Translocation


A translocation is a specific type of genetic change where a piece of one chromosome breaks off and attaches to another chromosome. Chromosomes are structures inside your cells that carry DNA, which contains the instructions your body needs to grow and function. When pieces of chromosomes switch places, they create new combinations of genetic material. Pathologists sometimes detect these changes when diagnosing cancers or other medical conditions.

Why do translocations occur?

Translocations happen when the DNA inside a cell breaks and then repairs itself incorrectly, causing pieces from two different chromosomes to join together. This can happen randomly or be triggered by factors like exposure to certain chemicals, radiation, or sometimes due to errors during cell division. Most translocations are random events that occur over time and are not inherited from parents.

What happens to a cell after a translocation takes place?

Once a translocation occurs, the genetic instructions inside the cell can change. The new combination of DNA may affect how specific genes are expressed, meaning the cell may behave differently. This can sometimes disrupt the cell’s normal function, causing it to grow or divide uncontrollably. Other times, a translocation may have no effect at all, depending on which genes are involved.

How do translocations cause cancer?

Translocations affecting genes that control cell growth or repair can cause cells to become cancerous. For example, a translocation might activate an oncogene (a gene that promotes cell growth) or disable a tumor suppressor gene (a gene that helps prevent uncontrolled growth). This can lead to cancers like leukemia, lymphoma, or carcinoma.

Do translocations always cause cancer?

No, not all translocations lead to cancer. Some translocations may not change the function of the affected genes, and the cell may continue to function normally. These are called benign or silent translocations. Other translocations may change the behavior of a gene, but not enough to cause disease. Pathologists look for specific translocations that drive cancer development to help guide diagnosis and treatment.

How do pathologists test for translocations?

Pathologists use specialized tests to detect translocations, including:

  1. Fluorescence In Situ Hybridization (FISH): FISH uses fluorescent dyes that bind to specific parts of the chromosomes to detect rearrangements.
  2. Polymerase Chain Reaction (PCR): PCR amplifies specific DNA sequences to check for known translocations.
  3. Karyotyping: This technique involves looking at the complete set of a person’s chromosomes under a microscope to identify any abnormal changes.
  4. Next-Generation Sequencing (NGS): This advanced test can identify translocations across the entire genome, even when they are too small to be seen by other methods.

Here is an example of a translocation result in a molecular report:

Test: Fluorescence In Situ Hybridization (FISH)
Result: Positive for PML::RARA fusion

Interpretation: A fusion was detected between the PML gene on chromosome 15 and the RARA gene on chromosome 17. This fusion causes the production of an abnormal protein that blocks normal blood cell development and promotes the growth of leukemia cells. The PML::RARA fusion is characteristic of acute promyelocytic leukemia (APL). Identifying this fusion confirms the diagnosis of APL. It indicates that the patient is likely to respond well to targeted treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

In this example, the report identifies the PML::RARA fusion, a translocation commonly associated with acute promyelocytic leukemia (APL). This fusion interferes with blood cell maturation and promotes the uncontrolled growth of leukemia cells. Detecting the PML::RARA fusion guides doctors in selecting highly effective treatments, such as ATRA and ATO, which specifically target the abnormal protein produced by this translocation.

What are the most common gene translocations?

The following is a list of common translocations and the cancers associated with them:

  • BCR::ABL1: Chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL)
  • EWSR1::FLI1: Ewing sarcoma
  • TMPRSS2::ERG: Prostate cancer
  • ALK::EML4: Non-small cell lung cancer (NSCLC)
  • PAX3::FOXO1: Alveolar rhabdomyosarcoma
  • NTRK1::TPM3: Thyroid cancer, soft tissue sarcoma
  • SYT::SSX: Synovial sarcoma
  • RET::CCDC6: Papillary thyroid carcinoma
  • ETV6::NTRK3: Congenital fibrosarcoma, secretory breast carcinoma
  • CBFB::MYH11: Acute myeloid leukemia (AML) with inversion 16
  • PML::RARA: Acute promyelocytic leukemia (APL)
  • RUNX1::RUNX1T1: AML with t(8;21)
  • CCND1::IGH: Mantle cell lymphoma
  • MYC::IGH: Burkitt lymphoma
  • BCL2::IGH: Follicular lymphoma
  • BCL6::IGH: Diffuse large B-cell lymphoma (DLBCL)
  • MLL::AF4: Infant ALL
  • MLL::AF9: AML with t(9;11)
  • MLL::ELL: AML with t(11;19)
  • EWSR1::ATF1: Clear cell sarcoma
  • EWSR1::WT1: Desmoplastic small round cell tumor
  • TCF3::PBX1: ALL with t(1;19)
  • ETV6::RUNX1: Childhood ALL
  • PLAG1::CTNNB1: Pleomorphic adenoma of the salivary gland
  • EWSR1::NR4A3: Myoepithelial carcinoma
  • NTRK3::ETV6: Infantile fibrosarcoma
  • ALK::NPM1: Anaplastic large cell lymphoma (ALCL)
  • SS18::SSX1: Synovial sarcoma
  • PRCC::TFE3: Xp11 translocation renal cell carcinoma
  • FUS::DDIT3: Myxoid liposarcoma
  • BRAF::KIAA1549: Pilocytic astrocytoma
  • FGFR3::TACC3: Glioblastoma, bladder cancer
  • EWSR1::POU5F1: Extraskeletal myxoid chondrosarcoma
  • RARA::STAT5B: Variant APL
  • EWSR1::PATZ1: Primary intracranial sarcoma
  • TFE3::NONO: Xp11 translocation renal cell carcinoma
  • CLTC::ALK: Inflammatory myofibroblastic tumor
  • TFEB::PRCC: Renal cell carcinoma
  • CREB3L1::SS18: Low-grade fibromyxoid sarcoma
  • ZBTB16::RARA: Variant APL

Each translocation plays a significant role in the cancers where they are found. Identifying them confirms the diagnosis and helps doctors choose therapies specifically designed to target these genetic changes.

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