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1.
Cell Rep Med ; 2(5): 100276, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-34095878

RESUMEN

Tumors with DNA damage repair (DDR) deficiency accumulate genomic alterations that may serve as neoantigens and increase sensitivity to immune checkpoint inhibitor. However, over half of DDR-deficient tumors are refractory to immunotherapy, and it remains unclear which mutations may promote immunogenicity in which cancer types. We integrate deleterious somatic and germline mutations and methylation data of DDR genes in 10,080 cancers representing 32 cancer types and evaluate the associations of these alterations with tumor neoantigens and immune infiltrates. Our analyses identify DDR pathway mutations that are associated with higher neoantigen loads, adaptive immune markers, and survival outcomes of immune checkpoint inhibitor-treated animal models and patients. Different immune phenotypes are associated with distinct types of DDR deficiency, depending on the cancer type context. The comprehensive catalog of immune response-associated DDR deficiency may explain variations in immunotherapy outcomes across DDR-deficient cancers and facilitate the development of genomic biomarkers for immunotherapy.


Asunto(s)
Biomarcadores de Tumor/inmunología , Daño del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Reparación del ADN/inmunología , Neoplasias/genética , Biomarcadores de Tumor/genética , Daño del ADN/genética , Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/genética , Genómica/métodos , Humanos , Inmunidad/genética , Inmunoterapia/métodos , Mutación/genética
2.
Immunology ; 147(1): 11-20, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26455503

RESUMEN

In recent years, several novel congenital human disorders have been described with defects in lymphoid B-cell and T-cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double-strand break repair, as well as compromised DNA damage-induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B-cell and T-cell development, as well as human diseases that arise through defects in these pathways.


Asunto(s)
Linfocitos B/patología , Daño del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/genética , Reparación del ADN/genética , Linfocitos T/patología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/patología , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/patología , Predisposición Genética a la Enfermedad , Humanos , Mutación , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Fenotipo , Recombinación Genética , Linfocitos T/inmunología , Linfocitos T/metabolismo
4.
Int J Hematol ; 95(3): 239-45, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22351161

RESUMEN

Ionizing radiation (IR), as well as a wide variety of chemicals and reactive oxygen species, can cause insults in DNA integrity. However, IR is distinct from other agents in that produces clustered DNA damage, particularly double-strand DNA breaks (DSBs). The discovery of radiosensitive human diseases has revealed that the molecular mechanisms underlying the biological effects of IR impact cellular responses to and repair of DSBs. One class of diseases, including ataxia-telangiectasia, displays a defect in checkpoint response to DSBs. Another class of diseases exhibits severe combined immunodeficiency and defects in DSB repair. Importantly, radiosensitive human diseases are also associated with increased risks of leukemia/lymphoma. In this review, we summarize the molecular nature of IR-induced DNA damage, and provide an overview of the molecular mechanisms of checkpoint response to and repair of DSBs. Lastly, we discuss the roles of these mechanisms in the development of the immune system and the suppression of lymphoma/leukemia, based on the clinical features and experiments with model mice.


Asunto(s)
Trastornos por Deficiencias en la Reparación del ADN/genética , Traumatismos por Radiación/genética , Tolerancia a Radiación/genética , Animales , Roturas del ADN/efectos de la radiación , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Humanos , Leucemia/epidemiología , Leucemia/etiología , Linfoma/epidemiología , Linfoma/etiología , Ratones , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/etiología , Traumatismos por Radiación/inmunología , Tolerancia a Radiación/inmunología , Riesgo
5.
Expert Rev Clin Immunol ; 7(2): 169-85, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21426255

RESUMEN

DNA double-strand break (DSB) repair is an essential cellular process required to maintain genomic integrity in the face of potentially lethal genetic damage. Failure to repair a DSB can trigger cell death, whereas misrepair of the break can lead to the generation of chromosomal translocations, which is a known causative event in the development or progression of cancer. DSBs can be induced following exposure to certain exogenous agents, such as ionising radiation or radiomimetic chemicals, as well as occurring naturally as intermediates of normal physiological processes, in particular during B and T cell antigen receptor assembly. Human syndromes with deficiencies in DSB repair commonly exhibit immunodeficiency, highlighting the critical nature of this pathway for development and maturation of the immune system. In this article we review the different pathways utilized by the cell to repair DSBs and how an inherited defect in some of the genes that are critical regulators of this process can be the underlying cause of human disorders associated with genome instability and immune system dysfunction. We focus on a newly described human immunodeficiency disorder called radiosensitivity, immunodeficiency dysmorphic features and learning difficulties (RIDDLE) syndrome, with particular reference to the function of the defective gene, RNF168. We also consider the implications of this finding on the mechanisms controlling development of the immune system.


Asunto(s)
Trastornos por Deficiencias en la Reparación del ADN/inmunología , Reparación del ADN , Sistema Inmunológico/metabolismo , Síndromes de Inmunodeficiencia/inmunología , Ubiquitina-Proteína Ligasas/metabolismo , Trastorno Dismórfico Corporal , Roturas del ADN de Doble Cadena , Reparación del ADN/genética , Reparación del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Trastornos por Deficiencias en la Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/fisiopatología , Predisposición Genética a la Enfermedad , Humanos , Sistema Inmunológico/embriología , Sistema Inmunológico/crecimiento & desarrollo , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/fisiopatología , Discapacidades para el Aprendizaje , Mutación/genética , Tolerancia a Radiación , Ubiquitina-Proteína Ligasas/genética
6.
Eur J Pediatr ; 170(3): 295-308, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21337117

RESUMEN

The syndromic primary immunodeficiencies are disorders in which not only the immune system but also other organ systems are affected. Other features most commonly involve the ectodermal, skeletal, nervous, and gastrointestinal systems. Key in identifying syndromic immunodeficiencies is the awareness that increased susceptibility to infections or immune dysregulation in a patient known to have other symptoms or special features may hint at an underlying genetic syndrome. Because the extraimmune clinical features can be highly variable, it is more difficult establishing the correct diagnosis. Nevertheless, correct diagnosis at an early age is important because of the possible treatment options. Therefore, diagnostic work-up is best performed in a center with extensive expertise in this field, having immunologists and clinical geneticists, as well as adequate support from a specialized laboratory at hand. This paper provides the general pediatrician with the main clinical features that are crucial for the recognition of these syndromes.


Asunto(s)
Trastornos por Deficiencias en la Reparación del ADN/diagnóstico , Síndromes de Inmunodeficiencia/diagnóstico , Aberraciones Cromosómicas , Trastornos por Deficiencias en la Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Susceptibilidad a Enfermedades , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Infecciones/etiología
7.
Adv Exp Med Biol ; 685: 146-65, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20687503

RESUMEN

Several DNA repair pathways have evolved to recognise and repair DNA damaged by exogenous and endogenous agents, in order to maintain genomic integrity. Defects in these pathways can lead to replication errors, loss or rearrangement ofgenomic material, mutation or cancer and eventual death. The creation of many diverse lymphocyte receptors to identify potential pathogens has evolved by breaking and randomly resorting the gene segments coding for antigen receptors. Subsequent steps utilise the ubiquitous repair proteins. Individuals with defective repair pathways are increasingly recognised with immunodeficiency, many of whom exhibit radiosensitivity. Our understanding of the role of repair proteins in the development of adaptive immunity by VDJ recombination, antibody isotype class switching and affinity maturation by somatic hyper-mutation has made significant progress over the last few years, partly by the identification of new genes involved in human disease. We describe the mechanisms involved in the development of adaptive immunity relating to DNA repair and describe the clinical consequences and treatment developments of primary immunodeficiency resulting from such defects.


Asunto(s)
Inmunidad Adaptativa , Trastornos por Deficiencias en la Reparación del ADN , Reparación del ADN , Cambio de Clase de Inmunoglobulina , Síndromes de Inmunodeficiencia , Hipermutación Somática de Inmunoglobulina , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Animales , Reparación del ADN/genética , Reparación del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/metabolismo , Trastornos por Deficiencias en la Reparación del ADN/terapia , Replicación del ADN/genética , Replicación del ADN/inmunología , Femenino , Reordenamiento Génico de Linfocito T/genética , Reordenamiento Génico de Linfocito T/inmunología , Inestabilidad Genómica/genética , Inestabilidad Genómica/inmunología , Humanos , Cambio de Clase de Inmunoglobulina/genética , Cambio de Clase de Inmunoglobulina/inmunología , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/metabolismo , Síndromes de Inmunodeficiencia/terapia , Masculino , Mutación/genética , Mutación/inmunología , Tolerancia a Radiación/genética , Tolerancia a Radiación/inmunología , Hipermutación Somática de Inmunoglobulina/genética , Hipermutación Somática de Inmunoglobulina/inmunología
8.
Expert Rev Mol Med ; 12: e9, 2010 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-20298636

RESUMEN

DNA-repair pathways recognise and repair DNA damaged by exogenous and endogenous agents to maintain genomic integrity. Defects in these pathways lead to replication errors, loss or rearrangement of genomic material and eventually cell death or carcinogenesis. The creation of diverse lymphocyte receptors to identify potential pathogens requires breaking and randomly resorting gene segments encoding antigen receptors. Subsequent repair of the gene segments utilises ubiquitous DNA-repair proteins. Individuals with defective repair pathways are found to be immunodeficient and many are radiosensitive. The role of repair proteins in the development of adaptive immunity by VDJ recombination, antibody isotype class switching and affinity maturation by somatic hypermutation has become clearer over the past few years, partly because of identification of the genes involved in human disease. We describe the mechanisms involved in the development of adaptive immunity relating to DNA repair, and the clinical consequences and treatment of the primary immunodeficiency resulting from such defects.


Asunto(s)
Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Síndromes de Inmunodeficiencia/complicaciones , Inmunidad Adaptativa , Animales , Daño del ADN , Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/diagnóstico , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/terapia , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/terapia , Polimorfismo Genético
9.
Curr Opin Allergy Clin Immunol ; 9(6): 510-6, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19858715

RESUMEN

PURPOSE OF REVIEW: It is important to assess 'radiosensitivity' in patients suspected of immunodeficiency because underlying DNA double strand break (DSB) repair defects have considerable impact on V(D)J recombination, class switching and lymphocyte maturation, leading to increased infections and cancer risk. In addition, the phenotype of 'radiosensitivity' may identify patients with increased toxicity to radiation and chemotherapeutic agents and could impact upon their preparation for stem cell transplantation. To date, the gold standard for evaluating 'radiosensitivity' has been the colony-survival assay (CSA), which reflects the efficiency of DNA repair of DSBs as it impacts upon replication and cell survival. Other methods measure other aspects of DNA repair; however, their limited specificity often leads to false negatives for predicting 'radiosensitivity', especially clinical radiosensitivity. Lastly, clinical awareness of an overarching syndrome of DSB repair disorders, XCIND, could help to raise diagnostic levels of suspicion and, thereby, identify additional patients with new forms of immunodeficiency, cancer susceptibility and radiosensitivity. RECENT FINDINGS: Within the past year, three new radiosensitivity disorders of DSB repair have been described, involving deficiencies of RNF168, RAD50, and DNA-PKcs. These are truly translational advances because they validate laboratory models and allow new patients to be identified. SUMMARY: Recognizing compromised genome stability is important but difficult. We review the evidence for correlations between DSB repair, abnormal colony formation, clinical radiosensitivity and other laboratory methods.


Asunto(s)
Roturas del ADN de Doble Cadena , Trastornos por Deficiencias en la Reparación del ADN/genética , Predisposición Genética a la Enfermedad , Mutación , Tolerancia a Radiación/genética , Inmunodeficiencia Combinada Grave/genética , Ácido Anhídrido Hidrolasas , Ensayo de Unidades Formadoras de Colonias , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Proteína Quinasa Activada por ADN/genética , Proteína Quinasa Activada por ADN/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Humanos , Neoplasias/genética , Neoplasias/inmunología , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Tolerancia a Radiación/inmunología , Inmunodeficiencia Combinada Grave/inmunología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología
10.
Hum Genet ; 124(2): 105-22, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18709565

RESUMEN

Heterozygous mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause the dominant adult cancer syndrome termed Lynch syndrome or hereditary non-polyposis colorectal cancer. During the past 10 years, some 35 reports have delineated the phenotype of patients with biallelic inheritance of mutations in one of these MMR genes. The patients suffer from a condition that is characterised by the development of childhood cancers, mainly haematological malignancies and/or brain tumours, as well as early-onset colorectal cancers. Almost all patients also show signs reminiscent of neurofibromatosis type 1, mainly café au lait spots. Alluding to the underlying mechanism, this condition may be termed as "constitutional mismatch repair-deficiency (CMMR-D) syndrome". To give an overview of the current knowledge and its implications of this recessively inherited cancer syndrome we summarise here the genetic, clinical and pathological findings of the so far 78 reported patients of 46 families suffering from this syndrome.


Asunto(s)
Reparación de la Incompatibilidad de ADN , Trastornos por Deficiencias en la Reparación del ADN/etiología , Adenosina Trifosfatasas/genética , Alelos , Neoplasias Encefálicas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Trastornos por Deficiencias en la Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Proteínas de Unión al ADN/genética , Genes de Neurofibromatosis 1 , Neoplasias Hematológicas/genética , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Mutación , Enfermedades de la Piel/etiología , Enfermedades de la Piel/genética , Síndrome
11.
Cell ; 124(2): 287-99, 2006 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-16439204

RESUMEN

DNA double-strand breaks (DSBs) occur at random upon genotoxic stresses and represent obligatory intermediates during physiological DNA rearrangement events such as the V(D)J recombination in the immune system. DSBs, which are among the most toxic DNA lesions, are preferentially repaired by the nonhomologous end-joining (NHEJ) pathway in higher eukaryotes. Failure to properly repair DSBs results in genetic instability, developmental delay, and various forms of immunodeficiency. Here we describe five patients with growth retardation, microcephaly, and immunodeficiency characterized by a profound T+B lymphocytopenia. An increased cellular sensitivity to ionizing radiation, a defective V(D)J recombination, and an impaired DNA-end ligation process both in vivo and in vitro are indicative of a general DNA repair defect in these patients. All five patients carry mutations in the Cernunnos gene, which was identified through cDNA functional complementation cloning. Cernunnos/XLF represents a novel DNA repair factor essential for the NHEJ pathway.


Asunto(s)
Trastornos por Deficiencias en la Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Trastornos del Crecimiento/genética , Linfopenia/genética , Microcefalia/genética , Adolescente , Linfocitos B/inmunología , Secuencia de Bases , Ciclo Celular/efectos de la radiación , Niño , Preescolar , Enzimas Reparadoras del ADN , Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Trastornos por Deficiencias en la Reparación del ADN/inmunología , ADN Complementario/metabolismo , Fibroblastos/inmunología , Fibroblastos/efectos de la radiación , Reordenamiento Génico de Linfocito B , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/inmunología , Humanos , Región de Unión de la Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Linfopenia/complicaciones , Linfopenia/inmunología , Microcefalia/complicaciones , Microcefalia/inmunología , Datos de Secuencia Molecular , Mutación , Tolerancia a Radiación/genética , Síndrome , Linfocitos T/inmunología
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