RATIONALE: Genetic studies may help in understanding the genetic processes involved in the development of some types of cancer.

PURPOSE: Genetic trial to study the genes of patients who have an inherited urologic (genitourinary) malignancy (cancer).

OBJECTIVES:

• Characterize the natural and clinical histories of patients with inherited urologic malignancies.
• Determine the genetic etiology of inherited urologic malignancies in which the gene defect is unknown, using linkage analysis, positional cloning, and evaluation of candidate genes.
• Correlate specific mutations and associated protein domains with disease phenotypic expression, in terms of presenting age, clinical manifestations, histopathology, and rate of recurrence, in this patient population.
• Identify and describe unknown or uncharacterized inherited urologic malignancies.

OUTLINE: Patients undergo genetic counseling and possible genetic testing followed by a detailed personal and family medical history, complete physical examination, and collection of blood and tissue samples. If clinically indicated, patients may undergo further diagnostic studies. Testing may be done over 1-4 days.

Blood and tissue samples are examined for specific mutations by single strand conformational polymorphism and DNA sequencing. If the genetic basis is unknown, linkage studies using polymorphic microsatellite markers may be conducted.

All patients receive the results of the clinical tests. Patients with urologic malignancies for which the genetic defect is known receive their genetic test results, with genetic counseling available.

Patients with active lesions are followed every 3 months to every 3 years, depending on clinical status.

PROJECTED ACCRUAL: A total of 3,500 patients will be accrued for this study. This study will include but is not limited to individuals from specific populations.

• Birt Hogg Dube Syndrome
• Kidney Cancer
• Multiple Endocrine Neoplasia
• Von Hippel-Lindau Syndrome

• Genetic: DNA ploidy analysis
• Genetic: genetic linkage analysis
• Genetic: mutation analysis
• Genetic: polymorphic microsatellite marker analysis
• Other: medical chart review

• Maranchie JK, Afonso A, Albert PS, Kalyandrug S, Phillips JL, Zhou S, Peterson J, Ghadimi BM, Hurley K, Riss J, Vasselli JR, Ried T, Zbar B, Choyke P, Walther MM, Klausner RD, Linehan WM. Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. Hum Mutat. 2004 Jan;23(1):40-6.
• Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003 Jul;73(1):95-106. Epub 2003 May 22.
• Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002 Aug;2(2):157-64.
• Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ. Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol. 2002 Dec;26(12):1542-52.
• Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):393-400.
• Phillips JL, Ghadimi BM, Wangsa D, Padilla-Nash H, Worrell R, Hewitt S, Walther M, Linehan WM, Klausner RD, Ried T. Molecular cytogenetic characterization of early and late renal cell carcinomas in von Hippel-Lindau disease. Genes Chromosomes Cancer. 2001 May;31(1):1-9.
• Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR, Turner ML, Duray P, Merino M, Hewitt S, Pavlovich CP, Glenn G, Greenberg CR, Linehan WM, Zbar B. Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet. 2001 Oct;69(4):876-82. Epub 2001 Aug 30.
• Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol. 2003 Dec;170(6 Pt 1):2163-72. Review.
• Zbar B, Klausner R, Linehan WM. Studying cancer families to identify kidney cancer genes. Annu Rev Med. 2003;54:217-33. Epub 2001 Dec 3. Review.

DISEASE CHARACTERISTICS:

• Patients or family members of patients in one of the following disease categories:

  • Suspected or established diagnosis of urologic malignant disorder for which genetic defect is known and mutation detection can be implemented, including the following:

    • von Hippel-Lindau (VHL) syndrome
    • Hereditary papillary renal carcinoma, Type I
    • Hereditary papillary renal carcinoma, Type II
    • Birt Hogg Dube syndrome
    • Multiple endocrine neoplasia 2 (MEN2)

  • Suspected or established diagnosis of an inherited urologic malignancy for which the genetic defect is unknown, including but not limited to:

    • Clear cell renal carcinoma
    • Hereditary renal oncocytoma
    • Hereditary chromophobe renal cell carcinoma
  • Urologic malignancy of suspected, but not proven, genetic etiology, including families with more than one individual affected by the same or related cancers

• Patients or their family members must manifest one or more of the following features in a pattern suggestive of a heritable urologic malignancy:

  • At least one histologically confirmed or suspected renal carcinoma and/or cyst
  • Cerebellar, spinal, medullary, or cerebral hemangioblastomas
  • Retinal angioma
  • Pancreatic neuroendocrine carcinoma, microcystadenoma, and/or cysts
  • Pheochromocytoma
  • Papillary cystadenoma of the epididymis or broad ligament
  • Endolymphatic sac tumor
  • Cutaneous fibrofolliculomas or multiple skin-colored papules
  • History of spontaneous pneumothorax
  • Lung cysts
  • Thyroid carcinoma
  • Intestinal polyposis with or without colon cancer
  • Cutaneous or uterine leiomyoma or uterine leiomyosarcoma or sarcoma
• Patients, their at-risk family members, or spouses of patients with suspected inherited urologic malignancies who demonstrate one or more of the above clinical findings but who live too far from NIH to be evaluated at the Clinical Center are also eligible* NOTE: *Local diagnostic testing and blood collection may be necessary
• Relatives or spouses enrolled primarily for genetic linkage studies are eligible but will not undergo imaging diagnostic testing

PATIENT CHARACTERISTICS:

Age:

• 2 and over

Performance status:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Not specified

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified