RESUMO
The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.
Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Pancitopenia , Humanos , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Diagnóstico Diferencial , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Anemia Aplástica/terapia , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Pancitopenia/diagnósticoRESUMO
Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
Assuntos
Disceratose Congênita/genética , Disceratose Congênita/metabolismo , Fibroblastos/metabolismo , NAD/metabolismo , Telomerase/genética , Telômero/metabolismo , ADP-Ribosil Ciclase 1/genética , Animais , Encéfalo/patologia , Linhagem Celular , Senescência Celular , Disceratose Congênita/patologia , Feminino , Homeostase , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Fenótipo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Compostos de Piridínio/metabolismo , Telomerase/metabolismoRESUMO
Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs, and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR), or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs (144 male, 86.6% known genotype, median age at diagnosis 19.4 years [range 0 to 71.6]), enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up (median follow-up 5.2 years [range 0 to 36.7]). Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure (BMF), severe liver disease, and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival (OS) of 52.8 years (95% confidence interval [CI] 45.5-57.6), and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better OS was present in AD vs AR/XLR/TINF2 disease (P < .01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines and risk stratification in patients with DC/TBDs. This trial was registered at www.clinicaltrials.gov as #NCT00027274.
Assuntos
Disceratose Congênita , Telomerase , Biologia , Progressão da Doença , Disceratose Congênita/genética , Disceratose Congênita/terapia , Humanos , Masculino , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo , Encurtamento do TelômeroRESUMO
Fanconi anemia (FA) is caused by pathogenic variants in the FA/BRCA DNA repair pathway genes, and is characterized by congenital abnormalities, bone marrow failure (BMF) and increased cancer risk. We conducted a genotype-phenotype and outcomes study of 203 patients with FA in our cohort. We compared across the genes, FA/BRCA DNA repair pathways (upstream, ID complex and downstream), and type of pathogenic variants (hypomorphic or null). We explored differences between the patients evaluated in our clinic (clinic cohort) and those who provided data remotely (field cohort). Patients with variants in upstream complex pathway had less severe phenotype [lacked VACTERL-H (Vertebral, Anal, Cardiac, Trachea-esophageal fistula, Esophageal/duodenal atresia, Renal, Limb, Hydrocephalus) association and/or PHENOS (Pigmentation, small-Head, small-Eyes, Neurologic, Otologic, Short stature) features]. ID complex was associated with VACTERL-H. The clinic cohort had more PHENOS features than the field cohort. PHENOS was associated with increased risk of BMF, and VACTERL-H with hypothyroidism. The cumulative incidence of severe BMF was 70%, solid tumors (ST) 20% and leukemia 6.5% as the first event. Head and neck and gynecological cancers were the most common ST, with further increased risk after hematopoietic cell transplantation. Among patients with FANCA, variants in exons 27-30 were associated with higher frequency of ST. Overall median survival was 37 years; patients with leukemia or FANCD1/BRCA2 variants had poorest survival. Patients with variants in the upstream complex had better survival than ID or downstream complex (p=0.001 and 0.016, respectively). FA is phenotypically and genotypically heterogeneous; detailed characterization provides new insights towards understanding this complex syndrome and guiding clinical management.
Assuntos
Anemia de Fanconi , Leucemia , Neoplasias , Estados Unidos , Humanos , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , National Cancer Institute (U.S.) , Fenótipo , Neoplasias/genética , GenótipoRESUMO
Fanconi anaemia (FA) is an inherited bone marrow failure syndrome (IBMFS) with a high cancer predisposition rate. Traditional diagnoses are made before age 10 years due to bone marrow failure (BMF) and characteristic birth defects. Up to 10% of published cases were adults at diagnosis. We hypothesized that FA subgroups diagnosed in childhood are distinct from those diagnosed as adults. We classified patients by age at diagnosis of FA as FA-PED (<18 years) or FA-ADULT (≥18 years). The National Cancer Institute IBMFS cohort included 178 FA-PED and 26 FA-ADULT cases. We compared various features; the cumulative incidences of first adverse events (severe BMF leading to haematopoietic cell transplant or death, leukaemia, or solid tumours) were compared using competing-risk analyses. FA-ADULT lacked the 'typical' FA features (birth defects and early-onset BMF or leukaemia), were mainly female, had more patients with FANCA genotype, and had or developed more head and neck squamous-cell carcinoma (HNSCC) and/or gynaecological cancers compared with FA-PED, albeit at similar ages in both subgroups. FA-ADULT is a distinct subgroup that remained unrecognized during childhood. Centres for adult haematology-oncology should consider FA diagnosis in patients with early-onset HNSCC or gynaecological cancer with or without haematologic problems.
Assuntos
Anemia de Fanconi , Neoplasias de Cabeça e Pescoço , Transplante de Células-Tronco Hematopoéticas , Leucemia , Adulto , Transtornos da Insuficiência da Medula Óssea , Criança , Síndrome Congênita de Insuficiência da Medula Óssea , Anemia de Fanconi/complicações , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Feminino , Humanos , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
PURPOSE: Fanconi anemia (FA) is a cancer-prone inherited bone marrow failure syndrome caused by biallelic pathogenic variants in one of >22 genes in the FA/BRCA DNA repair pathway. A major concern is whether the risk of cancer is increased in individuals with a single pathogenic FA gene variant. METHODS: We evaluated the risk of cancer in the relatives of patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome cohort. We genotyped all available relatives and determined the rates, types of cancer and the age of patients at cancer diagnosis. We calculated the observed-to-expected (O/E) cancer ratios using data from the Surveillance, Epidemiology, and End Results Program adjusted for age, sex, and birth cohort. RESULTS: The risk of cancer was not increased among all FA relatives and FA heterozygotes (O/E ratios of 0.78 and 0.79, respectively). In particular, the risk of cancer was not increased among FANCA or FANCC heterozygotes (O/E ratios of 0.92 and 0.71, respectively). Relatives did not have typical FA cancers, and age at cancer diagnosis was not younger than expected. CONCLUSION: Understanding the risk of cancer in individuals with single pathogenic FA variants is critical for counseling and management. We did not find increased risk of cancer in these individuals. These findings do not extend to the known cancer predisposition autosomal dominant FA genes, namely BRCA1, BRCA2, PALB2, BRIP1, and RAD51C.
Assuntos
Anemia de Fanconi , Neoplasias , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Neoplasias/epidemiologia , Neoplasias/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) associated with pancreatic insufficiency, neutropenia, and skeletal dysplasia. Biallelic pathogenic variants (PV) in SBDS account for >90% of SDS. We hypothesized that the SDS phenotype varies based on genotype and conducted a genotype-phenotype correlation study to better understand these complexities. METHODS: We reviewed records of all patients with SDS or SDS-like syndromes in the National Cancer Institute's (NCI) IBMFS study. Additional published SDS cohorts were reviewed and compared with the NCI cohort. RESULTS: PVs in SBDS were present in 32/47 (68.1%) participants. Biallelic inheritance of SBDS c.258 + 2T > C and c.183_184TA > CT was the most common genotype in our study (25/32, 78.1%) and published cohorts. Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%). Developmental delay was common (20/34, 58.8%). Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies. CONCLUSIONS: SDS is a complex childhood illness with a narrow genotypic spectrum. Patients may first present to primary care, gastroenterology, orthopedic, and/or hematology clinics. Coordinated multidisciplinary care is important for diagnosis and patient management. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00027274. IMPACT: The clinical and genetic spectrum of Shwachman Diamond Syndrome was comprehensively evaluated, and the findings illustrate the importance of a multidisciplinary approach for these complex patients. Our work reveals: 1. a narrow genotypic spectrum in SDS; 2. a low risk of solid tumors in patients with SDS; 3. patients with SDS have clinical manifestations in multiple organ systems.
Assuntos
Doenças da Medula Óssea , Insuficiência Pancreática Exócrina , Lipomatose , Neutropenia , Humanos , Síndrome de Shwachman-Diamond/complicações , Doenças da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Lipomatose/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/genética , Neutropenia/genética , GenótipoRESUMO
Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.
Assuntos
Disceratose Congênita/genética , Retardo do Crescimento Fetal/genética , Mutação em Linhagem Germinativa/genética , Deficiência Intelectual/genética , Microcefalia/genética , Serina Proteases/genética , Adulto , Criança , Pré-Escolar , Disceratose Congênita/patologia , Feminino , Retardo do Crescimento Fetal/patologia , Células HeLa , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Linhagem , Estrutura Terciária de Proteína , Deleção de Sequência/genética , Serina Proteases/química , Complexo Shelterina , Telomerase/metabolismo , Proteínas de Ligação a Telômeros/metabolismoRESUMO
Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.
Assuntos
Disceratose Congênita , Fertilidade , Pré-Eclâmpsia , Nascimento Prematuro , Saúde Reprodutiva , Doenças Uterinas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Disceratose Congênita/epidemiologia , Disceratose Congênita/genética , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/genética , Gravidez , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/genética , Doenças Uterinas/epidemiologia , Doenças Uterinas/genéticaRESUMO
OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
Assuntos
Hemorragia Gastrointestinal/etiologia , Telômero/genética , Adolescente , Adulto , Ataxia/complicações , Ataxia/genética , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/genética , Medula Óssea/anormalidades , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Calcinose/complicações , Calcinose/genética , Cistos do Sistema Nervoso Central/complicações , Cistos do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Disceratose Congênita/complicações , Disceratose Congênita/genética , Feminino , Retardo do Crescimento Fetal/genética , Hemorragia Gastrointestinal/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Leucoencefalopatias/complicações , Leucoencefalopatias/genética , Masculino , Microcefalia/complicações , Microcefalia/genética , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Mutação , Retina , Doenças Retinianas/complicações , Doenças Retinianas/genética , Convulsões/complicações , Convulsões/genética , Telômero/metabolismo , Telômero/patologia , Adulto JovemRESUMO
Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p<0.01) compared with all other pathogenic variants. Non-large deletion pathogenic variants were spread across RPL35A with no apparent hot spot and 56% of the individual family variants were observed more than once. In this, the largest known study of DBA patients with pathogenic RPL35A variants, we determined that patients with large deletions have a more severe phenotype that is clinically different from those with non-large deletion variants. Genes of interest also deleted in the 3q29 region that could be associated with some of these phenotypic features include LMLN and IQCG. Management of DBA due to large RPL35A deletions may be challenging due to complex problems and require comprehensive assessments by multiple specialists including immunologic, gastrointestinal, and developmental evaluations to provide optimal multidisciplinary care.
Assuntos
Anemia de Diamond-Blackfan , Anemia de Diamond-Blackfan/genética , Estudos de Associação Genética , Humanos , Mutação , Fenótipo , Proteínas Ribossômicas/genéticaRESUMO
Diamond-Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early-onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q-myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce the RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC.
Assuntos
Anemia de Diamond-Blackfan/genética , Mutação em Linhagem Germinativa , Proteínas Ribossômicas/genética , Adolescente , Sequência de Aminoácidos , Criança , Neoplasias Colorretais/genética , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , Penetrância , Estrutura Terciária de Proteína , Sequenciamento do ExomaRESUMO
Severe aplastic anemia (SAA) is most frequently immune-mediated; however, rare inherited bone marrow failure syndromes, such as Fanconi anemia (FA), may be causal and can present as aplastic anemia (AA). FA is primarily an autosomal recessive disorder caused by the presence of 2 pathogenic variants in a single FA/BRCA DNA repair pathway gene. Patients with SAA often undergo genetic testing during clinical evaluation that may identify single deleterious alleles in FA pathway genes. We quantified the rate of germline single deleterious alleles in 22 FA genes using both a general population database (3234 variants, 125,748 exomes) and in a cohort of patients with SAA undergoing hematopoietic cell transplantation (HCT) (21 variants in 730 patients). The variants were classified as deleterious using in silico tools (REVEL, MetaSVM, VEP) and database resources (ClinVar, LOVD-FA). We found similar rates of single deleterious alleles in FA genes in both groups (2.6% and 2.9%). The presence of a single deleterious variant in a gene for FA in SAA HCT recipients did not affect the overall survival after HCT (hazard ratio, 0.85; 95% CI, 0.37 to 1.95; P = 0.71), or post-HCT cancer risk (P = 0.52). Our results demonstrate that the identification of a germline monoallelic deleterious variant in an FA gene in patients with idiopathic SAA does not influence the outcome of HCT. Our findings suggest that there is no need for special treatment considerations for patients with SAA and a single deleterious FA allele identified on genetic testing.
Assuntos
Anemia Aplástica , Anemia de Fanconi , Transplante de Células-Tronco Hematopoéticas , Alelos , Anemia Aplástica/genética , Anemia Aplástica/terapia , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Frequência do Gene , HumanosRESUMO
In the original publication of the article, the first sentence in the abstract was published incorrectly.
RESUMO
PURPOSE: Germline pathogenic variants in BRCA1 (FANCD1) and BRCA2 (FANCS) do not explain all familial or sporadic cases with breast cancer. Several reports indicate a role for pathogenic variants in other genes in the Fanconi anemia/breast cancer DNA repair pathway; the strengths of these associations vary widely. Publications from 2006 through 2017 were reviewed to provide a better estimate of the role of pathogenic variants in genes in this pathway in breast cancer. METHODS: We identified cohorts and case-control reports describing heterozygous pathogenic variants in Fanconi anemia genes in breast cancer cases with high risk of a germline pathogenic variant in a non-BRCA1/2 breast cancer susceptibility gene ("familial"), and cases unselected for family history ("unselected"). Meta-analysis and meta-regression were used to estimate the frequencies of pathogenic variants in cohorts and the odds ratios (OR) in case-control studies. RESULTS: Meta-analysis of more than 100 reports of FANCN/PALB2 in familial breast cancer cases provided an overall pathogenic variant prevalence of 1.29% and an OR of 8.45. The prevalence in unselected cohorts was 0.64%, and the OR was 4.76. Pathogenic variants in FANCJ/BRIP1 had a prevalence of 0.5% in familial cases, and an OR of 1.62; their prevalence in unselected cases was 0.39%. FANCO/RAD51C, FANCP/SLX4, FANCU/XRCC2, FANCD2, and other FA-related genes all had prevalences of ≤ 0.5% among familial cases, and even lower in unselected cases. CONCLUSIONS: Heterozygous pathogenic variants in FANCN/PALB2 and possibly FANCJ/BRIP1 may account for 1-2% of familial non-BRCA1/2 breast cancer cases and 0.5-1% of unselected cases. Genetic counseling and testing may be suggested for unaffected relatives.
Assuntos
Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Triagem de Portadores Genéticos/estatística & dados numéricos , Mutação em Linhagem Germinativa , RNA Helicases/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Reparo do DNA/genética , Feminino , Aconselhamento Genético , Predisposição Genética para Doença , Heterozigoto , HumanosRESUMO
Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.
Assuntos
Fístula Arteriovenosa , Artéria Pulmonar/anormalidades , Veias Pulmonares/anormalidades , Telangiectasia , Telômero , Animais , Fístula Arteriovenosa/genética , Fístula Arteriovenosa/metabolismo , Fístula Arteriovenosa/patologia , Educação , Humanos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Veias Pulmonares/metabolismo , Veias Pulmonares/patologia , Telangiectasia/genética , Telangiectasia/metabolismo , Telangiectasia/patologia , Telômero/genética , Telômero/metabolismo , Telômero/patologiaRESUMO
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
Assuntos
Anemia Aplástica/genética , Anemia Aplástica/terapia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/terapia , Padrões de Herança/genética , Transtornos da Insuficiência da Medula Óssea , HumanosRESUMO
Dyskeratosis congenita (DC) is a genetic disorder of defective tissue maintenance and cancer predisposition caused by short telomeres and impaired stem cell function. Telomerase mutations are thought to precipitate DC by reducing either the catalytic activity or the overall levels of the telomerase complex. However, the underlying genetic mutations and the mechanisms of telomere shortening remain unknown for as many as 50% of DC patients, who lack mutations in genes controlling telomere homeostasis. Here, we show that disruption of telomerase trafficking accounts for unknown cases of DC. We identify DC patients with missense mutations in TCAB1, a telomerase holoenzyme protein that facilitates trafficking of telomerase to Cajal bodies. Compound heterozygous mutations in TCAB1 disrupt telomerase localization to Cajal bodies, resulting in misdirection of telomerase RNA to nucleoli, which prevents telomerase from elongating telomeres. Our findings establish telomerase mislocalization as a novel cause of DC, and suggest that telomerase trafficking defects may contribute more broadly to the pathogenesis of telomere-related disease.
Assuntos
Disceratose Congênita/enzimologia , Disceratose Congênita/genética , Mutação/genética , Transporte Proteico/fisiologia , Telomerase/metabolismo , Sequência de Aminoácidos , Animais , Disceratose Congênita/fisiopatologia , Humanos , Modelos Moleculares , Chaperonas Moleculares , Linhagem , Transporte Proteico/genética , Alinhamento de Sequência , Telomerase/genéticaRESUMO
Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991 and 2007. Outcome data and blood samples were available through the Center for International Blood and Marrow Transplant Research. For survival analyses, we used the Kaplan-Meier estimator to calculate the survival probabilities and the exact log-rank test to compare the survival differences across groups. Chromosomal aberrations were detected in 16 (22%) patients; most frequent were clonal copy loss in chromosome 7 (9.6%), clonal copy gains in the long arm (q) of chromosome 1 (chr1q+) (8.2%), and clonal or complete copy gains in the q arm of chromosome 3 (chr3q+) (8.2%). Seven (9.6%) patients had alterations in 3 or more chromosomes. Poor post-HCT overall survival (OS) was noted in patients with chr3q+ (P = .04), or those with abnormalities in ≥3 chromosomes (P = .03). The 1-year OS was 0% versus 45% in patients with either alteration versus its absence. No statistically significant differences in OS were noted in patients carrying deletions in chr7 (1-year OS = 29% versus 42%; log-rank P = .74). The study is limited by the small sample size. A larger, prospective study is warranted to validate our findings in light of recent improvement in transplant modalities and outcomes.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Anemia de Fanconi , Transplante de Células-Tronco Hematopoéticas , Doadores não Relacionados , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Anemia de Fanconi/genética , Anemia de Fanconi/mortalidade , Anemia de Fanconi/patologia , Anemia de Fanconi/terapia , Feminino , Humanos , Masculino , Estudos Prospectivos , Taxa de SobrevidaRESUMO
The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone marrow failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone marrow failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone marrow failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the syndromes. Cancer was most common in Fanconi anemia, followed by dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone marrow failure and specific cancers. clinicaltrials.gov Identifier: 00027274.