# Chromosomal translocation

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.
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).

## Reciprocal translocations

Reciprocal translocations are usually an exchange of material between non-homologous chromosomes and occur in about 1 in 491 live births. 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

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

## Robertsonian translocations

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. 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. 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

Some human diseases caused by translocations are:
* Cancer: Several forms of cancer are caused by acquired translocations (as opposed to those present from conception); this has been described mainly in leukemia (acute myelogenous leukemia and chronic myelogenous leukemia). Translocations have also been described in solid malignancies such as Ewing's sarcoma.
* Infertility: One of the would-be parents carries a balanced translocation, where the parent is asymptomatic but conceived fetuses are not viable.
* Down syndrome is caused in a minority (5% or less) of cases by a Robertsonian translocation of the chromosome 21 long arm onto the long arm of chromosome 14.
Chromosomal translocations between the sex chromosomes can also result in a number of genetic conditions, such as
* XX male syndrome: caused by a translocation of the SRY gene from the Y to the X chromosome

## By chromosome
### Denotation

The International System for Human Cytogenetic Nomenclature (ISCN) is used to denote a translocation between chromosomes. 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. 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

| Translocation | Associated diseases | Fused genes/proteins | Fused genes/proteins |
| Translocation | Associated diseases | First | Second |
| t(8;14)(q24;q32) | Burkitt's lymphoma – occurs in ~70% of cases, places MYC under IGH enhancer control | 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 – present in most cases | cyclin D1 on chromosome 11, gives fusion protein cell-proliferative ability | IGH@ (immunoglobulin heavy locus) on chromosome 14, induces massive transcription of fusion protein |
| t(14;18)(q32;q21) | Follicular lymphoma (~90% of cases) | IGH@ (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 | RET proto-oncogene on chromosome 10 | PTC (Papillary Thyroid Cancer) – Placeholder for any of several other genes/proteins |
| t(2;3)(q13;p25) | Follicular thyroid cancer | PAX8 – paired box gene 8 on chromosome 2 | PPARγ1 (peroxisome proliferator-activated receptor γ 1) on chromosome 3 |
| t(8;21)(q22;q22) | 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 |
| t(9;22)(q34;q11) Philadelphia chromosome | Chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) | Abl1 gene on chromosome 9 | BCR ("breakpoint cluster region" on chromosome 22 |
| t(15;17)(q22;q21) | 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 |
| 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 | BIRC3 (API-2) | MLT |
| t(1;11)(q42.1;q14.3) | Schizophrenia (familial translocation disrupting DISC1) | DISC1 (1q42) | DISC1FP1 (11q14) |
| 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) | ETV6 (TEL, 12p13) | ARNT (1q21) |
| t(X;18)(p11.2;q11.2) | Synovial sarcoma - 90% of cases | SS18 (18q11) | SSX1/SSX2 (Xp11) |
| 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 | Associated with the 1p/19q co-deletion in oligodendroglioma and oligoastrocytoma, rather than a specific gene fusion |
| t(17;19)(q22;p13) | Acute Lymphoblastic Leukemia very rare subtype, <1% of Acute Lymphoblastic Leukemia. (associated with poor prognosis) | TCF3 (E2A, 19p13) | HLF (17q22) |
| t(7,16) (q32-34;p11) or t(11,16) (p11;p11) | Low-grade fibromyxoid sarcoma – most cases | FUS (16p11) | CREB3L1 (11p11) |

## History

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). In 1938, Karl Sax demonstrated that X-ray irradiation could induce chromosomal translocations, observing radiation-induced fusions between different chromosomes in plant cells. During the 1940s, Barbara McClintock’s maize cytogenetics experiments revealed the breakage–fusion–bridge cycle of chromosomes, further illuminating mechanisms of chromosomal rearrangement. 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. In 1973, Janet Rowley identified the Philadelphia chromosome as a translocation between chromosomes 9 and 22, definitively linking a specific chromosomal translocation to leukemia
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. 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. 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.

## DNA double-strand break repair

The initiating event in the formation of a translocation is generally a double-strand break in chromosomal DNA. A type of DNA repair that has a major role in generating chromosomal translocations is the non-homologous end joining pathway. 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.