scholarly journals The Chromosomal Basis of Cancer

2005 ◽  
Vol 27 (5-6) ◽  
pp. 293-318
Author(s):  
Peter Duesberg ◽  
Ruhong Li ◽  
Alice Fabarius ◽  
Ruediger Hehlmann
Keyword(s):  
Down Syndrome ◽  
New Species ◽  
Cancer Cells ◽  
Genetic Disease ◽  
Trisomy 21 ◽  
Cellular Heterogeneity ◽  
Complex Phenotypes ◽  
Chromosomal Disease ◽  
Low Probability ◽  
Native Site

Conventional genetic theories have failed to explain why cancer (1) is not heritable and thus extremely rare in newborns, (2) is caused by non-mutagenic carcinogens, (3) develops only years to decades after initiation by carcinogens, (4) follows pre-neoplastic aneuploidy, (5) is aneuploid, (6) is chromosomally and phenotypically “unstable”, (7) carries specific aneusomies, (8) generates much more complex phenotypes than conventional mutation such as multidrug resistance, (9) generates nonselective phenotypes such as metastasis (no benefit at native site) and “immortality” (not necessary for tumorigenesis), and (10) does not contain carcinogenic mutations. We propose, instead, that cancer is a chromosomal disease. Accordingly carcinogenesis is initiated by random aneuploidies, which are induced by carcinogens or spontaneously. Since aneuploidy unbalances 1000s of genes, it corrupts teams of proteins that segregate, synthesize and repair chromosomes. Aneuploidy is therefore a steady source of chromosomal variations from which, in classical Darwinian terms, selection encourages the evolution and malignant progression of cancer cells. The rates of specific chromosomal variations can exceed conventional mutations by 4–11 orders of magnitude, depending on the degrees of aneuploidy. Based on their chromosomal constitution cancer cells are new cell “species” with specific aneusomies, but unstable karyotypes. The cancer-specific aneusomies generate complex, malignant phenotypes through the abnormal dosages of 1000s of genes, just as trisomy 21 generates Down syndrome. In sum, cancer is caused by chromosomal disorganization, which increases karyotypic entropy. Thus, cancer is a chromosomal rather than a genetic disease. The chromosomal theory explains (1) non-heritable cancer because aneuploidy is not heritable, (2) non-mutagenic carcinogens as aneuploidogens, (3) long neoplastic latencies by the low probability of evolving new species, (4) nonselective phenotypes via genes hitchhiking with selective chromosomes, and (5) immortality because, through their cellular heterogeneity, cancers survive negative mutations and cytotoxic drugs via resistant subspecies.

scholarly journals Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of down syndrome-related phenotypes

2021 ◽  
Author(s):  
Eva Lana-Elola ◽  
Heather Cater ◽  
Sheona Watson-Scales ◽  
Simon Greenaway ◽  
Jennifer Müller-Winkler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cognitive Deficits ◽  
Trisomy 21 ◽  
Heart Defects ◽  
Chromosome 21 ◽  
Phenotypic Analysis ◽  
Extra Copy ◽  
Human Chromosome 21 ◽  
Complex Phenotypes ◽  
Physiological Systems

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish if this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

scholarly journals Cytogenetic Analysis of Down Syndrome

2019 ◽  
Vol 1 (1) ◽  
pp. 37-40
Author(s):  
G S Kadakol ◽  
R S Bulagouda ◽  
S V Patil ◽  
Ishwar Bagoji
Keyword(s):  
Down Syndrome ◽  
Genetic Disease ◽  
Genetic Risk ◽  
Cytogenetic Analysis ◽  
Trisomy 21 ◽  
Robertsonian Translocation ◽  
Common Type ◽  
Chromosome 21 ◽  
Banding Technique ◽  
Mosaic Trisomy

Objective: Down syndrome is a common genetic disease, diagnosed with congenital malformation/mental retardation. Down syndrome occurs in all races & economic levels. It is caused by third copy of chromosome 21, there are there forms of DS. Simple Trisomy 21, Translocation Trisomy and Mosaic Trisomy.  The aim of the study is to know cause of Down syndrome. Chromosomal analysis was carried out by G banding technique. Materials and Methods: 1 ml of peripheral blood samples were collected in Out Patient Department of pediatrics  and Cytogenetic analysis was performed Results: out of 28, 3 female cases, 2 male cases were Down syndrome, All the 5 cases were free trisomy 21, which is common type of Down syndrome; we have not identified Robertsonian translocation and mosaic type of DS. Conclusion: The present analysis shows that genetic risk factors are responsible for the incidence of Down syndrome.

scholarly journals Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes

2021 ◽  
Author(s):  
Eva Lana-Elola ◽  
Heather Cater ◽  
Sheona Watson-Scales ◽  
Simon Greenaway ◽  
Jennifer Müller-Winkler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Bone Density ◽  
Cognitive Deficits ◽  
Trisomy 21 ◽  
Heart Defects ◽  
Chromosome 21 ◽  
Phenotypic Analysis ◽  
Extra Copy ◽  
Human Chromosome 21 ◽  
Complex Phenotypes

AbstractDown syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, causative genes remain mostly unknown. Animal models enable identification of these genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. Here, we comprehensively phenotype Dp1Tyb mice and find wide-ranging DS-like phenotypes including aberrant megakaryopoiesis, reduced bone density, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for studies of many complex DS phenotypes.

‘The Stuff of Slow Constitution’: Reading Down Syndrome for Race, Disability, and the Timing that Makes Them So

Somatechnics ◽  
2016 ◽  
Vol 6 (2) ◽  
pp. 235-248 ◽  
Author(s):  
Mel Y. Chen
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Historical Perspective ◽  
Early History ◽  
Present Moment ◽  
History Of ◽  
Living Being

In this paper I would like to bring into historical perspective the interrelation of several notions such as race and disability, which at the present moment seem to risk, especially in the fixing language of diversity, being institutionalised as orthogonal in nature to one another rather than co-constitutive. I bring these notions into historical clarity primarily through the early history of what is today known as Down Syndrome or Trisomy 21, but in 1866 was given the name ‘mongoloid idiocy’ by English physician John Langdon Down. In order to examine the complexity of these notions, I explore the idea of ‘slow’ populations in development, the idea of a material(ist) constitution of a living being, the ‘fit’ or aptness of environmental biochemistries broadly construed, and, finally, the germinal interarticulation of race and disability – an ensemble that continues to commutatively enflesh each of these notions in their turn.

scholarly journals Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Genetics ◽  
2003 ◽  
Vol 163 (2) ◽  
pp. 571-580 ◽  
Author(s):  
William B Raich ◽  
Celine Moorman ◽  
Clay O Lacefield ◽  
Jonah Lehrer ◽  
Dusan Bartsch ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Caenorhabditis Elegans ◽  
Trisomy 21 ◽  
Gene Dosage ◽  
Inducible Promoters ◽  
C Elegans ◽  
Dual Specificity ◽  
Specificity Protein

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

scholarly journals Medical vulnerability of individuals with Down syndrome to severe COVID-19–data from the Trisomy 21 Research Society and the UK ISARIC4C survey

2021 ◽  
Vol 33 ◽  
pp. 100769 ◽  
Author(s):  
Anke Hüls ◽  
Alberto C.S. Costa ◽  
Mara Dierssen ◽  
R. Asaad Baksh ◽  
Stefania Bargagna ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Research Society ◽  
The Uk

Molecular Cytogenetic Classification of Down Syndrome and Screening of Somatic Aneuploidy in Mothers

2021 ◽  
pp. 1-9
Author(s):  
Sushil Kumar Jaiswal ◽  
Ashok Kumar ◽  
Amit Kumar Rai
Keyword(s):  
Down Syndrome ◽  
Peripheral Blood ◽  
Trisomy 21 ◽  
Health Management ◽  
Chromosome 21 ◽  
Robertsonian Translocations ◽  
Significant Difference ◽  
And Control

Down Syndrome (DS) caused by trisomy 21 results in various congenital and developmental complications in children. It is crucial to cytogenetically diagnose the DS cases early for their proper health management and to reduce the risk of further DS childbirths in mothers. In this study, we performed a cytogenetic analysis of 436 suspected DS cases using karyotyping and fluorescent in situ hybridization. We detected free trisomies (95.3%), robertsonian translocations (2.4%), isochromosomes (0.6%), and mosaics (1.2%). We observed a slightly higher incidence of DS childbirth in younger mothers compared to mothers with advanced age. We compared the somatic aneuploidy in peripheral blood of mothers having DS children (MDS) and control mothers (CM) to identify biomarkers for predicting the risk for DS childbirths. No significant difference was observed. After induced demethylation in peripheral blood cells, we did not observe a significant difference in the frequency of aneuploidy between MDS and CM. In conclusion, free trisomy 21 is the most common type of chromosomal abnormality in DS. A small number of DS cases have translocations and mosaicism of chromosome 21. Additionally, somatic aneuploidy in the peripheral blood from the mother is not an effective marker to predict DS childbirths.

scholarly journals Low-pass whole genome bisulfite sequencing of neonatal dried blood spots identifies a role for RUNX1 in Down syndrome DNA methylation profiles

2020 ◽  
Author(s):  
Benjamin I Laufer ◽  
Hyeyeon Hwang ◽  
Julia M Jianu ◽  
Charles E Mordaunt ◽  
Ian F Korf ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Early Life ◽  
Trisomy 21 ◽  
Bisulfite Sequencing ◽  
Dried Blood Spots ◽  
Whole Genome ◽  
Genome Wide ◽  
Low Pass ◽  
Genome Bisulfite Sequencing

Abstract Neonatal dried blood spots (NDBS) are a widely banked sample source that enables retrospective investigation into early life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early life Down syndrome (DS) DNA methylation profiles. DS represents an example of genetics shaping epigenetics, as multiple array-based studies have demonstrated that trisomy 21 is characterized by genome-wide alterations to DNA methylation. By assaying over 24 million CpG sites, thousands of genome-wide significant (q < 0.05) differentially methylated regions (DMRs) that distinguished DS from typical development and idiopathic developmental delay were identified. Machine learning feature selection refined these DMRs to 22 loci. The DS DMRs mapped to genes involved in neurodevelopment, metabolism, and transcriptional regulation. Based on comparisons with previous DS methylation studies and reference epigenomes, the hypermethylated DS DMRs were significantly (q < 0.05) enriched across tissues while the hypomethylated DS DMRs were significantly (q < 0.05) enriched for blood-specific chromatin states. A ~28 kb block of hypermethylation was observed on chromosome 21 in the RUNX1 locus, which encodes a hematopoietic transcription factor whose binding motif was the most significantly enriched (q < 0.05) overall and specifically within the hypomethylated DMRs. Finally, we also identified DMRs that distinguished DS NDBS based on the presence or absence of congenital heart disease (CHD). Together, these results not only demonstrate the utility of low-pass WGBS on NDBS samples for epigenome-wide association studies, but also provide new insights into the early life mechanisms of epigenomic dysregulation resulting from trisomy 21.

scholarly journals Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. c9
Author(s):  
Triya Chakravorty ◽  
Irene Roberts
Keyword(s):  
Down Syndrome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Trisomy 21 ◽  
Children With Down Syndrome ◽  
Transient Abnormal Myelopoiesis ◽  
Increased Risk ◽  
Leukaemic Cells ◽  
Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

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