Case Report: Rubella Virus-Induced Cutaneous Granulomas in Two Pediatric Patients With DNA Double Strand Breakage Repair Disorders - Outcome After Hematopoietic Stem Cell Transplantation.

We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced naïve T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas.

Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors.

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

Human RAD50 deficiency: Confirmation of a distinctive phenotype.

DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient-derived fibroblasts and provided evidence for a markedly reduced radiation-induced AT-mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that RAD50 mutations lead to a similar, but distinctive phenotype.

Early Onset Diabetes in Two Children due to Progeria, a Monogenic Disease of DNA Repair

Progeria syndrome is a rare disorder in childhood which causes accelerated systemic aging. Due to the accelerated aging process, disorders which normally occur only in old age will appear in these children at a much younger age. We report two children with progeria syndrome, in whom fulminant diabetes mellitus manifested at a very early age.

Current Understanding and Future Research Priorities in Malignancy Associated With Inborn Errors of Immunity and DNA Repair Disorders: The Perspective of an Interdisciplinary Working Group.

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.

Multiple skin cancers in patients with mycosis fungoides after long-term ultraviolet phototherapy.

Phototherapy is a useful noninvasive therapy, but it can induce cutaneous malignant tumours, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). We report on a 79-year-old man who had long-standing mycosis fungoides for 40 years, which had been treated with psoralen ultraviolet A therapy for 37 years at a dose of approximately 5000 J/cm2 . Approximately 6 years before presentation, numerous types of cutaneous malignancies, including actinic keratosis, BCC and SCC, had begun to develop all over the patient's body. We hypothesized that he was experiencing a pathogenesis similar to patients with xeroderma pigmentosum (XP), and we therefore assessed his DNA repair capacity. Based on these investigations, the patient was eventually diagnosed as non-XP, even though we detected that his DNA repair capacity was slightly lower than that of normal controls, which may have led to the skin cancers. We speculate that multiple skin malignancies can be induced by long-term phototherapy in patients with slightly impaired DNA repair capacity.

DNA Repair Deficiency Is Common in Advanced Prostate Cancer: New Therapeutic Opportunities.

UNLABELLED: : Advances in DNA sequencing technology have created a wealth of information regarding the genomic landscape of prostate cancer. It had been thought that BRCA1 and BRCA2 mutations were associated with only a small fraction of prostate cancer cases. However, recent genomic analysis has revealed that germline or somatic inactivating mutations in BRCA1 or BRCA2, or other genes involved in the homologous recombination (HR) pathway of DNA repair collectively occur in as much as 20%-25% of advanced prostate cancers. A synthetic lethal therapeutic approach using poly(ADP-ribose) polymerase inhibitor therapy has been developed for BRCA mutant- and HR deficient-related cancers (those with "BRCAness") and is being studied in multiple clinical trials. This article discusses the current understanding of the genomic landscape of prostate cancer, focusing on the occurrence of DNA repair mutations and the therapeutic opportunities that this presents. IMPLICATIONS FOR PRACTICE: This review aims to update oncologists about the increased understanding of the genomes of prostate cancers and, in particular, the prevalence of mutations in DNA repair genes. These observations provide potential new therapeutic opportunities for the use of poly(ADP-ribose) polymerase inhibitors and other therapies, especially in advanced forms of the disease. Of note is the recent U.S. Food and Drug Administration breakthrough therapy designation of olaparib for the treatment of BRCA1/2- or ATM-mutated metastatic castration-resistant prostate cancer. The implications of this new knowledge for clinical practice now and in the future are discussed.

[Ocular manifestations in hereditary diseases with defects in DNA repair]. / Zaburzenia narzadu wzroku w przebiegu chorób genetycznych zwiazanych z naprawa DNA.

DNA repair is involved in maintaining the stability of the genome and accurate sending of genetic information. DNA repair pathways remove many DNA damages induced by endo- and exogenous factors. There are several DNA repair pathways in human cells, including base or nucleotide excision system, homologous recombination system and non-homologous end joining. Mutation in DNA repair genes may results in rare genetic disorders, including Xeroderma pigmentosum, Cockayne syndrom, trichothiodystrophy, Nijmegen syndrome, ataxia teleangiectasia, Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome. These diseases may be associated with various visual disturbances. In this work we review we focus on human genetic diseases linked with mutations in DNA repair genes associated with visual impairment.

Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium "Care for CMMR-D" (C4CMMR-D).

Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.

Rapid and progressive pulmonary fibrosis in 2 families with DNA repair deficiencies of undetermined etiology.

Known genetic causes of pediatric interstitial lung disease include disorders of surfactant metabolism, telomerase, and DNA repair. We report 4 children from 2 families with rapidly progressive and fatal pulmonary fibrosis. A novel DNA repair defect unrelated to the ataxia-telangiectasia mutated gene was found in 1 child from each family.

Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair.

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1(Δ/-) mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.

Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis.

The study of cancer predisposition syndromes leads to identification and understanding of mutations in genes coding for proteins and cellular pathways leading to cancer development, as well as normal cell growth and death regulators. Many patients with cancer predisposition syndromes experience excess toxicity with standard therapeutic regimens and are at lifelong risk for development of additional cancers and must be followed closely; early diagnosis is crucial for appropriate management of these patients. This review describes specific leukemia-predisposing conditions, including the clinical and historical findings that should trigger testing for these syndromes, and discusses recent insights into the management of these disorders. Disorders are organized by mechanism: (1) DNA damage repair defects, including Fanconi anemia, ataxia-telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome; (2) cell cycle and differentiation defects, such as neurofibromatosis type 1, Noonan and Noonan-like syndromes, and severe congenital neutropenia; (3) the hereditary transcription factor syndromes familial platelet disorder with predisposition to myeloid malignancy and CEBPA deficiency; and (4) aneuploidy-associated leukemia predisposition, exemplified by Down syndrome. Identifying the specific mechanisms underlying these relatively rare conditions allows for better understanding of leukemogenesis and development of targeted therapies that benefit a much broader population than simply those with genetic predispositions to leukemia.

DNA double-strand break repair, immunodeficiency and the RIDDLE syndrome.

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.

Primary immunodeficiencies associated with DNA-repair disorders.

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.

Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.

Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.

A novel DNA repair disorder with thrombocytopenia, nephrosis and features overlapping Cockayne syndrome.

We report on four siblings with Cockayne-like syndrome with thrombocytopenia and nephrotic syndrome. The parents were healthy and consanguineous, consistent with an autosomal recessive mode of disease inheritance. UV irradiation of fibroblasts revealed an intermediate sensitivity between normal and standard Cockayne syndrome (CS) control cells. A genome-wide linkage scan conducted using Affymetrix 10K arrays provided exclusion of the known CS genes in the family, and evidence that the disease gene maps to 1p33-p31.1. Thrombocytopenia has not previously been linked with CS, but two patients with CS in association with nephrotic syndrome have previously been documented and the phenotypes are compared with the patients described here. We suggest that this Cockayne-like phenotype with thrombocytopenia and nephrotic syndrome may be a novel DNA repair disorder, and propose that further investigation of other affected families may help identify the causative genetic defect.

Clinical radiation sensitivity with DNA repair disorders: an overview.

Adverse reactions to radiotherapy represent a confounding phenomenon in radiation oncology. These reactions are rare, and many have been associated with individuals with DNA repair disorders such as ataxia-telangiectasia and Nijmegen Breakage syndrome. A paucity of published data is available detailing such circumstances. This overview describes four exemplary situations, a comprehensive list of 32 additional cases, and some insights gleaned from this overall experience. Fanconi anemia was associated with more than one-half of the reports. The lowest dose given to a patient that resulted in a reaction was 3 Gy, given to an ataxia-telangiectasia patient. Most patients died within months of exposure. It is clear that the patients discussed in this report had complicated illnesses, in addition to cancer, and the radiotherapy administered was most likely their best option. However, the underlying DNA repair defects make conventional radiation doses dangerous. Our findings support previous wisdom that radiotherapy should either be avoided or the doses should be selected with great care in the case of these radiosensitive genotypes, which must be recognized by their characteristic phenotypes, until more rapid, reliable, and functional assays of DNA repair become available.