RATIONALE: Genetic studies may help in understanding the genetic processes involved in the development of some types of cancer and may help doctors identify patients who are at risk for cancer.

PURPOSE: Genetic study of cancer risk and gene identification in patients and families who have Fanconi's anemia or other inherited bone marrow disorders.

OBJECTIVES:

• Establish a cohort of North American families with Fanconi's anemia (FA) or other inherited bone marrow failure syndromes (IBMFS) to determine the incident and prevalent rates of cancer (for all cancer and each type of cancer) in patients with these disorders.
• Determine the specific types of cancer associated with each type of IBMFS.
• Compare the biology of incident and prevalent tumors in IBMFS patients vs their sporadic counterparts in the general population.
• Determine whether FA or other IBMFS gene products are involved in the cancer pathways of the sporadic cancers seen in the general population that are common in patients with IBMFS.
• Determine differences, including genotype, phenotype, cancer susceptibility differences, modifier genes (gene-gene interactions), and environmental risk factors (gene-environment interactions), between those patients with FA or IBMFS who develop cancer and those with the same IBMFS who do not develop cancer.
• Determine the risk of cancer in individuals who are carriers of FA or other IBMFS gene mutations.
• Compare cellular and molecular characteristics of tumor biopsies and specimens from IBMFS patients vs cancers in the same tissues from the general population.
• Compare myelodysplastic syndromes (MDS) in these patients vs primary and secondary MDS in the general adult and pediatric population.
• Examine germline and tumor specimen DNA for IBMFS mutations from individuals not previously diagnosed with an IBMFS if they have tumors typical of IBMFS and do not have the risk factors seen in the general population.
• Search for genes that might modify cancer susceptibility in these patients using single nucleotide polymorphisms for candidate regions.
• Determine, using molecular methods, whether viral agents, such as human papilloma virus, are in the causal pathway of IBMFS-associated cancers.

OUTLINE: Patients and family members complete questionnaires and undergo clinical examinations and laboratory tests, which may include blood, bone marrow, urine, stool, buccal scraping, oral cavity brushing, oropharynx brushing, skin biopsy, hair, deciduous teeth, or tissue biopsies or pathology samples from tumors. Information is gathered retrospectively through questionnaires, review of medical records, and examination of archived materials and prospectively through additional questionnaires, clinical examinations, and laboratory tests.

Genetic education, counseling, and germline testing, as well as disclosure of the results, are available to patients and family members.

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

PROJECTED ACCRUAL: A total of 4,000 patients and family members will be accrued for this study.

• Genetic: comparative genomic hybridization
• Genetic: cytogenetic analysis
• Genetic: microarray analysis
• Other: biologic sample preservation procedure
• Other: medical chart review
• Other: questionnaire administration

• Atkinson JC, Harvey KE, Domingo DL, Trujillo MI, Guadagnini JP, Gollins S, Giri N, Hart TC, Alter BP. Oral and dental phenotype of dyskeratosis congenita. Oral Dis. 2008 Jul;14(5):419-27.
• Giri N, Batista DL, Alter BP, Stratakis CA. Endocrine Abnormalities in Patients with Fanconi Anemia. J Clin Endocrinol Metab. 2007 Apr 10; [Epub ahead of print]
• Rosenberg PS, Socie G, Alter BP, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood. 2005 Jan 1;105(1):67-73. Epub 2004 Aug 26.
• Rosenberg PS, Huang Y, Alter BP. Individualized risks of first adverse events in patients with Fanconi anemia. Blood. 2004 Jul 15;104(2):350-5. Epub 2004 Apr 1.
• Alter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, Peters JA, Giri N, Lansdorp PM. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood. 2007 Sep 1;110(5):1439-47. Epub 2007 Apr 27.
• Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007 Jan;44(1):1-9. Epub 2006 Jul 6.
• Giri N, Pitel PA, Green D, Alter BP. Splenic peliosis and rupture in patients with dyskeratosis congenita on androgens and granulocyte colony-stimulating factor. Br J Haematol. 2007 Sep;138(6):815-7. No abstract available.
• Hutson SP, Alter BP. Experiences of siblings of patients with Fanconi anemia. Pediatr Blood Cancer. 2007 Jan;48(1):72-9.
• Alter BP. The association between FANCD1/BRCA2 mutations and leukaemia. Br J Haematol. 2006 May;133(4):446-8; author reply 448. No abstract available.
• Braun M, Giri N, Alter BP, Cowen EW. Thrombocytopenia, multiple mucosal squamous cell carcinomas, and dyspigmentation. J Am Acad Dermatol. 2006 Jun;54(6):1056-9. No abstract available.
• Alter BP. Fanconi's anemia, transplantation, and cancer. Pediatr Transplant. 2005 Dec;9 Suppl 7:81-6.
• Alter BP, Joenje H, Oostra AB, Pals G. Fanconi anemia: adult head and neck cancer and hematopoietic mosaicism. Arch Otolaryngol Head Neck Surg. 2005 Jul;131(7):635-9. No abstract available.
• Rosenberg PS, Alter BP, Socie G, Gluckman E. Secular trends in outcomes for Fanconi anemia patients who receive transplants: implications for future studies. Biol Blood Marrow Transplant. 2005 Sep;11(9):672-9.
• Alter BP. Growth hormone and the risk of malignancy. Pediatr Blood Cancer. 2004 Oct;43(5):534-5. No abstract available.
• Tong BC, Dhir K, Ha PK, Westra WH, Alter BP, Sidransky D, Koch WM, Califano JA. Use of single nucleotide polymorphism arrays to identify a novel region of loss on chromosome 6q in squamous cell carcinomas of the oral cavity. Head Neck. 2004 Apr;26(4):345-52.
• Velazquez I, Alter BP. Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions. Am J Hematol. 2004 Nov;77(3):257-67. Review.
• Alter BP, Greene MH, Velazquez I, Rosenberg PS. Cancer in Fanconi anemia. Blood. 2003 Mar 1;101(5):2072. No abstract available.
• Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood. 2003 Feb 1;101(3):822-6. Epub 2002 Sep 5. Erratum in: Blood. 2003 Mar 15;101(6):2136.

DISEASE CHARACTERISTICS:

• Suspected (at the investigator's discretion) or proven diagnosis of 1 of the following inherited bone marrow failure syndromes (IBMFS):

  • Fanconi's anemia
  • Diamond-Blackfan anemia
  • Dyskeratosis congenita
  • Shwachman-Diamond syndrome
  • Amegakaryocytic thrombocytopenia
  • Thrombocytopenia absent radii
  • Severe congenital neutropenia
  • Pearson's syndrome
  • Other IBMFS (including Revesz, WT limb-blood syndrome, IVIC syndrome, radio-ulnar synostosis, and ataxia-pancytopenia) OR
• First-degree relatives (i.e., full or half siblings, biologic parents, and children) and grandparents of IBMFS patients OR
• Patients in the general population diagnosed with a sporadic tumor of the type seen in IBMFS (head and neck, gastrointestinal, or anogenital cancer) with none of the usual risk factors for that tumor (e.g., smoking, drinking, or human papilloma viral infection)
• No evidence that the hematologic disorder is acquired (e.g., temporal relation of aplastic anemia to known marrow suppressant drugs, chemicals, toxins, or viruses) in the absence of evidence indicative of an inherited marrow failure disorder

• No known causes of cytopenias, including any of the following:

  • Autoantibodies to red blood cells, platelets, or neutrophils
  • Viruses (especially hepatitis)
  • Micronutrient deficiencies
  • Transient erythroblastopenia of childhood
  • Cyclic neutropenia
• No physical findings indicative of other syndromes or causes that are not part of the IBMFS disease spectrum

PATIENT CHARACTERISTICS:

Age

• Any age

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• See Disease Characteristics

Renal

• Not specified

Other

• Able and willing to complete questionnaires and permit access to medical records and pathology specimens

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified