RATIONALE: Studying individuals and families at high risk for cancer may help to identify other persons at risk and identify cancer genes.

PURPOSE: This clinical trial is studying genetic and environmental factors related to cancer risk in individuals and families at high risk for cancer.

OBJECTIVES:

• Identify individuals at high risk of cancer, especially due to personal or family medical history.
• Evaluate and define clinical spectrum of disease in syndromes predisposing to cancer.
• Quantify risks of tumors in family members.
• Map, clone, and determine function of tumor susceptibility genes.
• Identify genetic determinants and gene-environmental interactions conferring cancer risk in individuals and families.
• Evaluate gene-gene and gene-environmental interactions in tumor formation.
• Evaluate potential precursor states of disease in families at risk of cancer.

OUTLINE: One family member completes a family history questionnaire for verification of diagnosis and construction of a family pedigree. Individuals and families undergo clinical evaluation comprising at least a medical history, physical examination, and testing of blood specimens. Other biologic specimens may also be obtained from some individuals, and some individuals may undergo other diagnostic studies and examinations, depending on the type of familial neoplasm being studied.

If a family is already participating in the study and a specific mutation in a tumor predisposing gene predictive of disease has already been identified in the family, individuals may be eligible for genetic testing. Genes tested include RB1, APC, BRCA1/2, NF2, and VHL. Individuals under age 18 are only eligible to be tested for APC (familial adenomatous polyposis), NF2 (neurofibromatosis type 2), PTCH (nevoid basal cell carcinoma syndrome), RB1 (retinoblastoma), and VHL (von Hippel-Lindau disease).

Individuals may receive results of the genetic testing and genetic counseling is offered to all individuals who are tested.

A certificate of confidentiality protecting the identity of research participants in this project has been issued by the National Cancer Institute.

Families are followed every 1-2 years. In selected instances, individuals and families may return to the Clinical Center periodically for study-specific follow-up evaluations.

PROJECTED ACCRUAL: A total of 7,500 individuals will be accrued for this study. Substudies, involving subsets of the 7,500 individuals, are part of the overall study design.

• Bladder Cancer
• Brain and Central Nervous System Tumors
• Chordoma
• Lung Cancer
• Non-Melanomatous Skin Cancer
• Retinoblastoma
• Sarcoma

• Genetic: comparative genomic hybridization
• Genetic: gene rearrangement analysis
• Genetic: genetic linkage analysis
• Genetic: mutation analysis
• Other: laboratory biomarker analysis
• Other: questionnaire administration

• Ng D, Stavrou T, Liu L, Taylor MD, Gold B, Dean M, Kelley MJ, Dubovsky EC, Vezina G, Nicholson HS, Byrne J, Rutka JT, Hogg D, Reaman GH, Goldstein AM. Retrospective family study of childhood medulloblastoma. Am J Med Genet A. 2005 May 1;134(4):399-403. Erratum in: Am J Med Genet A. 2005 Jul 15;136(2):226.
• Yang XR, Beerman M, Bergen AW, Parry DM, Sheridan E, Liebsch NJ, Kelley MJ, Chanock S, Goldstein AM. Corroboration of a familial chordoma locus on chromosome 7q and evidence of genetic heterogeneity using single nucleotide polymorphisms (SNPs). Int J Cancer. 2005 Sep 1;116(3):487-91.
• Baser ME, Makariou EV, Parry DM. Predictors of vestibular schwannoma growth in patients with neurofibromatosis Type 2. J Neurosurg. 2002 Feb;96(2):217-22.
• Chan CC, Koch CA, Kaiser-Kupfer MI, Parry DM, Gutmann DH, Zhuang Z, Vortmeyer AO. Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2. J Pathol. 2002 Sep;198(1):14-20.
• Patronas NJ, Courcoutsakis N, Bromley CM, Katzman GL, MacCollin M, Parry DM. Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype. Radiology. 2001 Feb;218(2):434-42.
• Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF. Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet. 1996 Sep;59(3):529-39.
• Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn JM, Hall BD, Propping P, Rouleau GA. Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Am J Hum Genet. 1996 Aug;59(2):331-42.
• R Yang X, Pfeiffer RM, Goldstein AM. Influence of glutathione-S-transferase (GSTM1, GSTP1, GSTT1) and cytochrome p450 (CYP1A1, CYP2D6) polymorphisms on numbers of basal cell carcinomas (BCCs) in families with the naevoid basal cell carcinoma syndrome. J Med Genet. 2006 Apr;43(4):e16.
• Baser ME, Kuramoto L, Woods R, Joe H, Friedman JM, Wallace AJ, Ramsden RT, Olschwang S, Bijlsma E, Kalamarides M, Papi L, Kato R, Carroll J, Lazaro C, Joncourt F, Parry DM, Rouleau GA, Evans DG. The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet. 2005 Jul;42(7):540-6. Review.
• Baser ME, Mautner VF, Parry DM, Evans DG. Methodological issues in longitudinal studies: vestibular schwannoma growth rates in neurofibromatosis 2. J Med Genet. 2005 Dec;42(12):903-6. Epub 2005 Apr 14. Review.
• Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002 Jul;31(3):306-10. Epub 2002 Jun 17.
• Zhao Y, Kumar RA, Baser ME, Evans DG, Wallace A, Kluwe L, Mautner VF, Parry DM, Rouleau GA, Joe H, Friedman JM. Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2). Genet Epidemiol. 2002 Oct;23(3):245-59.
• Kelley MJ, Korczak JF, Sheridan E, Yang X, Goldstein AM, Parry DM. Familial chordoma, a tumor of notochordal remnants, is linked to chromosome 7q33. Am J Hum Genet. 2001 Aug;69(2):454-60. Epub 2001 Jul 10.

DISEASE CHARACTERISTICS:

• Family or personal medical history of neoplasia of unusual type, pattern, or number

  • Two or more living affected cases among family members are required

  • The following types of familial cancers are eligible:

    • Bone (non-neuroaxis, such as osteosarcoma)
    • Bladder
    • Brain
    • Chordoma
    • Lung
    • Nevoid basal cell carcinoma syndrome (NBCC)

  • The following type of familial benign neoplasm is eligible:

    • Neurofibromatosis type 2 (bilateral acoustic neurofibromatosis) OR

• Known or suspected factor(s) predisposing to neoplasia, meeting 1 of the following criteria:

  • Environmental exposure, including:

    • Medications
    • Occupation
    • Radiation
    • Diet
    • Infectious agents

  • Genetic and/or congenital factors, including:

    • Birth defects
    • Metabolic phenotype
    • Chromosomal anomalies
    • Mendelian traits associated with tumors

  • Unusual demographic features, including:

    • Very young age of onset
    • Multiple tumors
• Personal and family medical history must be verified through questionnaires, interviews, and review of pathology slides and medical records
• Ineligible for familial melanoma, lymphoproliferative, breast-ovarian cancer, or testicular cancer protocols

PATIENT CHARACTERISTICS:

Age:

• 1 month to 95 years

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• Not pregnant (for parts of protocol involving ionizing radiation or magnetic fields)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified