Chromosomal translocation - Wikipedia
No correlation was found between the presence of this translocation and bcl-2 protein . Both the MBR and mcr of the t(14;18) chromosomal translocation were . In many B-cell lymphomas, chromosomal translocations are considered t o t( 14; 18) translocations in lymphoid tissues with overt follic- clonal relationship. Objective: To understand the relationship between (14; 18) chromosomal translocation and hepatocellular carcinoma. Methods: Semi-nested in situ PCR.
TK domain in these fusion proteins is intact although they are the truncated proteins 278 As the regulatory parts of kinase are often lost and replaced by unrelated sequences, the kinase activity of these fusion proteins is determined by the N-terminal partners.
The functions of fusion proteins as TKs and associated malignant tumors. ABL protein has two isoforms, 1a and b. ABL1b contains a C14 myristoyl saturated fatty acid moiety covalently linked to the Cap region at the N-terminus and is expressed at higher levels than ABL1a, which is not myristoylated.
Dasatinib and nilotinib, second generation inhibitors of ABL, have also been approved to treat patients with imatinib-resistant CML RET lacks the signal peptide and transmembrane domain in this chimeric oncoprotein, thus the aberrant TK activity of RET fusion is controlled by H4 partner which provides an active promoter and dimerization domain for ligand-independent activation of the fusion protein Oncogenes under the control of a stronger promoter Proto-oncogenes are brought into proximity with the new cis-regulatory elements, leading to their overexpression which is seen in several types of lymphoma and leukemia, particularly in B and T cell malignancies.
However, V D J recombination may also increase the risk of chromosomal translocation in the same regions, which may partly explain why chromosomal translocation frequently occurs in several types of lymphoma and leukemia.
The promoter is usually located upstream of the gene, while the enhancer can be located upstream, downstream, or even within the gene it control. The TCR is composed of two different protein chains.
TLX1 overexpression has also been demonstrated in the absence of a 10q24 rearrangement, suggesting that other mechanisms, such as epigenetic alterations, can lead to this aberrant expression of TLX1 The situation is similar to TAL1 1p NOTCH1 plays crucial roles in cell development, hematopoietic stem cell maintenance and T cell fate specification in the mature organism NOTCH1 is regarded as an oncoprotein.
In a low number of human T-ALL patients, they had t 7;9 q34;q Conclusion Chromosomal translocations in human cancer are not random and tend to occur in some specific sites with spatial proximity in genome organization. The oncogenic chromosomal translocations may provide a selective growth advantage or chance of secondary mutations in some stem or progenitor cells via different pathways, such as the formation of oncogenic fusion proteins and under the control of the new regulatory elements.
Understanding the mechanisms of chromosomal translocations in cancer may help us to develop new approaches in early the diagnosis and target therapy of cancer.
t(14;18) Translocations and risk of follicular lymphoma.
Acknowledgements Dr Peng Gao is acknowledged for the images and comments on this review. This study was in part supported by a grant from the Ministry of Education, China no. The impact of translocations and gene fusions on cancer causation. Chromosomal translocations in cancer. Chromosomal abnormalities in cancer. N Engl J Med.
Causes of oncogenic chromosomal translocation. DNA structures at chromosomal translocation sites. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Spatial genome organization in the formation of chromosomal translocations. The topological organization of chromosomes 9 and 22 in cell nuclei has a determinative role in the induction of t 9,22 translocations and in the pathogenesis of t 9,22 leukemias.
Retinoic acid receptors, hematopoiesis and leukemogenesis. Spatial proximity of translocation-prone gene loci in human lymphomas. The inner life of the genome. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh.
Follicular lymphoma can be distinguished from benign follicular hyperplasia by flow cytometry using simultaneous staining of cytoplasmic bcl-2 and cell surface CD Am J Clin Pathol.
Templated nucleotide addition and immunoglobulin JH-gene utilization in t 11;14 junctions: Anaplastic lymphoma kinase in human cancer. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma. Mechanisms of chromosomal rearrangements in solid tumors: Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer.
Prostate cancer as a model system for genetic diversity in tumors. Recurrent gene fusions in prostate cancer. ETS transcription factors and their emerging roles in human cancer. Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription. Induced chromosomal proximity and gene fusions in prostate cancer.
ERG fusion in nonmalignant prostate epithelial cells. Completely inactive mitotic checkpoints may cause non-disjunction at multiple chromosomes, possibly all.every teen needs to hear this.
Such a scenario could result in each daughter cell possessing a disjoint set of genetic material. Merotelic attachment occurs when one kinetochore is attached to both mitotic spindle poles. One daughter cell would have a normal complement of chromosomes; the second would lack one.
A third daughter cell may end up with the 'missing' chromosome. Such a mitotic division would result in one daughter cell for each spindle pole; each cell may possess an unpredictable complement of chromosomes. This produces a single daughter cell with its copy number doubled. A tetraploid intermediate may be produced as the end-result of the monopolar spindle mechanism.
In such a case, the cell has double the copy number of a normal cell, and produces double the number of spindle poles as well. This results in four daughter cells with an unpredictable complement of chromosomes, but in the normal copy number. Somatic mosaicism in the nervous system[ edit ] Mosaicism for aneuploid chromosome content may be part of the constitutional make-up of the mammalian brain.
However, these forms of mosaic aneuploidy occur through mechanisms distinct from those typically associated with genetic syndromes involving complete or mosaic aneuploidy, such as chromosomal instability  due to mitotic segregation defects in cancer cells. Therefore, the molecular processes that lead to aneuploidy are targets for the development of cancer drugs.
Both resveratrol and aspirin have been found in vivo in mice to selectively destroy tetraploid cells that may be precursors of aneuploid cells, and activate AMPKwhich may be involved in the process. It has been suggested that aneuploidy might directly contribute to carcinogenesis by disrupting the asymmetric division of adult stem cells, thereby leaving those cells capable of "limitless expansion".
A pericentric inversion can provoke miscarriages, sterility more often in the maleand lead to unbalanced products at meiosis. During meiosis, crossing over in the inversion loop will produce recombinant chromosomes rec with duplication of one segment and deficiency of another a duplication p - deficiency q will be recorded as rec dup p. Duplicated-deficient segments are those outside of the inversion loop see Figure, bottom right.
If the inversion is large, the probability of crossing over in the inversion loop will be higher, and duplicated-deficient segments outside the loop smaller. However, the risk will then be greater, since the probability that the conceptus is viable is higher. Conversely, a small inversion has a lower probability of crossing over in the small inversion loop.
However, if it occurs, the very large duplicated-deficient segments will have a strong negative selection pressure effect, and the risk of a malformed offspring will be lower. Notes on paracentric and pericentric inversions: Crossing over outside the inverted segments out of the loop are without consequence. Wherever the crossing over occurs in the loop, the consequence will be the same.
This is an unbalanced rearrangement. Recorded as i, followed by a bracket with the number of the chromosome and the arm e. This rearrangement is frequent on X chromosome Turner syndrome with i Xq. It is also frequent as an acquired anomaly in cancers e.
Mechanisms of formation of an isochromosome are varied Figure. If it arises in the first meiotic division, the duplicated material will be heterozygous. In somatic cells, the most likely origin is from an isochromatid deletion, with sister union, occurring within the centromeric region. The inserted segment may be positioned with its original orientation with respect to the centromere or inverted.
This is usually a balanced rearrangement. Recorded as ins, followed by a bracket with the number of the chromosome which receives the segment preceding the number of the chromosome which donates the segment if different.
A second bracket indicates the one breakpoint where it inserts, followed by the 2 breakpoints which define the ends of the deleted segment. An insertion can be direct dir ins if the segment keeps its orientation in relation to the centromere the most proximal band remaining the closest to the centromere; In the example above, band q31 precedes band q An insertion can be inverted inv ins if the most proximal band becomes the farthest from the centromere e. This aberration can be balanced and stable in somatic cells, and be transmitted for many cell generations.
However, it is pretty devastating at meiosis. In many cases the inserted segment will not be large enough to cause the formation of a quadrivalent. Even so, random segregation at Meiosis 1 means that half of the gametes will be imbalanced. What it would actually look like in reality is an interesting thought. Interesting exercise for students: A segment of chromosome is repeated, once or several times, the duplicated segment keeping the same orientation with respect to the centromere "tandem duplication".
The duplicated segment takes the opposite orientation.
Is an unbalanced rearrangement. Recorded as dup, followed by a bracket with the number of the chromosome, and a second bracket indicating the breakpoint s and the duplicated region. Simplistically, it is the alternative rejoining mode of the reciprocal translocation, but it can originate by several other mechanisms. It is an unbalanced rearrangement, leading to mechanical separation problems at anaphase "bridges". Recorded as dic, or psu dic pseudo dicentricwhen one of the centromeres inactivates, precluding anaphase bridge formation.
Inactivation seems principally to be a function of the intercalary distance between the centromeres. Persistent dicentrics are frequent in the case of Robertsonian translocations, but very rare as a constitutional anomaly, unless the short arm of an acrocentric is involved. Rare as an acquired anomaly. Dicentrics other than Robertsonian translocations are highly unstable unless: The only proofs of the presence of 2 active centromeres are: As pointed out above, such aberrations now appear to be much more frequent than we have realised.
Many changes seen in cancer cells are of this type. Frequency of malformations in apparently balanced carriers genetic counselling. Issue in prenatal diagnosis. Since FISH-painting techniques have been developed, many markers have been shown to be highly rearranged chromosomes, involving many participants and many breakpoints.
Appear as very small, usually paired dots. Quite often numerous, but because they are acentric, segregation is irregular and numbers very variable.
In the simplest case they represent interstitial deletions, and would normally be rapidly lost from a cell population.