RESUMEN
The complementation Q group (FANCQ) subtype of Fanconi anemia (FA) caused by the ERCC4/XPF mutation is very rare. Two siblings, aged 13 and 10 with Fanconi phenotypic features, presented with right hemiparesis and focal-onset seizures. In both cases, cranial magnetic resonance imaging (MRI) showed mass-like lesions accompanied by peripheral edema and calcification. In one case, oral steroid treatment and surgical excision were performed, while in the other case, the cranial lesion regressed just with steroid treatment and without surgery. Both siblings remained wheelchair-bound due to neurological dysfunction. One case died due to hepatocellular carcinoma. ERCC4/XPF gene mutation was detected in both siblings.
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Proteínas de Unión al ADN , Anemia de Fanconi , Hermanos , Humanos , Anemia de Fanconi/complicaciones , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Masculino , Proteínas de Unión al ADN/genética , Niño , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/complicaciones , Femenino , Imagen por Resonancia Magnética , Mutación , Diagnóstico DiferencialRESUMEN
ABSTRACT: Fanconi anemia (FA) is a complex inherited bone marrow failure syndrome characterized by chromosomal instability and defective DNA repair, causing sensitivity to DNA interstrand crosslinking agents. Our understanding of the full adult phenotype of the disease continues to evolve, because most patients with FA died of marrow failure in the first decade of life before more recent advances in allogeneic hematopoietic cell transplantation. Herein, we report a previously undescribed, clinically concerning, progressive neurologic syndrome in patients with FA. Nine nonimmunosuppressed pediatric patients and young adults with FA presented with acute and chronic neurological signs and symptoms associated with distinct neuroradiological findings. Symptoms included, but were not limited to, limb weakness, papilledema, gait abnormalities, headaches, dysphagia, visual changes, and seizures. Brain imaging demonstrated a characteristic radiographic appearance of numerous cerebral and cerebellar lesions with associated calcifications and often a dominant ring-enhancing lesion. Tissue from the dominant brain lesions in 4 patients showed nonspecific atypical glial proliferation, and a small number of polyomavirus-infected microglial cells were identified by immunohistochemistry in 2 patients. Numerous interventions were pursued across this cohort, in general with no improvement. Overall, these patients demonstrated significant progressive neurologic decline. This cohort highlights the importance of recognizing FA neuroinflammatory syndrome, which is distinct from malignancy, and warrants careful ongoing evaluation by clinicians.
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Encéfalo , Anemia de Fanconi , Enfermedades Neuroinflamatorias , Humanos , Anemia de Fanconi/complicaciones , Anemia de Fanconi/patología , Anemia de Fanconi/diagnóstico , Masculino , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/patología , Femenino , Niño , Adolescente , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Adulto Joven , Adulto , Preescolar , Imagen por Resonancia MagnéticaRESUMEN
Patients with Fanconi anemia (FA) are often perceived to have poor growth when general population growth curves are utilized. We hypothesize that FA patients have unique growth and aimed to create FA-specific growth charts. Height and weight data from ages 0 to 20 years were extracted from medical records of patients treated at the Fanconi Anemia Comprehensive Care Clinic at the University of Minnesota. Height, weight, and BMI growth curves were generated and fitted to reference percentiles using the Lambda-Mu-Sigma method. FA-specific percentiles were compared to WHO standards for ages 0-2 and CDC references for ages 2-20. In FA males, the 50th height- and weight-for-age percentiles overlap with the 3rd reference percentile. In FA females, only the 50th height-for-age percentile overlaps with the 3rd reference percentile. For weight, FA females show progressive growth failure between 6 and 24 months followed by stabilization around the 50th percentile. The FA BMI-for-age percentiles show similar patterns to the weight-for-age percentiles but have different timing of onset of adiposity rebound and broader variability in females. Growth in FA patients follows a different trajectory than available normative curves. FA-specific growth charts may be useful to better guide accurate growth expectations, evaluations, and treatment.
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Estatura , Índice de Masa Corporal , Peso Corporal , Anemia de Fanconi , Gráficos de Crecimiento , Humanos , Femenino , Masculino , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/patología , Anemia de Fanconi/genética , Anemia de Fanconi/fisiopatología , Niño , Adolescente , Preescolar , Lactante , Adulto Joven , Recién NacidoRESUMEN
PURPOSE: Fanconi anemia (FA) is a bone marrow failure and cancer predisposition syndrome caused primarily by biallelic pathogenic variants in 1 of 22 genes involved in DNA interstrand cross-link repair. An enduring question concerns cancer risk of those with a single pathogenic FA gene variant. To investigate all FA genes, this study utilized the DiscovEHR cohort of 170,503 individuals with exome sequencing and electronic health data. METHODS: 5822 subjects with a single pathogenic variant in an FA gene were identified. Two control groups were used in primary analysis deriving cancer risk signals. Secondary exploratory analysis was conducted using the UK Biobank and The Cancer Genome Atlas. RESULTS: Signals for elevated cancer risk were found in all 5 known cancer predisposition genes. Among the remaining 15 genes associated with autosomal recessive inheritance cancer risk signals were found for 4 cancers across 3 genes in the primary cohort but were not validated in secondary cohorts. CONCLUSION: To our knowledge, this is the first and largest FA heterozygote study to use genomic ascertainment and validates well-established cancer predispositions in 5 genes, whereas finding insufficient evidence of predisposition in 15 others. Our findings inform clinical surveillance given how common pathogenic FA variants are in the population.
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Anemia de Fanconi , Neoplasias , Humanos , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Heterocigoto , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Genotipo , Neoplasias/epidemiología , Neoplasias/genéticaRESUMEN
INTRODUCTION: Fanconi anemia (FA) is an inherited condition associated with genetic mutations that affect DNA repair proteins. More than 20 genes involved in the FA/BRCA pathway have been implicated in FA, including BRIP1 . Tumefactive brain lesions are rare in FA. CASE REPORT: We describe a patient with FA and recurrent tumefactive brain lesions preceded by calcifications on head computed tomography. A biopsy revealed white-matter gliosis with severe vasculopathy. Whole-genome sequencing demonstrated a BRIP1 homozygous variant with a final diagnosis of recurrent tumefactive brain lesions due to BRIP1 -associated CNS vasculopathy. Immunosuppressive treatment was ineffective in the present case. CONCLUSIONS: Mechanistically, the specific role of BRIP1 mutation in CNS inflammation and vasculopathy is unclear. However, immunodeficiency disorders can lead to autoimmunity and/or immune dysregulation due to the possible loss or gain of function of components of the immune system.
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Anemia de Fanconi , Humanos , Anemia de Fanconi/complicaciones , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Mutación/genética , Sistema Nervioso Central/patologíaRESUMEN
OBJECTIVE: The aim of this study was to elaborate a specific protocol for the assessment and early identification of skin lesions in pediatric patients with Fanconi anemia undergoing hematopoietic stem cell transplantation. METHODS: This is a longitudinal, retrospective, and descriptive study. The medical records of 136 pediatric patients with Fanconi anemia who underwent hematopoietic stem cell transplantation between 2008 and 2018 at the Clinical Hospital of the Federal University of Paraná were reviewed. A specific protocol was created for data collection, which included age, sex, skin color, age at diagnosis of Fanconi anemia, transplantation data, family history of consanguinity, and pre- and post-transplant complications. In addition, the data included the presence of graft-versus-host disease of the skin and other organs, its classification, type of lesion, location, and also skin lesions not related to graft-versus-host disease. RESULTS: Among the skin manifestations in pre-transplant period, café-au-lait spots stood out (32.4%). At least one organ was affected by graft-versus-host disease in 55.1% of patients; the most common involvement being the mouth, followed by the skin. Rash and erythema were the most frequently observed cutaneous manifestations of graft-versus-host disease. CONCLUSION: A high prevalence of cutaneous manifestations of the disease was observed, as well as cutaneous manifestations of graft-versus-host disease. The protocol developed gathers relevant and standardized information for the follow-up of patients with Fanconi anemia undergoing hematopoietic stem cell transplantation, ensuring greater reliability of the information, and its implementation will allow the prospective evaluation of patients.
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Anemia de Fanconi , Enfermedad Injerto contra Huésped , Niño , Humanos , Anemia de Fanconi/terapia , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/patología , Estudios Retrospectivos , Reproducibilidad de los Resultados , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/patología , EritemaRESUMEN
Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA interstrand crosslinks (ICLs). In this study, we have developed and characterized a new tool to investigate ICL repair: a clickable version of the crosslinking agent melphalan which we name click-melphalan. Our results demonstrate that click-melphalan is as effective as its unmodified counterpart in generating ICLs and associated toxicity. The lesions induced by click-melphalan can be detected in cells by post-labelling with a fluorescent reporter and quantified using flow cytometry. Since click-melphalan induces both ICLs and monoadducts, we generated click-mono-melphalan, which only induces monoadducts, in order to distinguish between the two types of DNA repair. By using both molecules, we show that FANCD2 knock-out cells are deficient in removing click-melphalan-induced lesions. We also found that these cells display a delay in repairing click-mono-melphalan-induced monoadducts. Our data further revealed that the presence of unrepaired ICLs inhibits monoadduct repair. Finally, our study demonstrates that these clickable molecules can differentiate intrinsic DNA repair deficiencies in primary FA patient cells from those in primary xeroderma pigmentosum patient cells. As such, these molecules may have potential for developing diagnostic tests.
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Anemia de Fanconi , Melfalán , Humanos , Melfalán/farmacología , Anemia de Fanconi/patología , Reparación del ADN , Daño del ADN , ADNRESUMEN
Many inherited bone marrow failure syndromes (IBMFSs) present a high risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). During transformation of IBMFSs, hematopoietic stem and progenitor cells (HSPCs) with poor fitness gain ectopic, dysregulated self-renewal secondary to somatic mutations via undefined mechanisms. Here, in the context of the prototypical IBMFS Fanconi anemia (FA), we performed multiplexed gene editing of mutational hotspots in MDS-associated genes in human induced pluripotent stem cells (iPSCs) followed by hematopoietic differentiation. We observed aberrant self-renewal and impaired differentiation of HSPCs with enrichment of RUNX1 insertions and deletions (indels), generating a model of IBMFS-associated MDS. We observed that compared to the failure state, FA MDS cells show mutant RUNX1-mediated blunting of the G1/S cell cycle checkpoint that is normally activated in FA in response to DNA damage. RUNX1 indels also lead to activation of innate immune signaling, which stabilizes the homologous recombination (HR) effector BRCA1, and this pathway can be targeted to abrogate viability and restore sensitivity to genotoxins in FA MDS. Together, these studies develop a paradigm for modeling clonal evolution in IBMFSs, provide basic understanding of the pathogenesis of MDS, and uncover a therapeutic target in FA-associated MDS.
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Anemia de Fanconi , Células Madre Pluripotentes Inducidas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Anemia de Fanconi/terapia , Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Células Madre Pluripotentes Inducidas/patología , Síndromes Mielodisplásicos/patología , Mutación , Leucemia Mieloide Aguda/patologíaRESUMEN
Fanconi anaemia (FA) is a rare autosomal recessive condition resulting in changes in the FANC gene family. This report describes a case of Fanconi anaemia in a family with complex biallelic variants. The patient is a 32-year-old female diagnosed with FA on cascade testing during childhood with chromosome breakage studies. On examination she had a fixed deformity of the right thumb and the proximal interphalangeal joint was immobile. Her brother shared this radial abnormality and had FA, requiring a bone marrow transplant. She presented in adulthood seeking further BRCA advice and had next generation sequencing that showed three variants in the FANCA gene. One allele a known pathogenic change, the other had two sequence variants in tandem that have been reported as variants of uncertain significance. There is one other unrelated case of these two variants occurring together in cis, resulting in Fanconi anaemia. This case is an interesting example of three variants in the FANCA gene, one allele with a pathogenic deletion and the other with a single complex allele made up of two missense variants of uncertain significance, likely manifesting with FA. It highlights the utility of different genetic technologies in the interpretation of next generation sequencing.
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Anemia de Fanconi , Humanos , Masculino , Femenino , Adulto , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Proteína del Grupo de Complementación A de la Anemia de Fanconi/genética , Genómica , Mutación Missense , MutaciónRESUMEN
Secondary acute myeloid leukemia (sAML) may develop following a prior therapy or may evolve from an antecedent hematological disorder such as Fanconi Anemia (FA). Pathophysiology of leukemic evolution is not clear. Etoposide (Eto) is a chemotherapeutic agent implicated in development of sAML. FA is an inherited bone marrow (BM) failure disease characterized by genomic instability and xenobiotic susceptibility. Here, we hypothesized that alterations in the BM niche may play a critical/driver role in development of sAML in both conditions. Expression of selected genes involved in xenobiotic metabolism, DNA double-strand break response, endoplasmic reticulum (ER) stress, heat shock response and cell cycle regulation were determined in BM mesenchymal stem cells (MSCs) of healthy controls and FA patients at steady state and upon exposure to Eto at different concentrations and in recurrent doses. Expression of CYPA1, p53, CCNB1, Dicer1, CXCL12, FLT3L and TGF-Beta genes were significantly downregulated in FA-MSCs compared with healthy controls. Eto exposure induced significant alterations in healthy BM-MSCs with increased expression of CYP1A1, GAD34, ATF4, NUPR1, CXCL12, KLF4, CCNB1 and nuclear localization of Dicer1. Interestingly, FA-MSCs did not show significant alterations in these genes upon Eto exposure. As opposed to healthy MSCs DICER1 gene expression and intracellular localization was not altered on FA BM-MSCs after Eto treatment. These results showed that Eto is a highly potent molecule and has pleiotropic effects on BM-MSCs, FA cells show altered expression profile compared to healthy controls and Eto exposure on FA cells shows differential profile than healthy controls.
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Anemia de Fanconi , Leucemia Mieloide Aguda , Células Madre Mesenquimatosas , Humanos , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patología , Etopósido/farmacología , Etopósido/metabolismo , Xenobióticos/metabolismo , Proliferación Celular , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Células Madre Mesenquimatosas/metabolismo , Ribonucleasa III/metabolismo , ARN Helicasas DEAD-box/metabolismoRESUMEN
We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C. Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5 and 37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the hypothesis of a rare phenomenon of hypermutation. Eight-hundred-thirty apparent de novo SNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants. The VAFs showed a bimodal distribution, with one component having an average VAF of 25% (range: 18.7-37.41%) (n = 446), representing potential postzygotic first mitotic events, and the other component with an average VAF of 12.5% (range 9.55-18.69%) (n = 384), describing potential second mitotic events. No increased rate of CNV formation was observed. The mutational pattern analysis for somatic single base substitution showed SBS40, SBS5, and SBS3 as the top recognized signatures. SBS3 is a known signature associated with homologous recombination-based DNA damage repair error. Our data demonstrate that biallelic RAD51C variants show evidence for defective genomic DNA damage repair and thereby result in a hypermutator phenotype with the accumulation of postzygotic de novo mutations, at least in the prenatal period. This 'genome hypermutator phenomenon' might contribute to the observed hematological manifestations and the predisposition to tumors in patients with FA. We propose that other FA groups should be investigated for genome-wide de novo variants.
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Anemia de Fanconi , Predisposición Genética a la Enfermedad , Humanos , Proteínas de Unión al ADN/genética , Anemia de Fanconi/genética , Anemia de Fanconi/patología , FenotipoRESUMEN
Fanconi anemia (FA) is a heritable malformation, bone marrow failure and cancer predisposition syndrome that confers an exceptionally high risk of squamous carcinomas. These carcinomas originate in epithelia lining the mouth, proximal esophagus, vulva and anus: their origins are not understood, and no effective ways have been identified to prevent or delay their appearance. Many FA-associated carcinomas are also therapeutically challenging: they may be multi-focal and stage-advanced at diagnosis, and most individuals with FA cannot tolerate standard-of-care systemic therapies such as DNA cross-linking drugs or ionizing radiation due to constitutional DNA damage hypersensitivity. We developed the Fanconi Anemia Cancer Cell Line Resource (FA-CCLR) to foster new work on the origins, treatment and prevention of FA-associated carcinomas. The FA-CCLR consists of Fanconi-isogenic head and neck squamous cell carcinoma (HNSCC) cell line pairs generated from five individuals with FA-associated HNSCC, and five individuals with sporadic HNSCC. Sporadic, isogenic HNSCC cell line pairs were generated in parallel with FA patient-derived isogenic cell line pairs to provide comparable experimental material to use to identify cell and molecular phenotypes driven by germline or somatic loss of Fanconi pathway function, and the subset of these FA-dependent phenotypes that can be modified, complemented or suppressed. All 10 FANC-isogenic cell line pairs are available to academic, non-profit and industry investigators via the "Fanconi Anemia Research Materials" Resource and Repository at Oregon Health & Sciences University, Portland OR.
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Carcinoma de Células Escamosas , Anemia de Fanconi , Neoplasias de Cabeza y Cuello , Femenino , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Anemia de Fanconi/genética , Anemia de Fanconi/complicaciones , Anemia de Fanconi/patología , Ciencia Traslacional Biomédica , Neoplasias de Cabeza y Cuello/genética , Carcinoma de Células Escamosas/genética , Línea Celular TumoralRESUMEN
Fanconi anaemia (FA) is a rare chromosomal-instability syndrome caused by mutations of any of the 22 known FA DNA-repair genes. FA individuals have an increased risk of head-and-neck squamous-cell-carcinomas (HNSCC), often fatal. Systemic intolerance to standard cisplatin-based protocols due to somatic-cell hypersensitivity underscores the urgent need to develop novel therapies. Here, we performed unbiased siRNA screens to unveil genetic interactions synthetic-lethal with FA-pathway deficiency in FA-patient HNSCC cell lines. We identified based on differential-lethality scores between FA-deficient and FA-proficient cells, next to common-essential genes such as PSMC1, PSMB2, and LAMTOR2, the otherwise non-essential RBBP9 gene. Accordingly, low dose of the FDA-approved RBBP9-targeting drug Emetine kills FA-HNSCC. Importantly both RBBP9-silencing as well as Emetine spared non-tumour FA cells. This study provides a minable genome-wide analyses of vulnerabilities to address treatment challenges in FA-HNSCC. Our investigation divulges a DNA-cross-link-repair independent lead, RBBP9, for targeted treatment of FA-HNSCCs without systemic toxicity.
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Anemia de Fanconi , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Proteínas de Ciclo Celular/genética , ADN , Emetina/uso terapéutico , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Estudio de Asociación del Genoma Completo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Neoplasias/genética , ARN Interferente Pequeño/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genéticaRESUMEN
The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients.
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Aldehído Deshidrogenasa Mitocondrial , Neoplasias de la Mama , Anemia de Fanconi , Femenino , Humanos , Aldehído Deshidrogenasa Mitocondrial/genética , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Pueblos del Este de Asia , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Predisposición Genética a la Enfermedad , Mutación , Proteína BRCA2/genéticaRESUMEN
Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.
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Reparación del ADN , Anemia de Fanconi , Genómica , Neoplasias de Cabeza y Cuello , Humanos , Aldehídos/efectos adversos , Aldehídos/metabolismo , Reparación del ADN/genética , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patología , Neoplasias de Cabeza y Cuello/inducido químicamente , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Infecciones por Papillomavirus , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Daño del ADN/efectos de los fármacosRESUMEN
Defective DNA damage repair is a key mechanism affecting tumor susceptibility, treatment response, and survival outcome of endometrial cancer (EC). Fanconi anemia complementation group D2 (FANCD2) is the core component of the Fanconi anemia repair pathway. To explore the function of FANCD2 in EC, we examined the expression of FANCD2 in human specimens and databases, and discussed the possible mechanism of carcinogenesis by in vitro assays. Immunohistochemistry results showed overexpression of FANCD2 was detected in EC tissues compared to normal and atypical hyperplasia endometrium. Higher FANCD2 expression was correlated with deeper myometrial invasion (MI) and proficient mismatch repair status. The Cancer Genome Atlas (TCGA) database analysis showed FANCD2 was upregulated in EC compared with normal tissue. The high expression of FANCD2 was associated with poor overall survival in EC. Knockdown of FANCD2 expression in EC cell lines inhibited malignant proliferation and migration ability. We demonstrated that decreased FANCD2 expression results in increased DNA damage and decreased S-phase cells, leading to a decrease in proliferative capacity in EC cells. Down-regulated FANCD2 confers sensitivity of EC cells to interstrand crosslinking agents. This study provides evidence for the malignant progression and prognostic value of FANCD2 in EC.
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Neoplasias Endometriales , Anemia de Fanconi , Femenino , Humanos , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Pronóstico , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Daño del ADN/genética , Neoplasias Endometriales/genética , Endometrio/metabolismo , Reparación del ADN/genéticaRESUMEN
Fanconi anemia (FA) patients frequently develop oral squamous cell carcinoma (OSCC). This cancer in FA patients is diagnosed within the first 3-4 decades of life, very often preceded by lesions that suffer a malignant transformation. In addition, they respond poorly to current treatments due to toxicity or multiple recurrences. Translational research on new chemopreventive agents and therapeutic strategies has been unsuccessful partly due to scarcity of disease models or failure to fully reproduce the disease. Here we report that Fanca gene knockout mice (Fanca-/-) frequently display pre-malignant lesions in the oral cavity. Moreover, when these animals were crossed with animals having conditional deletion of Trp53 gene in oral mucosa (K14cre;Trp53F2-10/F2-10), they spontaneously developed OSCC with high penetrance and a median latency of less than ten months. Tumors were well differentiated and expressed markers of squamous differentiation, such as keratins K5 and K10. In conclusion, Fanca and Trp53 genes cooperate to suppress oral cancer in mice, and Fanca-/-;K14cre;Trp53F2-10/F2-10 mice constitute the first animal model of spontaneous OSCC in FA.
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Carcinoma de Células Escamosas , Anemia de Fanconi , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Animales , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Modelos Animales de Enfermedad , Anemia de Fanconi/complicaciones , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Queratinas , Ratones , Ratones Noqueados , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Background: Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical. Methods: This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis. Results: The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A. Conclusions: For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.
Asunto(s)
Anemia de Fanconi , Síndrome de Fanconi , Trasplante de Riñón , Insuficiencia Renal , Escoliosis , Aloinjertos , Antivirales/efectos adversos , Creatinina , Anemia de Fanconi/patología , Síndrome de Fanconi/inducido químicamente , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/terapia , Humanos , Trasplante de Riñón/efectos adversos , Túbulos Renales Proximales/patología , Estudios Retrospectivos , Escoliosis/inducido químicamente , Escoliosis/patología , Tacrolimus/efectos adversosRESUMEN
Fanconi Anaemia (FA) is a rare recessive genetic disorder characterized by a defective DNA repair mechanism. Although aplastic anaemia is the principal clinical sign in FA, patients develop a head and neck squamous cell carcinoma (HNSCC) with a frequency 500-700 folds higher than the general population, which appears more aggressive, with survival of under two years. Since FA gene mutations are also associated with a defect in the aerobic metabolism and an increased oxidative stress accumulation, this work aims to evaluate the effect of FANCA mutation on the energy metabolism and the relative mitochondrial quality control pathways in an HNSCC cellular model. Energy metabolism and cellular antioxidant capacities were evaluated by oximetric, luminometric, and spectrophotometric assays. The dynamics of the mitochondrial network, the quality of mitophagy and autophagy, and DNA double-strand damage were analysed by Western blot analysis. Data show that the HNSCC cellular model carrying the FANCA gene mutation displays an altered electron transport between respiratory Complexes I and III that does not depend on the OxPhos protein expression. Moreover, FANCA HNSCC cells show an imbalance between fusion and fission processes and alterations in autophagy and mitophagy pathways. Together, all these alterations associated with the FANCA gene mutation cause cellular energy depletion and a metabolic switch to glycolysis, exacerbating the Warburg effect in HNSCC cells and increasing the growth rate. In addition, the altered DNA repair due to the FANCA mutation causes a higher accumulation of DNA damage in the HNSCC cellular model. In conclusion, changes in energy metabolism and mitochondrial dynamics could explain the strict correlation between HNSCC and FA genes, helping to identify new therapeutic targets.