Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 56
Author(s):  
Jeffrey M. Lipton ◽  
Christine L. S. Molmenti ◽  
Pooja Desai ◽  
Alexander Lipton ◽  
Steven R. Ellis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Bone Marrow ◽  
Cancer Risk ◽  
Early Onset ◽  
Bone Marrow Failure ◽  
Osteogenic Sarcoma ◽  
Case Series ◽  
Cancer Predisposition Syndrome ◽  
Diamond Blackfan Anemia ◽  
Screening And Surveillance

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry.

Myelodysplastic Syndrome and Gastrointestinal Carcinomas Characterize the Cancer Risk in Diamond Blackfan Anemia: A Report from the Diamond Blackfan Anemia Registry

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 333-333 ◽  
Author(s):  
Adrianna Vlachos ◽  
Philip S Rosenberg ◽  
Jessica Kang ◽  
Eva Atsidaftos ◽  
Blanche P Alter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cancer Risk ◽  
Myelodysplastic Syndrome ◽  
Solid Tumors ◽  
Myeloid Leukemia ◽  
Osteogenic Sarcoma ◽  
Diamond Blackfan Anemia ◽  
Acute Myeloid

Abstract Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterized by red cell aplasia and congenital anomalies. In our 2012 report the predisposition to cancer was quantified for the first time by the DBA Registry of North America (DBAR), the largest established DBA patient cohort with prospective follow-up since 1991. Five years from the original analysis, this update of the cancer incidence in patients with DBA reveals additional solid tumors, in particular gastrointestinal tumors, and an alarming incidence of myelodysplastic syndrome (MDS). In this study we report the types, ages, outcomes and hazard rates in DBA patients with neoplasia enrolled in the DBAR. The patients/families and their physicians completed a detailed questionnaire. Information was verified through medical records and telephone interviews. The ratio of observed to expected (O/E) cancers was computed using SEER data, and the cumulative incidence and hazard rate of hematopoietic stem cell transplant (HSCT), acute myeloid leukemia (AML), solid tumors (ST), and MDS by age were calculated. There were 702 patients with 12,376 person-years of follow-up. Twenty-three had solid tumors, 3 had acute myeloid leukemia (AML), and 8 had MDS. The median age at diagnosis of a solid tumor for the patients who had not received a bone marrow transplant was 35 years (range, 11-63). There were 9 gastrointestinal carcinomas (7 colon, 1 gastroesophageal, and 1 esophageal), 4 osteogenic sarcoma, 2 breast cancer and 2 squamous cell carcinomas (vaginal and oral) and 9 others, with 3 patients having more than one cancer. Cancer incidence in DBA was significantly elevated with an observed-to-expected (O/E) ratio for all cancers combined of 4.75, (95% confidence interval 3.15-6.86); significant O/E ratios were 352 for MDS, 45 for colon carcinoma, excluding rectum, 42 for osteogenic sarcoma, and 29 for AML. Although the sample size is small it appears that the cancer risk by genotype correlates only with the relative incidence of that genotype in the DBAR cohort (RPS19, 7; RPL11, 2; RPL5, 2; RPL35a, 3; and RPS17, 1). By their mid-40s, 24% had received a HSCT, 23% had died, 2% had AML, and 12% had developed a ST; 61% had died or experienced a serious adverse event. The median overall survival was 51 years and the actuarial risk of MDS in the absence of any competing risks was 50% by age 30 years. Cancer risks in DBA appear to have reached those seen in dyskeratosis congenita (DC) and are still lower than in Fanconi anemia (FA). Furthermore, the type of solid tumors in DBA (gastrointestinal carcinoma and osteogenic sarcoma) vs. FA (head and neck squamous cell carcinoma) are quite different suggesting different mechanisms of carcinogenesis from nucleolar stress vs. genomic instability. Importantly the risk of MDS in DBA is elevated, as it is in FA and DC. This report also confirms the observation that there was no specific association of cancer type or frequency with genotype. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia

Blood ◽  
2011 ◽  
Vol 118 (23) ◽  
pp. 6087-6096 ◽  
Author(s):  
Pekka Jaako ◽  
Johan Flygare ◽  
Karin Olsson ◽  
Ronan Quere ◽  
Mats Ehinger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Rna Interference ◽  
Ribosomal Protein ◽  
Mouse Models ◽  
Bone Marrow Failure ◽  
Macrocytic Anemia ◽  
Down Regulation ◽  
Hematopoietic Stem ◽  
Diamond Blackfan Anemia ◽  
Ribosomal Protein S19

Abstract Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging because the phenotype is highly dependent on the level of RPS19 down-regulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded down-regulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.

scholarly journals Pancreatic lipomatosis in Diamond-Blackfan anemia: The importance of genetic testing in bone marrow failure disorders

2018 ◽  
Vol 93 (9) ◽  
pp. 1194-1195
Author(s):  
John M. Gansner ◽  
Elissa Furutani ◽  
Dean R. Campagna ◽  
Mark D. Fleming ◽  
Akiko Shimamura
Keyword(s):  
Bone Marrow ◽  
Genetic Testing ◽  
Bone Marrow Failure ◽  
Diamond Blackfan Anemia

Author response for "Is BRCA2 involved in early onset colorectal cancer risk?"

2019 ◽  
Author(s):  
Mathilde Gay‐Bellile ◽  
Maud Privat ◽  
Alexandra Martins ◽  
Sandrine M. Caputo ◽  
Céline Pebrel‐Richard ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Early Onset ◽  
Colorectal Cancer Risk ◽  
Author Response ◽  
Early Onset Colorectal Cancer

Gene Therapy Corrects the Lethal Bone Marrow Failure in a Mouse Model for RPS19-Deficient Diamond-Blackfan Anemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 513-513
Author(s):  
Pekka Jaako ◽  
Shubhranshu Debnath ◽  
Karin Olsson ◽  
Axel Schambach ◽  
Christopher Baum ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Mouse Model ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Diamond Blackfan Anemia ◽  
Stem And Progenitor Cells

Abstract Abstract 513 Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia associated with physical abnormalities and predisposition to cancer. Mutations in genes that encode ribosomal proteins have been identified in approximately 60–70 % of the patients. Among these genes, ribosomal protein S19 (RPS19) is the most common DBA gene (25 % of the cases). Current DBA therapies involve risks for serious side effects and a high proportion of deaths are treatment-related underscoring the need for novel therapies. We have previously demonstrated that enforced expression of RPS19 improves the proliferation, erythroid colony-forming potential and differentiation of patient derived RPS19-deficient hematopoietic progenitor cells in vitro (Hamaguchi, Blood 2002; Hamaguchi, Mol Ther 2003). Furthermore, RPS19 overexpression enhances the engraftment and erythroid differentiation of patient-derived hematopoietic stem and progenitor cells when transplanted into immunocompromised mice (Flygare, Exp Hematol 2008). Collectively these studies suggest the feasibility of gene therapy in the treatment of RPS19-deficient DBA. In the current project we have assessed the therapeutic efficacy of gene therapy using a mouse model for RPS19-deficient DBA (Jaako, Blood 2011; Jaako, Blood 2012). This model contains an Rps19-targeting shRNA (shRNA-D) that is expressed by a doxycycline-responsive promoter located downstream of Collagen A1 gene. Transgenic animals were bred either heterozygous or homozygous for the shRNA-D in order to generate two models with intermediate or severe Rps19 deficiency, respectively. Indeed, following transplantation, the administration of doxycycline to the recipients with homozygous shRNA-D bone marrow results in an acute and lethal bone marrow failure, while the heterozygous shRNA-D recipients develop a mild and chronic phenotype. We employed lentiviral vectors harboring a codon-optimized human RPS19 cDNA driven by the SFFV promoter, followed by IRES and GFP (SFFV-RPS19). A similar vector without the RPS19 cDNA was used as a control (SFFV-GFP). To assess the therapeutic potential of the SFFV-RPS19 vector in vivo, transduced c-Kit enriched bone marrow cells from control and homozygous shRNA-D mice were injected into lethally irradiated wild-type mice. Based on the percentage of GFP-positive cells, transduction efficiencies varied between 40 % and 60 %. Three months after transplantation, recipient mice were administered doxycycline in order to induce Rps19 deficiency. After two weeks of doxycycline administration, the recipients transplanted with SFFV-RPS19 or SFFV-GFP control cells showed no differences in blood cellularity. Remarkably, at the same time-point the recipients with SFFV-GFP homozygous shRNA-D bone marrow showed a dramatic decrease in blood cellularity that led to death, while the recipients with SFFV-RPS19 shRNA-D bone marrow showed nearly normal blood cellularity. These results demonstrate the potential of enforced expression of RPS19 to reverse the severe anemia and bone marrow failure in DBA. To assess the reconstitution advantage of transduced hematopoietic stem and progenitor cells with time, we performed similar experiments with heterozygous shRNA-D bone marrow cells. We monitored the percentage of GFP-positive myeloid cells in the peripheral blood, which provides a dynamic read-out for bone marrow activity. After four months of doxycycline administration, the mean percentage of GFP-positive cells in the recipients with SFFV-RPS19 heterozygous shRNA-D bone marrow increased to 97 %, while no similar advantage was observed in the recipients with SFFV-RPS19 or SFFV-GFP control bone marrow, or SFFV-GFP heterozygous shRNA-D bone marrow. Consistently, SFFV-RPS19 conferred a reconstitution advantage over the non-transduced cells in the bone marrow. Furthermore, SFFV-RPS19 reversed the hypocellular bone marrow observed in the SFFV-GFP heterozygous shRNA-D recipients. Taken together, using mouse models for RPS19-deficient DBA, we demonstrate that the enforced expression of RPS19 rescues the lethal bone marrow failure and confers a strong reconstitution advantage in vivo. These results provide a proof-of-principle for gene therapy in the treatment of RPS19-deficient DBA. Disclosures: No relevant conflicts of interest to declare.

Pearson Marrow Pancreas Syndrome In a Cohort Of Diamond Blackfan Anemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1226-1226
Author(s):  
Katelyn E Gagne ◽  
Roxanne Ghazvinian ◽  
Daniel Yuan ◽  
Rebecca L. Zon ◽  
Kelsie Storm ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Diagnostic Evaluation ◽  
Clinical Samples ◽  
Study Cohort ◽  
Deletion Mapping ◽  
Deletion Event ◽  
Diamond Blackfan Anemia ◽  
Mtdna Deletions

Abstract Pearson marrow pancreas syndrome (PS) is a congenital multisystem disorder characterized by sideroblastic anemia, pancreatic insufficiency, metabolic acidosis, and other defects, and is caused by mitochondrial DNA (mtDNA) deletions. Diamond Blackfan anemia (DBA) is a congenital hypoproliferative anemia with associated physical malformations, and in which mutations in ribosomal protein (RP) genes and GATA1 have been implicated. The clinical presentation of both of these bone marrow failure (BMF) syndromes shares several features including early onset of severe anemia, sporadic genetic inheritance, variable penetrance and manifestations, and episodes of spontaneous hematologic improvement. PS is less frequently occurring than DBA, with estimated incidences of < 1/1,000,000 versus 1/100,000 respectively, and therefore less often encountered by hematologists. We hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. To test this hypothesis, we retrospectively evaluated DNA samples from a cohort of patients that were submitted to a research study for DBA genetic testing. The study cohort consists of clinical samples and/or data from 362 patients, with a primary inclusion criterion of known or suspected congenital anemia. Prior genetic studies from this cohort have yielded the novel identification or confirmation of mutations and deletions in several genes implicated in DBA (e.g. RP genes, GATA1), which are to date identifiable in 175/362 samples (48%), a proportion consistent with that found in independent DBA registries. We screened peripheral blood DNA samples available from 173 genetically uncharacterized patients using a long PCR strategy, and found that 8 samples (4.6%) contained large mtDNA deletions. Deletion mapping and Southern blot analysis on DNA from these 8 patients confirmed the presence of a single deletion event within each patient, ranging in size from 2.3 - 7.0 kb of the 16.6 kb mitochondrial genome, existing as monomer or multimer mtDNA species, and in a proportion ranging from 55-80% of total mtDNA, all of which are consistent with the molecular diagnosis of PS. Follow-up with referring providers in the 1 month to 8 year time span since sample submission revealed that 2 of the 8 patients (25%) were subsequently diagnosed with PS. Of the remaining 6 undiagnosed patients, 2 had died from complications of bone marrow transplantation, performed for worsening cytopenias and concern for myelodysplasia; one patient died from bacterial sepsis; and 3 were alive with the provisional diagnosis of DBA. One of the 3 patients had become transfusion-independent. Review of bone marrow examinations revealed that the pathological hallmarks of ringed sideroblasts and/or vacuolization of precursors described in PS were inconsistently present or reported in the diagnostic evaluation. We conclude that PS is frequently overlooked in the diagnostic evaluation of children with congenital anemia. Establishing the diagnosis of PS, as distinct from DBA and other BMF disorders, holds important implications for patient management and family counseling. mtDNA deletion testing should be performed in the initial genetic evaluation of all patients with congenital anemia. Disclosures: Szczepanski: Octapharma AG: Investigator Other.

scholarly journals Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2296-2304 ◽  
Author(s):  
Anupama Narla ◽  
Shilpee Dutt ◽  
J. Randall McAuley ◽  
Fatima Al-Shahrour ◽  
Slater Hurst ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Expression Profiles ◽  
Bone Marrow Failure ◽  
Gene Expression Profiles ◽  
Absolute Number ◽  
Red Blood Cell Transfusion ◽  
Erythroid Progenitor ◽  
Diamond Blackfan Anemia ◽  
Cd34 Cells

Abstract Corticosteroids and lenalidomide decrease red blood cell transfusion dependence in patients with Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome (MDS), respectively. We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34+ cells and from CD34+ cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number of burst-forming units-erythroid (BFU-E), whereas lenalidomide specifically increased colony-forming unit-erythroid (CFU-E). Use of the drugs in combination demonstrated that their effects are not redundant. In addition, dexamethasone and lenalidomide induced distinct gene-expression profiles. In coculture experiments, we examined the role of the microenvironment in response to both drugs and found that the presence of macrophages, the central cells in erythroblastic islands, accentuated the effects of both agents. Our findings indicate that dexamethasone and lenalidomide promote different stages of erythropoiesis and support the potential clinical utility of combination therapy for patients with bone marrow failure.

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