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Advances in Anatomic Pathology Jul 2018Osteosarcoma (OS) is the most common primary bone tumor affecting predominantly adolescents and young adults. It accounts for about 5% of all childhood cancers. Although... (Review)
Review
Osteosarcoma (OS) is the most common primary bone tumor affecting predominantly adolescents and young adults. It accounts for about 5% of all childhood cancers. Although the majority of OSs are sporadic, a small percentage occur as a component of hereditary cancer syndromes. Early onset, bilateral, multifocal, and metachronous tumors suggest genetic predisposition. The inheritance patterns can be autosomal dominant or recessive. These syndromes predispose to a wide variety of mesenchymal and epithelial cancers with propensity for certain mutations being prevalent in specific cancer subtypes. Li-Fraumeni syndrome, retinoblastoma, Rothmund-Thompson syndrome (type 2), Werner syndrome, and Bloom syndrome, constitute the majority of the tumor syndromes predisposing to OS and will be the focus for this review.
Topics: Bone Neoplasms; Genetic Predisposition to Disease; Humans; Neoplastic Syndromes, Hereditary; Osteosarcoma
PubMed: 29668499
DOI: 10.1097/PAP.0000000000000190 -
Genetics in Medicine : Official Journal... Jul 2022This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these...
PURPOSE
This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined.
METHODS
Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed.
RESULTS
Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants.
CONCLUSION
We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.
Topics: Adult; Bloom Syndrome; Hematologic Neoplasms; Humans; Incidence; Neoplasms; Registries
PubMed: 35420546
DOI: 10.1016/j.gim.2022.03.008 -
Ageing Research Reviews Jan 2017Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic... (Review)
Review
Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic integrity. The RecQ family of DNA helicases is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes - BLM, WRN, and RECQL4 - give rise to Bloom's syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. WS is a prototypic premature aging disorder; however, the clinical features present in BS and RTS do not indicate accelerated aging. The BLM helicase has pivotal functions at the crossroads of DNA replication, recombination, and repair. BS cells exhibit a characteristic form of genomic instability that includes excessive homologous recombination. The excessive homologous recombination drives the development in BS of the many types of cancers that affect persons in the normal population. Replication delay and slower cell turnover rates have been proposed to explain many features of BS, such as short stature. More recently, aberrant transcriptional regulation of growth and survival genes has been proposed as a hypothesis to explain features of BS.
Topics: Aging; Aging, Premature; Bloom Syndrome; DNA Helicases; DNA Replication; Genomic Instability; Humans; Mutation; RecQ Helicases; Werner Syndrome; Werner Syndrome Helicase
PubMed: 27238185
DOI: 10.1016/j.arr.2016.05.010 -
Journal of Clinical Medicine Feb 2020Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on... (Review)
Review
Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements.
PubMed: 32106411
DOI: 10.3390/jcm9030613 -
Journal of Clinical Immunology Jan 2018Bloom's syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA...
Bloom's syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20-80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR.
Topics: Adult; B-Lymphocytes; Bloom Syndrome; Cell Differentiation; Child; DNA Repair; Female; Humans; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Deficiency Syndromes; Immunophenotyping; Lymphocyte Activation; Male; Middle Aged; Mutation; RecQ Helicases; Somatic Hypermutation, Immunoglobulin; T-Lymphocytes
PubMed: 29098565
DOI: 10.1007/s10875-017-0454-y -
Cell Cycle (Georgetown, Tex.) 2018
Topics: DNA; DNA Breaks, Double-Stranded; DNA Helicases; DNA Repair; Recombination, Genetic
PubMed: 29278995
DOI: 10.1080/15384101.2017.1421045 -
Structure (London, England : 1993) Feb 2021The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for... (Review)
Review
The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for the maintenance of accurate homologous recombination. Mutations to any of the genes encoding these proteins cause numerous physical and developmental markers as well as phenotypes of genome instability, infertility, and cancer predisposition. Here we review the published structural and biochemical data on each of the components of the complex: the helicase BLM, the type IA topoisomerase TOP3A, and the OB-fold-containing RMI and RPA subunits. We describe how each component contributes to function, interacts with each other, and the DNA that it manipulates/repairs.
Topics: Bloom Syndrome; DNA Topoisomerases, Type I; DNA-Binding Proteins; Homologous Recombination; Humans; RecQ Helicases
PubMed: 33357470
DOI: 10.1016/j.str.2020.11.020 -
Chromosome Research : An International... Mar 2019More than half of the human genome consists of repetitive sequences, with the ribosomal DNA (rDNA) representing two of the largest repeats. Repetitive rDNA sequences may... (Review)
Review
More than half of the human genome consists of repetitive sequences, with the ribosomal DNA (rDNA) representing two of the largest repeats. Repetitive rDNA sequences may form a threat to genomic integrity and cellular homeostasis due to the challenging aspects of their transcription, replication, and repair. Predisposition to cancer, premature aging, and neurological impairment in ataxia-telangiectasia and Bloom syndrome, for instance, coincide with increased cellular rDNA repeat instability. However, the mechanisms by which rDNA instability contributes to these hereditary syndromes and tumorigenesis remain unknown. Here, we review how cells govern rDNA stability and how rDNA break repair influences expansion and contraction of repeat length, a process likely associated with human disease. Recent advancements in CRISPR-based genome engineering may help to explain how cells keep their rDNA intact in the near future.
Topics: Animals; DNA Damage; DNA Repair; DNA Replication; DNA, Ribosomal; Genetic Association Studies; Genetic Predisposition to Disease; Genomic Instability; Genomics; Humans; Repetitive Sequences, Nucleic Acid; Transcription, Genetic
PubMed: 30556094
DOI: 10.1007/s10577-018-9594-z -
Mechanisms of Ageing and Development Jul 2018Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is... (Review)
Review
Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is adult onset and results from disease-causing DNA sequence variants in the RecQ helicase gene WRN, and Hutchison-Gilford progeria syndrome, which is childhood-onset and results from unique, recurrent disease-causing DNA sequence variants of the gene LMNA that encodes nuclear intermediate filaments. Related single gene RecQ disorders are Bloom syndrome and Rothmund-Thomson syndrome. The RecQ disorders Cockayne syndrome and xeroderma pigmentosum result from disease-causing DNA sequence variants in genes involved in the nucleotide excision repair pathway. RECQ2018: The International Meeting on RECQ Helicases and Related Diseases was held on February 16-18, 2018 in Chiba, Japan. The purpose of the meeting was to facilitate clinical and research collaborations for the goal of developing effective treatments for RECQ disorders and other progeroid syndromes.
Topics: Animals; Cockayne Syndrome; Congresses as Topic; DNA Repair; DNA Repair-Deficiency Disorders; Humans; Japan; Werner Syndrome Helicase
PubMed: 29752965
DOI: 10.1016/j.mad.2018.05.002 -
Frontiers in Cell and Developmental... 2021RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions,... (Review)
Review
RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions, including DNA replication, transcription, DNA repair, and telomere maintenance. Humans have five RecQ helicases: RECQL1, Bloom syndrome protein (BLM), Werner syndrome helicase (WRN), RECQL4, and RECQL5. Defects in BLM and WRN cause autosomal disorders: Bloom syndrome (BS) and Werner syndrome (WS), respectively. Mutations in RECQL4 are associated with three genetic disorders, Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome. Although no genetic disorders have been reported due to loss of RECQL1 or RECQL5, dysfunction of either gene is associated with tumorigenesis. Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. The importance of DSB repair is supported by the observations that defective DSB repair can cause chromosomal aberrations, genomic instability, senescence, or cell death, which ultimately can lead to premature aging, neurodegeneration, or tumorigenesis. In this review, we will introduce the human RecQ helicase family, describe in detail their roles in DSB repair, and provide relevance between the dysfunction of RecQ helicases and human diseases.
PubMed: 33718381
DOI: 10.3389/fcell.2021.640755