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Acta Dermato-venereologica Apr 2019Skin cancer has become the most common type of cancer worldwide as a result of environmental exposure and medical treatments. A small group of patients are genetically... (Review)
Review
Skin cancer has become the most common type of cancer worldwide as a result of environmental exposure and medical treatments. A small group of patients are genetically predisposed to skin cancer and this article is intended as a diagnostic tool when encountering patients with multiple skin cancer lesions. The disorders are described with clinical characteristics, genetics and management. The most common syndromes associated with basal cell carcinoma are: Gorlin-Goltz syndrome, Rombo syndrome, and Bazex-Dupré-Christol syndrome. Multiple squamous cell carcinomas can be related to: xeroderma pigmentosum, Ferguson-Smith, Muir-Torre syndrome, Mibelli-type porokeratosis, keratitis-ichthyosis-deafness syndrome, Rothmund-Thomson syndrome, Bloom syndrome, and epidermodysplasia verruciformis. Malignant melanoma can be inherited, as in familial atypical multiple mole melanoma syndrome.
Topics: Adolescent; Adult; Biomarkers, Tumor; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Male; Melanoma; Middle Aged; Mutation; Neoplastic Syndromes, Hereditary; Phenotype; Risk Assessment; Risk Factors; Skin; Skin Neoplasms; Treatment Outcome; Young Adult
PubMed: 30653245
DOI: 10.2340/00015555-3123 -
Nucleic Acids Research Nov 2021The human RecQ helicase BLM is involved in the DNA damage response, DNA metabolism, and genetic stability. Loss of function mutations in BLM cause the genetic...
The human RecQ helicase BLM is involved in the DNA damage response, DNA metabolism, and genetic stability. Loss of function mutations in BLM cause the genetic instability/cancer predisposition syndrome Bloom syndrome. However, the molecular mechanism underlying the regulation of BLM in cancers remains largely elusive. Here, we demonstrate that the deubiquitinating enzyme USP37 interacts with BLM and that USP37 deubiquitinates and stabilizes BLM, thereby sustaining the DNA damage response (DDR). Mechanistically, DNA double-strand breaks (DSB) promotes ATM phosphorylation of USP37 and enhances the binding between USP37 and BLM. Moreover, knockdown of USP37 increases BLM polyubiquitination, accelerates its proteolysis, and impairs its function in DNA damage response. This leads to enhanced DNA damage and sensitizes breast cancer cells to DNA-damaging agents in both cell culture and in vivo mouse models. Collectively, our results establish a novel molecular mechanism for the USP37-BLM axis in regulating DSB repair with an important role in chemotherapy and radiotherapy response in human cancers.
Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Cell Line, Tumor; DNA; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; Endopeptidases; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Humans; MCF-7 Cells; Mice; Phosphorylation; Protein Binding; Protein Stability; Proteolysis; RNA, Small Interfering; RecQ Helicases; Survival Analysis; Ubiquitination; Xenograft Model Antitumor Assays
PubMed: 34606619
DOI: 10.1093/nar/gkab842 -
Nature Reviews. Disease Primers Sep 2019Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage)... (Review)
Review
Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.
Topics: Ataxia Telangiectasia; Bloom Syndrome; DNA Damage; DNA Repair-Deficiency Disorders; Fanconi Anemia; Humans; Nijmegen Breakage Syndrome
PubMed: 31537806
DOI: 10.1038/s41572-019-0113-0 -
Aging Cell Oct 2023Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor...
Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.
Topics: Humans; Animals; Mice; Bloom Syndrome; Epigenesis, Genetic; Aging; Aging, Premature; Methylation; DNA Methylation
PubMed: 37594403
DOI: 10.1111/acel.13964 -
Pathogens (Basel, Switzerland) Mar 2023DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased... (Review)
Review
DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. Consequently, the characteristics of the infections may vary from mild upper respiratory tract infections to severe, opportunistic, and even fatal infections with bacteria, viruses, or fungi. Here, infections in 15 rare and sporadic DNA repair defects that are associated with immunodeficiencies are discussed. Because of the rarity of some of these conditions, limited information is available regarding infectious complications.
PubMed: 36986362
DOI: 10.3390/pathogens12030440 -
JMIR Dermatology Oct 2023Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a... (Review)
Review
BACKGROUND
Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a red skin rash occurring on sun-exposed areas of the body, and an increased risk of cancer. CTE is one of many genodermatoses and photodermatoses associated with defects in DNA repair. CTE is caused by a mutation occurring in the BLM gene, which causes abnormal breaks in chromosomes.
OBJECTIVE
We aimed to analyze the existing literature on CTE to provide additional insight into its heredity, the spectrum of clinical presentations, and the management of this disorder. In addition, the gaps in current research and the use of artificial intelligence to streamline clinical diagnosis and the management of CTE are outlined.
METHODS
A literature search was conducted on PubMed, DOAJ, and Scopus using search terms such as "congenital telangiectatic erythema," "bloom syndrome," and "bloom-torre-machacek." Due to limited current literature, studies published from January 2000 to January 2023 were considered for this review. A total of 49 sources from the literature were analyzed.
RESULTS
Through this scoping review, the researchers were able to identify several publications focusing on Bloom syndrome. Some common subject areas included the heredity of CTE, clinical presentations of CTE, and management of CTE. In addition, the literature on rare diseases shows the potential advancements in understanding and treatment with artificial intelligence. Future studies should address the causes of heterogeneity in presentation and examine potential therapeutic candidates for CTE and similarly presenting syndromes.
CONCLUSIONS
This review illuminated current advances in potential molecular targets or causative pathways in the development of CTE as well as clinical features including erythema, increased cancer risk, and growth abnormalities. Future studies should continue to explore innovations in this space, especially in regard to the use of artificial intelligence, including machine learning and deep learning, for the diagnosis and clinical management of rare diseases such as CTE.
PubMed: 37796556
DOI: 10.2196/48413