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Chromosomal translocation

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Chromosomal reciprocal translocation of the 4th and 20th chromosome.

In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal, and Robertsonian translocation. Reciprocal translocation is a chromosome abnormality caused by exchange of parts between non-homologous chromosomes. Two detached fragments of two different chromosomes are switched. Robertsonian translocation occurs when two non-homologous chromosomes get attached, meaning that given two healthy pairs of chromosomes, one of each pair "sticks" and blends together homogeneously.[1]

A gene fusion may be created when the translocation joins two otherwise-separated genes. It is detected on cytogenetics or a karyotype of affected cells. Translocations can be balanced (in an even exchange of material with no genetic information extra or missing, and ideally full functionality) or unbalanced (where the exchange of chromosome material is unequal resulting in extra or missing genes).[1][2]

Reciprocal translocations

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Reciprocal translocations are usually an exchange of material between non-homologous chromosomes and occur in about 1 in 491 live births.[3] Such translocations are usually harmless, as they do not result in a gain or loss of genetic material, though they may be detected in prenatal diagnosis. However, carriers of balanced reciprocal translocations may create gametes with unbalanced chromosome translocations during meiotic chromosomal segregation. This can lead to infertility, miscarriages or children with abnormalities. Genetic counseling and genetic testing are often offered to families that may carry a translocation. Most balanced translocation carriers are healthy and do not have any symptoms.

It is important to distinguish between chromosomal translocations that occur in germ cells, due to errors in meiosis (i.e. during gametogenesis), and those that occur in somatic cells, due to errors in mitosis. The former results in a chromosomal abnormality featured in all cells of the offspring, as in translocation carriers. Somatic translocations, on the other hand, result in abnormalities featured only in the affected cell and its progenitors, as in chronic myelogenous leukemia with the Philadelphia chromosome translocation.

Nonreciprocal translocation

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Nonreciprocal translocation involves the one-way transfer of genes from one chromosome to another nonhomologous chromosome.[4]

Robertsonian translocations

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Main article: Robertsonian translocation

Robertsonian translocation is a type of translocation caused by breaks at or near the centromeres of two acrocentric chromosomes. The reciprocal exchange of parts gives rise to one large metacentric chromosome and one extremely small chromosome that may be lost from the organism with little effect because it contains few genes. The resulting karyotype in humans leaves only 45 chromosomes, since two chromosomes have fused together.[5] This has no direct effect on the phenotype, since the only genes on the short arms of acrocentrics are common to all of them and are present in variable copy number (nucleolar organiser genes).

Robertsonian translocations have been seen involving all combinations of acrocentric chromosomes. The most common translocation in humans involves chromosomes 13 and 14 and is seen in about 0.97 / 1000 newborns.[6] Carriers of Robertsonian translocations are not associated with any phenotypic abnormalities, but there is a risk of unbalanced gametes that lead to miscarriages or abnormal offspring. For example, carriers of Robertsonian translocations involving chromosome 21 have a higher risk of having a child with Down syndrome. This is known as a 'translocation Downs'. This is due to a mis-segregation (nondisjunction) during gametogenesis. The mother has a higher (10%) risk of transmission than the father (1%). Robertsonian translocations involving chromosome 14 also carry a slight risk of uniparental disomy 14 due to trisomy rescue.

Role in disease

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Some human diseases caused by translocations are:

Chromosomal translocations between the sex chromosomes can also result in a number of genetic conditions, such as

By chromosome

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Overview of some chromosomal translocations involved in different cancers, as well as implicated in some other conditions, e.g. schizophrenia,[8] with chromosomes arranged in standard karyogram order. Abbreviations:
ALL – Acute lymphoblastic leukemia
AML – Acute myeloid leukemia
CML – Chronic myelogenous leukemia
DFSP – Dermatofibrosarcoma protuberans
Human karyotype with annotated bands and sub-bands as used for the nomenclature of chromosomal abnormalities. It shows dark and white regions as seen on G banding. Each row is vertically aligned at centromere level. It shows 22 homologous autosomal chromosome pairs as well as both the female (XX) and male (XY) versions of the two sex chromosomes.
Further information: Karyotype

Denotation

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The International System for Human Cytogenetic Nomenclature (ISCN) is used to denote a translocation between chromosomes.[9] The designation t(A;B)(p1;q2) is used to denote a translocation between chromosome A and chromosome B. The information in the second set of parentheses, when given, gives the precise location within the chromosome for chromosomes A and B respectively—with p indicating the short arm of the chromosome, q indicating the long arm, and the numbers after p or q refers to regions, bands and sub-bands seen when staining the chromosome with a staining dye.[10] See also the definition of a genetic locus.

The translocation is the mechanism that can cause a gene to move from one linkage group to another.

Examples of translocations on human chromosomes

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For an explanation of the symbols and abbreviations used in these examples, see Cytogenetic notation.
Translocation Associated diseases Fused genes/proteins
First Second
t(8;14)(q24;q32) Burkitt's lymphoma

– occurs in ~70% of cases, places MYC under IGH enhancer control [11]

c-myc on chromosome 8,
gives the fusion protein lymphocyte-proliferative ability		 IGH@ (immunoglobulin heavy locus) on chromosome 14,
induces massive transcription of fusion protein
t(11;14)(q13;q32) Mantle cell lymphoma[12] – present in most cases [13] cyclin D1[12] on chromosome 11,
gives fusion protein cell-proliferative ability		 IGH@[12] (immunoglobulin heavy locus) on chromosome 14,
induces massive transcription of fusion protein
t(14;18)(q32;q21) Follicular lymphoma (~90% of cases)[14] IGH@[12] (immunoglobulin heavy locus) on chromosome 14,
induces massive transcription of fusion protein		 Bcl-2 on chromosome 18,
gives fusion protein anti-apoptotic abilities
t(10;(various))(q11;(various)) Papillary thyroid cancer[15] RET proto-oncogene[15] on chromosome 10 PTC (Papillary Thyroid Cancer) – Placeholder for any of several other genes/proteins[15]
t(2;3)(q13;p25) Follicular thyroid cancer[15] PAX8 – paired box gene 8[15] on chromosome 2 PPARγ1[15] (peroxisome proliferator-activated receptor γ 1) on chromosome 3
t(8;21)(q22;q22)[14] Acute myeloblastic leukemia with maturation ETO on chromosome 8 AML1 on chromosome 21
found in ~7% of new cases of AML, carries a favorable prognosis and predicts good response to cytosine arabinoside therapy[14]
t(9;22)(q34;q11) Philadelphia chromosome Chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) Abl1 gene on chromosome 9[16] BCR ("breakpoint cluster region" on chromosome 22[16]
t(15;17)(q22;q21)[14] Acute promyelocytic leukemia PML protein on chromosome 15 RAR-α on chromosome 17
persistent laboratory detection of the PML-RARA transcript is strong predictor of relapse[14]
t(12;15)(p13;q25) Acute myeloid leukemia, congenital fibrosarcoma, secretory breast carcinoma, mammary analogue secretory carcinoma of salivary glands, cellular variant of mesoblastic nephroma TEL on chromosome 12 TrkC receptor on chromosome 15
t(9;12)(p24;p13) CML, ALL JAK on chromosome 9 TEL on chromosome 12
t(12;16)(q13;p11) Myxoid liposarcoma DDIT3 (formerly CHOP) on chromosome 12 FUS gene on chromosome 16
t(12;21)(p12;q22) ALL TEL on chromosome 12 AML1 on chromosome 21
t(11;18)(q21;q21) MALT lymphoma[17] BIRC3 (API-2) MLT[17]
t(1;11)(q42.1;q14.3) Schizophrenia[8] (familial translocation disrupting DISC1) [18] DISC1 (1q42) [18] DISC1FP1 (11q14)[18]
t(2;5)(p23;q35) Anaplastic large cell lymphoma ALK NPM1
t(11;22)(q24;q11.2-12) Ewing's sarcoma FLI1 EWS
t(17;22) DFSP COL1A1/Collagen I on chromosome 17 Platelet derived growth factor B on chromosome 22
t(1;12)(q21;p13) Acute myelogenous leukemia (rare subtype)[19] ETV6 (TEL, 12p13)[19] ARNT (1q21)[19]
t(X;18)(p11.2;q11.2) Synovial sarcoma - 90% of cases[20] SS18 (18q11)[20] SSX1/SSX2 (Xp11)[20]
t(1;19)(q10;p10) Oligodendroglioma and oligoastrocytoma Associated with the 1p/19q co-deletion in oligodendroglioma and oligoastrocytoma, rather than a specific gene fusion[21][22]
t(17;19)(q22;p13) Acute Lymphoblastic Leukemia very rare subtype, <1% of Acute Lymphoblastic Leukemia. (associated with poor prognosis)[23] TCF3 (E2A, 19p13)[23] HLF (17q22)[23]
t(7,16) (q32-34;p11) or t(11,16) (p11;p11) Low-grade fibromyxoid sarcoma – most cases [24] FUS (16p11) [24] CREB3L1 (11p11)[24]

History

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Chromosomal translocations – in which a segment of one chromosome breaks off and attaches to another – were first observed in the early 20th century. In 1916, American zoologist William R. B. Robertson documented a chromosomal fusion in grasshoppers (now known as a Robertsonian translocation).[citation needed] In 1938, Karl Sax demonstrated that X-ray irradiation could induce chromosomal translocations, observing radiation-induced fusions between different chromosomes in plant cells [25]. During the 1940s, Barbara McClintock’s maize cytogenetics experiments revealed the breakage–fusion–bridge cycle of chromosomes, further illuminating mechanisms of chromosomal rearrangement[26] . A major breakthrough came in 1960 with the discovery of the Philadelphia chromosome in chronic myelogenous leukemia – the first consistent chromosomal abnormality linked to a human cancer.[citation needed] In 1973, Janet Rowley identified the Philadelphia chromosome as a translocation between chromosomes 9 and 22, definitively linking a specific chromosomal translocation to leukemia [27]

In subsequent decades, technological advances greatly enhanced the detection and understanding of translocations. The introduction of chromosome banding techniques in the 1970s (e.g. Q-banding and G-banding) allowed more precise identification of individual chromosomes and their abnormalities in karyotypes [28]. The development of fluorescence in situ hybridization (FISH) in the early 1980s enabled researchers to label specific DNA sequences with fluorescent probes on chromosomes, dramatically improving the mapping of translocation breakpoints [28]. In the 21st century, high-throughput DNA sequencing (such as whole-genome sequencing) has made it possible to detect translocations at single-nucleotide resolution, leading to the discovery of numerous previously undetected translocations across different cancers and genetic disorders[26] .

DNA double-strand break repair

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The initiating event in the formation of a translocation is generally a double-strand break in chromosomal DNA.[29] A type of DNA repair that has a major role in generating chromosomal translocations is the non-homologous end joining pathway.[29][30] When this pathway functions appropriately it restores a DNA double-strand break by reconnecting the originally broken ends, but when it acts inappropriately it may join ends incorrectly resulting in genomic rearrangements including translocations. In order for the illegitimate joining of broken ends to occur, the exchange partners DNAs need to be physically close to each other in the 3D genome.[31]

See also

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References

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  1. ^ a b "EuroGentest: Chromosome Translocations". www.eurogentest.org. Archived from the original on January 24, 2018. Retrieved March 29, 2019.
  2. ^ "Can changes in the structure of chromosomes affect health and development?". Genetics Home Reference. National Library of Medicine. Retrieved July 15, 2020.
  3. ^ Milunsky, Aubrey; Milunsky, Jeff M. (2015). Genetic Disorders and the Fetus: Diagnosis, Prevention, and Treatment (7th ed.). Hoboken: John Wiley & Sons. p. 179. ISBN 978-1-118-98152-8. Retrieved July 15, 2020.
  4. ^ "Translocation". Carmel Clay Schools. Archived from the original on December 1, 2017. Retrieved March 2, 2009.
  5. ^ Hartwell, Leland H. (2011). Genetics: From Genes to Genomes. New York: McGraw-Hill. p. 443. ISBN 978-0-07-352526-6.
  6. ^ E. Anton; J. Blanco; J. Egozcue; F. Vidal (April 29, 2004). "Sperm FISH studies in seven male carriers of Robertsonian translocation t(13;14)(q10;q10)". Human Reproduction. 19 (6): 1345–1351. doi:10.1093/humrep/deh232. ISSN 1460-2350. PMID 15117905.
  7. ^ "Causes". nhs.uk. Archived from the original on June 4, 2017. Retrieved September 16, 2023.
  8. ^ a b Semple CA, Devon RS, Le Hellard S, Porteous DJ (April 2001). "Identification of genes from a schizophrenia-linked translocation breakpoint region". Genomics. 73 (1): 123–6. doi:10.1006/geno.2001.6516. PMID 11352574.
  9. ^ Schaffer, Lisa. (2005) International System for Human Cytogenetic Nomenclature S. Karger AG ISBN 978-3-8055-8019-9
  10. ^ "Characteristics of chromosome groups: Karyotyping". rerf.jp. Radiation Effects Research Foundation. Retrieved June 30, 2014.
  11. ^ Zheng, Jie (November 1, 2013). "Oncogenic chromosomal translocations and human cancer (Review)". Oncology Reports. 30 (5): 2011–2019. doi:10.3892/or.2013.2677. ISSN 1021-335X. PMID 23970180.
  12. ^ a b c d Li JY, Gaillard F, Moreau A, et al. (May 1999). "Detection of translocation t(11;14)(q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization". Am. J. Pathol. 154 (5): 1449–52. doi:10.1016/S0002-9440(10)65399-0. PMC 1866594. PMID 10329598.
  13. ^ Zheng, Jie (November 1, 2013). "Oncogenic chromosomal translocations and human cancer (Review)". Oncology Reports. 30 (5): 2011–2019. doi:10.3892/or.2013.2677. ISSN 1021-335X. PMID 23970180.
  14. ^ a b c d e Burtis, Carl A.; Ashwood, Edward R.; Bruns, David E. (December 16, 2011). "44. Hematopoeitic malignancies". Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Elsevier Health Sciences. pp. 1371–1396. ISBN 978-1-4557-5942-2. Retrieved November 5, 2012.
  15. ^ a b c d e f Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Mitchell, Richard Sheppard (2007). "Chapter 20: The Endocrine System". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 978-1-4160-2973-1.
  16. ^ a b Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M (May 2003). "Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics". Ann. Intern. Med. 138 (10): 819–30. doi:10.7326/0003-4819-138-10-200305200-00010. PMID 12755554. S2CID 25865321.
  17. ^ a b Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Mitchell, Richard Sheppard (2007). Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. p. 626. ISBN 978-1-4160-2973-1.
  18. ^ a b c Eykelenboom, Jennifer E; Briggs, Gareth J; Bradshaw, Nicholas J; Soares, Dinesh C; Ogawa, Fumiaki; Christie, Sheila; Malavasi, Elise LV; Makedonopoulou, Paraskevi; Mackie, Shaun; Malloy, Mary P; Wear, Martin A; Blackburn, Elizabeth A; Bramham, Janice; McIntosh, Andrew M; Blackwood, Douglas H (April 30, 2012). "A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins". Human Molecular Genetics. 21 (15): 3374–3386. doi:10.1093/hmg/dds169. PMC 3392113. PMID 22547224.
  19. ^ a b c "t(1;12)(q21;p13) ETV6/ARNT". atlasgeneticsoncology.org. Retrieved March 12, 2025.
  20. ^ a b c Przybyl, Joanna; Sciot, Raf; Rutkowski, Piotr; Siedlecki, Janusz A.; Vanspauwen, Vanessa; Samson, Ignace; Debiec-Rychter, Maria (December 1, 2012). "Recurrent and novel SS18-SSX fusion transcripts in synovial sarcoma: description of three new cases". Tumor Biology. 33 (6): 2245–2253. doi:10.1007/s13277-012-0486-0. ISSN 1423-0380. PMC 3501176. PMID 22976541.
  21. ^ Eckel-Passow, Jeanette E.; Lachance, Daniel H.; Molinaro, Annette M.; Walsh, Kyle M.; Decker, Paul A.; Sicotte, Hugues; Pekmezci, Melike; Rice, Terri; Kosel, Matt L.; Smirnov, Ivan V.; Sarkar, Gobinda; Caron, Alissa A.; Kollmeyer, Thomas M.; Praska, Corinne E.; Chada, Anisha R. (June 25, 2015). "Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors". The New England Journal of Medicine. 372 (26): 2499–2508. doi:10.1056/NEJMoa1407279. ISSN 1533-4406. PMC 4489704. PMID 26061753.
  22. ^ Cairncross, Gregory; Jenkins, Robert (November–December 2008). "Gliomas With 1p/19q Codeletion:a.k.a. Oligodendroglioma". The Cancer Journal. 14 (6): 352–357. doi:10.1097/PPO.0b013e31818d8178. ISSN 1540-336X. PMID 19060598.
  23. ^ a b c Wu, Shuiyan; Lu, Jun; Su, Dongni; Yang, Fan; Zhang, Yongping; Hu, Shaoyan (March 2021). "The advantage of chimeric antigen receptor T cell therapy in pediatric acute lymphoblastic leukemia with E2A-HLF fusion gene positivity: a case series". Translational Pediatrics. 10 (3): 686–691. doi:10.21037/tp-20-323. ISSN 2224-4344. PMC 8041607. PMID 33880339.
  24. ^ a b c Mohamed, Mustafa; Fisher, Cyril; Thway, Khin (June 2017). "Low-grade fibromyxoid sarcoma: Clinical, morphologic and genetic features". Annals of Diagnostic Pathology. 28: 60–67. doi:10.1016/j.anndiagpath.2017.04.001. ISSN 1532-8198. PMID 28648941.
  25. ^ HROMAS, ROBERT; WILLIAMSON, ELIZABETH; LEE, SUK-HEE; NICKOLOFF, JAC (2016). "Preventing the Chromosomal Translocations That Cause Cancer". Transactions of the American Clinical and Climatological Association. 127: 176–195. PMC 5216476. PMID 28066052.
  26. ^ a b Oviedo de Valeria, Jenny (August 2, 1994). "Problemas multiplicativos tip transformacion lineal: tareas de compra y venta". Educación matemática. 6 (2): 73–86. doi:10.24844/em0602.06. ISSN 2448-8089.
  27. ^ Rowley, Janet D. (June 1973). "A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining". Nature. 243 (5405): 290–293. Bibcode:1973Natur.243..290R. doi:10.1038/243290a0. ISSN 1476-4687.
  28. ^ a b Case, Sean (July 27, 2020). "History and Evolution of Cytogenetics". Behind the Bench. Retrieved March 13, 2025.
  29. ^ a b Agarwal, S.; Tafel, A. A.; Kanaar, R. (2006). "DNA double-strand break repair and chromosome translocations". DNA Repair. 5 (9–10): 1075–1081. doi:10.1016/j.dnarep.2006.05.029. PMID 16798112.
  30. ^ Bohlander, S. K.; Kakadia, P. M. (2015). "DNA Repair and Chromosomal Translocations". Chromosomal Instability in Cancer Cells. Recent Results in Cancer Research. Vol. 200. pp. 1–37. doi:10.1007/978-3-319-20291-4_1. ISBN 978-3-319-20290-7. PMID 26376870. {{cite book}}: |journal= ignored (help)
  31. ^ Rocha, P. P.; Chaumeil, J.; Skok, J. A. (2013). "Molecular biology. Finding the right partner in a 3D genome". Science. 342 (6164): 1333–1334. doi:10.1126/science.1246106. PMC 3961821. PMID 24337287.
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