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Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry.

ABSTRACT: Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by red cell aplasia and congenital anomalies. A predisposition to cancer has been suggested but not quantified by case reports. The DBA Registry of North America (DBAR) is the largest established DBA patient cohort, with prospective follow-up since 1991. This report presents the first quantitative assessment of cancer incidence in DBA. Among 608 patients with 9458 person-years of follow-up, 15 solid tumors, 2 acute myeloid leukemias, and 2 cases of myelodysplastic syndrome were diagnosed at a median age of 41 years in patients who had not received a bone marrow transplant. Cancer incidence in DBA was significantly elevated. The observed-to- expected ratio for all cancers combined was 5.4 (P < .05); significant observed-to-expected ratios were 287 for myelodysplastic syndrome, 28 for acute myeloid leukemia, 36 for colon carcinoma, 33 for osteogenic sarcoma, and 12 for female genital cancers. The median survival was 56 years, and the cumulative incidence of solid tumor/leukemia was approximately 20% by age 46 years. As in Fanconi anemia and dyskeratosis congenita, DBA is both an inherited bone marrow failure syndrome and a cancer predisposition syndrome; cancer risks appear lower in DBA than in Fanconi anemia or dyskeratosis congenita. This trial was registered at www.clinicaltrials.gov as #NCT00106015.

SUBMITTER: Vlachos A

PROVIDER: S-EPMC3335385 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry.

Vlachos Adrianna A Rosenberg Philip S PS Atsidaftos Eva E Alter Blanche P BP Lipton Jeffrey M JM

Blood 20120223 16

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by red cell aplasia and congenital anomalies. A predisposition to cancer has been suggested but not quantified by case reports. The DBA Registry of North America (DBAR) is the largest established DBA patient cohort, with prospective follow-up since 1991. This report presents the first quantitative assessment of cancer incidence in DBA. Among 608 patients with 9458 person-years of follow-up, 15 solid tumors, ...[more]

PMID: 22362038

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Project description:Diamond Blackfan Anemia (DBA) is a rare, congenital erythrocyte aplasia that is usually caused by haploinsufficiency of ribosomal proteins due to diverse mutations in one of several ribosomal protein genes. A striking feature of this disease is that a range of different mutations in ribosomal proteins results in similar disease phenotypes primarily characterized by erythrocyte abnormalities and macrocytic anemia, while most other cell types are minimally affected. Previously, we analyzed the erythrocyte membrane proteomes of several DBA patients and identified several proteins that are not typically associated with this cell type that suggested inflammatory mechanisms contribute to the pathogenesis of DBA. In this study, we evaluated the erythrocyte cytosolic proteome of DBA patients through in-depth analysis of hemoglobin-depleted erythrocyte cytosol. The simple, reproducible, hemoglobin depletion using nickel columns enabled in-depth analysis of over 1000 cytosolic erythrocyte proteins with minimal subsequent fractionation of the proteome. Label-free quantitation and statistical analysis identified 29 proteins that were significantly changed in DBA patients compared to matched healthy control donors. Some of the proteins that were significantly increased in DBA erythrocyte cytoplasm included three proteasome subunit beta proteins that make up the immunoproteasome and proteins induced by interferon-γ such as n-myc interactor and interferon-induced 25 kDa protein [NMI and IFI35 respectively]. Pathway analysis confirmed the presence of an inflammatory signature with erythrocytes of DBA patients and predicted key upstream regulators including mitogen activated kinase 1, interferon-γ, tumor suppressor p53, and tumor necrosis factor. These results show that erythrocytes in DBA patients are intrinsically different from those in healthy controls which may be due to an inflammatory response resulting from the inherent molecular defect of ribosomal protein haploinsufficiency or changes in the bone marrow microenvironment that leads to red cell aplasia in DBA patients.

Dataset Information

Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry.

Publications

Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry.

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