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Study Description

Background:

  • A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders.
  • Mutations in IBMFS genes are relevant to carcinogenesis in sporadic cancers.
  • Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer.
  • These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer.
  • Carriers of IBMFS gene mutations are at increased risk of cancer.
  • The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied.

Objectives:

  • To determine the types and incidence of specific cancers in patients with an IBMFS.
  • To investigate the relevance of IBMFS gene mutations in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers.
  • To identify risk factors for IBMFS-related cancers in addition to the primary germline mutations.
  • To determine the risk of cancer in IBMFS carriers.

Design:

  • Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance.
  • Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS.
  • Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

Authorized Access
Publicly Available Data
  Link to other NCBI resources related to this study
Study Inclusion/Exclusion Criteria

Eligibility:

  • North American families (or other eligible families) with a proband with an IBMFS.
  • IBMFS suspected by phenotype, confirmed by mutation in an IBMFS gene, or by clinical diagnostic test.
  • Fanconi anemia: birth defects, marrow failure, early onset malignancy; positive chromosome breakage result.
  • Diamond-Blackfan anemia: pure red cell aplasia; elevated red cell red cell adenosine deaminase.
  • Dyskeratosis congenita: dysplastic nails, lacey pigmentation, leukoplakia; marrow failure.
  • Shwachman-Diamond Syndrome: malabsorption; neutropenia.
  • Amegakaryocytic thrombocytopenia: early onset thrombocytopenia.
  • Thrombocytopenia absent radii: absent radii; early onset thrombocytopenia.
  • Severe Congenital Neutropenia: neutropenia, pyogenic infections, bone marrow maturation arrest.
  • Pearson Syndrome: malabsorption, neutropenia, marrow failure, metabolic acidosis; ringed sideroblasts.
  • Other bone marrow failure syndromes: e.g. Revesz Syndrome, WT, IVIC, radio-ulnar synostosis, ataxia-pancytopenia.
  • First degree relatives of IBMFS-affected subjects as defined here, i.e. siblings (half or full), biologic parents, and children.
  • Grandparents of IBMFS-affected subjects.
  • Patients in the general population with sporadic tumors of the types seen in the IBMFS (head and neck, gastrointestinal, and anogenital cancer), with none of the usual risk factors (e.g. smoking, drinking, HPV).

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Exome Sequencing Roche NimbleGen SeqCap EZHuman Exome Library v3.0 N/A N/A
Study History

Accrual to this protocol began in January 2002. We continue to recruit through various mechanisms, including our web site (www.marrowfailure.cancer.gov), disease-specific family support groups, NORD, NCI PDQ, and linkage to related studies, as well as presentations at relevant major medical meetings. Participants are all enrolled in the Field Cohort (FC); those who are seen at the NIH Clinical Center are then moved to the Clinical Center Cohort (CC). We added 90 new subjects since the last CR (from November 1, 2015, until September 30, 2016) for a total of 1987 subjects since 2002. The total reflects 101 accrued (1886 total individuals reported last year and 1987 this year) because we received consents on 11 people following the last CR report that were actually signed in the previous report period (prior to 11/1/2015). This includes those affected with each syndrome, as well as their relatives, and those seen at the Clinical Center, as well as those in the Field Cohort who are not seen at the Clinical Center. We have continued enrollment of new families, evaluation of selected participants at the NIH Clinical Center, and review of records from those seen at the NIH as well as the participants who remain in the Field Cohort. We have reinforced the fact that clinical phenotype and laboratory data are much more complete for those who came to the Clinical Center than for those whose information came solely from review of medical records. Seven new families visited the Clinical Center since the last review, for a total of 175 families. We identified the genotype and specific mutations in many of the families in our study, including 86% of those with Fanconi Anemia, 67% of those with dyskeratosis congenita, 52% of those with Diamond-Blackfan anemia, and 90% with Shwachman-Diamond Syndrome. Families in which we have not identified a gene include those in which all known genes have been tested, as well as more recent additions to the cohort. We provided genetic counseling to those for whom we planned and/or have genetic testing information. We continue to gather information on prevalent and incident cancers, and to search for new genes in families without mutations in known genes.

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
Links to Related Genes
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Study Attribution
  • Principal Investigator
    • Blanche P. Alter. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.