of von Hippel-Lindau (VHL) syndrome or hereditary papillary renal carcinoma (HPRC), Type I.
  -  Individuals and family members with a suspected or an established diagnosis of an inherited urologic malignancy in which the disease gene is not yet known, specifically hereditary forms of Type II papillary renal cancer, clear cell renal carcinoma, renal oncocytoma, chromophobe renal carcinoma or Birt Hogg Dube syndrome.
  -  Individuals and family members who have urologic malignant diseases of suspected, but not proven genetic etiology, including families with more than one individual affected by the same or related cancers.
  Design:
  -  These rare 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.

Eligibility: -  INCLUSION CRITERIA - Subject Category A:
  Category A will include patients, and relatives, who may or may not be affected who will be evaluated in the Warren G. Magnuson Clinical Center. Patients in this category will be eligible if they or their family members manifest one or more of the following features in a pattern suggestive of a heritable urologic malignant disorder:
  -  One or more histologically proven or suspected renal carcinomas and/or cysts
  -  Cerebellar, spinal, medullary or cerebral hemangioblastomas
  -  Retinal angioma
  Pancreatic neuro-endocrine carcinoma, microcystadenoma and/or cysts
  -  Pheochromocytoma
  -  Papillary cystadenoma of the epididymis or broad ligament
  -  Endolymphatic sac tumor
  -  Known or suspected cutaneous fibrofolliculomas or multiple skin-colored papules
  -  History of spontaneous pneumothorax
  -  Lung cysts
  -  Thyroid carcinoma
  -  Intestinal polyposis + / - colon cancer
  -  Cutaneous or Uterine leiomyoma or uterine leiomyosarcoma, sarcoma
  INCLUSION CRITERIA - Subject Category B:
  Category B will include patients, their at-risk relatives and spouses of patients with inherited urologic malignancies with the above listed clinical findings who live at a distance and who will not be evaluated at the Clinical Center. In some cases, local diagnostic testing may be necessary for these individuals in addition to collection of a blood sample for molecular analysis.
  INCLUSION CRITERIA - Subject Category C:
  Category C will include relatives and spouses who enroll in this study primarily for genetic linkage studies. These individuals will contribute a blood sample for DNA analysis only. No imaging diagnostic testing will be performed on individuals from this category.
  EXCLUSION CRITERIA:
  Persons unable to give informed consent.

Relevance to patient case: not relevant