Patient case: 39-year-old female with melanoma; genetic feature: KIT (N822Y)

Clinical trial: Cancer in Inherited Bone Marrow Failure Syndromes

Summary: 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's 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.
  Eligibility:
  North American families with a proband with an IBMFS.
  IBMFS suspected by phenotype, confirmed by mutation in an IBMFS gene, or by clinical diagnostic test.
  Fanconi's anemia: birth defects, marrow failure, early onset malignancy; positive chromosome breakage result.
  Diamond-Blackfan anemia: pure red cell aplasia; elevated 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's 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).
  Design:
  Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory test, 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..

Detailed 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's 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.
  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's anemia: birth defects, marrow failure, early onset malignancy; positive chromosome breakage result.
  Diamond-Blackfan anemia: pure red cell aplasia; elevated 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's 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).
  Design:
  Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory test, 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.

Eligibility: -  INCLUSION CRITERIA - PATIENTS:
  -  Fanconi s anemia.
  -  Diamond-Blackfan anemia.
  -  Dyskeratosis congenita.
  -  Shwachman-Diamond Syndrome.
  -  Amegakaryocytic thrombocytopenia.
  -  Thrombocytopenia absent radii.
  -  Severe congenital neutropenia.
  -  Pearson s Syndrome.
  -  Other bone marrow failure syndromes.
  -  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, specifically for Hypothesis 4.
  -  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 for those tumors (e.g. smoking, drinking, HPV).
  -  Adult patients and family members who are unable to provide consent.
  INCLUSION CRITERIA - UNAFFECTED SIBLING STUDY:
  Eligibility for this amendment will be assessed only after the subject has been deemed eligible for the parent protocol.
  Specific eligibility for the proposed amendment are as follows:
  -  Ability to read, write, and speak in English.
  -  Between the ages of 11 & 21.
  -  Informant has at least one biologically related, living sibling (full or half) who has an IBMFS.
  EXCLUSION CRITERIA - PARENT PROTOCOL:
  -  Evidence that the hematologic disorder is acquired rather than genetic. Such evidence includes temporal relation of the aplastic anemia to known marrow suppressant drugs, chemicals, toxins, or viruses (in the absence of evidence indicative of an inherited marrow failure disorder).
  -  Known causes of cytopenias such as autoantibodies to red cells, platelets, or neutrophils, viruses (especially hepatitis), micronutrient deficiencies, transient erythroblastopenia of childhood, and cyclic neutropenia.
  -  Assignment of the patient s physical findings to other syndromes or causes that are not part of the IBMFS disease spectrum.
  -  Inability or unwillingness to complete the questionnaires or permit access to medical records and pathology specimens.
  -  There are no other exclusion parameters not related to the primary disease.
  EXCLUSION CRITERIA - UNAFFECTED SIBLING STUDY:
  -  Diagnosis of an IBMFS or any other chronic illness.
  -  Cognitive impairment or inability to express feelings or experiences verbally or inability to provide informed consent.
  -  Emotional distress at the time of the interview.

Relevance to patient case: not relevant