In many B-cell lymphomas, chromosomal translocations are considered t o be an t(8;14) in Burkitt's lymphoma, t(14; 18) in follicular lymphoma, and t(I 1; 14) in date 1 X 10' to 20 X IO3 circulating B cells with a t(14; 18) translocation and an lymphoma (3/, inhabitants per year in The Nether- lands) exclude the. May 1, Translocation of the long arms between chromosomes 17 and 18, t(17;18), F/ 54, AML‐M1, 46, XX/ 45, X,−X/45, X,−X,t(17;18)(p11;q11), 14 a 10‐year period expressed the translocation t(17;18)(q10;q10). Patient, Diagnosis (date), Cytogenetics, Therapy, Response, Survival from Dx (months), Status. Chromosomal Translocations in Lymphomas—Vega & Medeiros t(8;14) in Burkitt lymphoma/leukemia and the t(14;18) in To date, the t(11;18) only.
There is no consanguinity with her partner. When the patient came to our attention, a karyotype was already performed, six months before, in another laboratory. A hundred metaphases were analyzed with G-banding and C-banding at resolution of bands.I'm 18 With A 15 Year Old Girlfriend!!!
Images of the array were acquired with Agilent scanner GB and analyzed with Feature Extraction software v9. Graphical overviews of results were obtained with Genomic Workbench Standard Edition software v5. Results The patient had already performed a karyotype on peripheral blood lymphocytes in another laboratory, six months before coming to our attention. This previous study showed a female karyotype in mosaic, with two cell lines: A 46 chromosomes cell line with a reciprocal translocation between the short arm of a chromosome 18 and the long arm of a chromosome 21, involving bands 18p The patient cytogenetic study, performed in our laboratory, showed a 45 chromosome female karyotype with the derivative chromosome Cytogenetic study of our patient showing a 45 chromosome female karyotype with a derivative chromosome Genome-wide array CGH analysis: FISH analysis confirmed the presence of the derivative chromosome 18 and positioned the breakpoints respectively in 18p The result of Genome-wide array CGH analysis of the proband was: Feb hg19 Figure 2.
Chromosomal translocation - Wikipedia
No deletion was detected on the short arm of chromosome 18 first oligo probe in used platform at 14, bp from telomere. Discussion Karyotyping in our patient revealed a complex structural chromosomal abnormality in mosaic. Cellular mosaicism is characterized by the simultaneous presence of two or more cell lines, which can be present in different percentage in different tissues, thus resulting in a variable clinical expression. Breakpoints, defined by FISH, are located in 18p Studying by array-CGH showed the presence of a partial deletion of the short and long arms of chromosome 21 of about 9 Mb.
The chromosome 18 appears to be involved from the end part of p As noted, when we repeated the cytogenetic study six months later, we found out only a 45 chromosome cell line with absence of derivative 18;21 p We can explain this finding because of the instability of derivative chromosomes. Indeed, derivative chromosomes are not stable structures and they may be lost over time. Thus the percentage of mosaicism can be variable in time. However, we cannot exclude that the two cell lines are present in different percentages in other tissues, since our study limited only to peripheral lymphocytes.
Moreover, considering the complexity of the rearrangement in combination with instability, mFISH multicolor fluorescence in situ hybridization analysis would probably have given additional information on the genomic composition in the sample.
The partial deletion of chromosome 21, revealed by array-CGH, involves many genes. Among these, TPTE is the only one located on the short arm of chromosome 21 and encodes a putative tyrosine phosphatase. These findings suggest the spatial arrangements of chromosomes and gene loci in the interphase nucleus are responsible for non-random chromosomal translocations in human cancer.
Chromosomal translocations are favored in neighboring chromosomes or genes in spatial proximity within the nucleus. Chromosomal translocations leading to cancer are generally via two ways, formation of oncogenic fusion protein or oncogene activation by a new promoter or enhancer.
This review focuses mainly on the recent advances in oncogenic chromosomal translocations in human cancer. Introduction Chromosomal translocations are very common in human cancer, particularly in hematopoietic and lymphoid tumors 1. They are involved in the initiation of some types of cancer although the exact mechanism is not fully understood. These translocations may provide a selective growth advantage or chance of subsequent mutations in some stem or progenitor cells, which may subsequently initiate the development of some malignant tumors.
For oncogenic chromosomal translocations, gene rearrangements may change the original locations of proto-oncogenes to generate the obvious effects on phenotype via the two major ways 23.
One is to generate oncogenic fusion proteins. The best example is translocation between chromosomes 9 and 22 [t 9;22 ], i. Another way is that proto-oncogenes are brought into proximity with the new cis-regulatory elements. Chromosomal translocations in vivo are a complex biological process and there are two essential steps for the formation of chromosomal translocations. Second, the ends of DSBs need to approach each other and are illegitimately joined together.
Aside from these essential steps, increasing evidence shows that there are still several factors that influence the formation of chromosomal translocations, such as nuclear architecture, activation induced deaminase AID -mediated V D J recombination, gene expression, and other unknown mechanisms 5 — 7.
In the present study, I focus on the effects of chromosome or gene positioning on chromosomal translocations, on the functional impacts owing to oncogenic chromosomal translocations in human cancer. Chromosomal translocations are related to chromosome or gene positioning Chromosomal translocations in cancer are generally considered to be no-random.
The factors that could influence chromosomal translocation are complex and several factors, such as the spatial positions of broken loci, recombination, DNA repair elements, are involved. The two spatial proximal broken loci have more probability to illegitimately join than two distant broken loci 8.
For example, investigations have shown that chromosomes 9 and 22 neighbor in lymphoid cells 9 This may partly explain why t 9;22 easily occurs in lymphocytes. The study also showed that chromosomes 15 and 17 were close to each other in lymphoid cells 10 ; this may also partly explain why t 15;17 easily occurs in hematopoietic cells.
Research has shown that when B lymphocytes are stimulated, the MYC gene is preferentially recruited to the same transcription factory as the highly transcribed IGH gene.
While the c-MYC and IGH are close to each other, it increases the incidence of specific chromosomal translocations In fact, the mechanism of t 2;8 or t 8;22 translocation is similar to that of t 8;14 in Burkitt lymphoma, relating to spatial organization of the B cell genome Proto-oncogenes are under the control of the cis-IGH-regulatory elements in B cell malignancies.
IGH is on chromosome Chromosomal translocations make c-MYC and other proto-oncogenes under the control of cis-IGH locus in Burkitt lymphoma and other B cell lymphomas as indicated. Measuring BCL-2 expression can be used to distinguish follicular lymphoma from benign follicular hyperplasia, in which BCL-2 expression is low In mantle cell lymphoma, an aggressive subtype of B cell lymphoma, most tumor cells have a t 11;14i.
Cyclin D1, a cell cycle regulator, is not expressed in normal B cells. The mechanism of chromosomal translocations in follicular lymphoma, mantle cell lymphoma and DLBCL are similar to that in Burkitt lymphoma, relating to spatial proximity of translocation-prone gene loci in the interphase nucleus Accumulating evidence suggests that DSBs and the formation of translocation are preceded by the two gene loci being in close proximity.
For example, Mathas et al 20 found that the formation of ALK-NPM fusion gene was related to spatial proximity of two gene loci which was prior to the generation of translocation. Aside from interchromosomal translocations, intrachromosomal translocations are also associated with spatial distance of two gene loci. The H4 protein is widely expressed in the nucleus and cytoplasm and its function is unknown These rearrangements can lead to constitutively ligand-independent RET activity, involved in thyroid carcinogenesis.
Although the distances between RET and H4 loci are 18 Mb, chromosome folding can offer two loci close to each other in thyroid cells, thus increasing the probability of recombination between them in the interphase nuclei.
This chromosomal folding is specific for thyroid cells, and this may explain why inv 10 q The translocation of H4 and RET occurs less in other types of cells. If it happens in non-thyroid cells, this type of translocation may not cause tumor.
Hormones also influence chromosomal translocations via their receptors. The translocations of ETS are often found in human cancer, such as Ewing sarcoma 3132leukemia 3334prostate cancer 127 — 28 and breast cancer TMPRSS2 is a specific expression gene in the prostate and its expression is increased in prostate cancer 28 Although it is 2.
That hormones induce interactions between gene loci on different chromosomes is also found in estrogen. We can image if the broken ends are relatively stable, they may be rejoined by themselves, thereby preventing chromosomal translocation. If the broken ends roam, it increases the chances of illegitimate recombination.
Thus, the relative stability of the broken ends decreases the probability of gene rearrangement and favor genomic integrity 40 Effects of oncogenic chromosomal translocations Effects of oncogenic chromosomal translocations on cellular phenotypes are complex and diverse.
- Oncogenic chromosomal translocations and human cancer (Review)
Following translocations, oncogenes may influence cellular phenotypes via the formation of oncogenic fusion proteins or under the control of the new regulatory elements 1 — 3. Oncogenic fusion proteins Although the products of oncogenic fusion genes are diverse, they can primarily be classified into two groups, transcription factors and TKs.
Several oncogenic fusion proteins are transcription factors and TKs. In fact, the products of fusion genes are diverse; some may be neutral, some may play less important roles in cellular phenotypes and some may cause cell death in which we can not see this type of the translocation.
The translocations found in cancer, however, clearly have critical functions in tumorigenesis. Generally, transcription factors and TKs play more important roles in cellular phenotypes, and this may partly explain why many fusion proteins detected in human cancer are transcription factors and TKs. It should be noted, that these so-called oncogenic fusion proteins as transcription factors and TKs are already different from their functions of parental proteins in several aspects and they often acquire some new functions.
It is clear that the sites of DSBs are related to the functional consequences of fusion genes. DSBs are not random 42 and occur preferentially in large and evolutionarily conserved genes 4344fragile sites 45transcription start sites 144647 and euchromatin 48 The breakpoints do not usually occur in their functional domains if these genes are encoded for transcription factors or TKs, thus fusion proteins can still retain the activities of transcription factors or TKs Several studies have shown that DSBs preferentially occur in euchromatin, consistent with a greater chance for translocation to occur in the sites with transcription activity 1446 Following exposure to ionizing radiation, DSBs occur more often in euchromatin than heterochromatin, suggesting the highly compacted chromatin can prevent from radiation damage.
From another point, euchromatin is relatively loose and has a lack of protective mechanism, so it is easily attacked by radiation 48 In addition, the mechanisms of DSB repair in euchromatin are also different from heterochromatin.
Oncogenic chromosomal translocations and human cancer (Review)
Since the time for DSB repair in heterochromatin is longer than euchromatin 5051by extrapolation, the higher frequency of chromosomal translocations in euchromatin than in heterochromatin is reasonable. Oncogenic fusion protein as transcription factor The products of several oncogenic fusion genes function as transcription factors.
In this group, each fusion protein consists of N-terminal partner fused to the DNA binding domain at the C-terminus Fig. The functions of fusion proteins as transcription factors and associated malignant tumors. Fusion proteins consist of two parts from different genes. The functions of these fusion proteins are different from their parental proteins. In the C-terminus, these oncogenic fusion proteins retain the DNA binding domains. The functions of the fusion proteins as oncogenic transcription factors are various.
In most cases, ETS retains DNA-binding domain, which can stimulate the transcription of target genes for cell growth, invasion and metastasis and promote prostate cancer progression 26 ,