Fusion



In a molecular pathology report, the word fusion refers to a specific genetic change in which two different genes that are normally separate join together. This joining creates a new, hybrid gene that produces an abnormal protein. These fusion events happen inside the cancer cells and are not something a person is born with. Because they are only found in cancer cells, identifying a fusion can help doctors diagnose specific types of cancer, guide treatment decisions, and predict how the disease may behave.

Why do gene fusions occur?

Gene fusions usually happen when the DNA inside a cell is damaged. DNA contains the instructions for all of the body’s cells, and when broken, the pieces can be rearranged incorrectly. If two separate genes become fused during this process, the result is a new hybrid gene. DNA damage that leads to gene fusions can happen by chance or be triggered by exposure to environmental factors, such as radiation or chemicals. However, in many cases, the exact cause is unknown.

What happens to a cell after a fusion takes place?

When a fusion occurs, the new hybrid gene instructs the cell to make an abnormal protein. In many cases, these proteins interfere with the cell’s normal processes. They can tell the cell to divide uncontrollably, ignore signals to stop growing or avoid normal cell death. As a result, the cell with the fusion becomes cancerous, and these abnormal cells can multiply and form a tumour.

How do gene fusions cause cancer?

Gene fusions are important drivers of cancer because they can produce proteins that disrupt the normal control mechanisms of the cell. Some fusion proteins act like a gas pedal, telling the cell to keep growing and dividing. Others can disable proteins that usually act as brakes, preventing the cell from stopping or repairing itself. Gene fusions are often found in blood cancers, like leukemia, and solid tumors, such as sarcomas and certain lung cancers. Because these fusions are unique to cancer cells, they can also serve as targets for specific cancer therapies.

How do pathologists test for gene fusions?

Pathologists use several specialized tests to identify gene fusions. These tests look at the genetic material in cancer cells to detect whether two genes have fused.

Here are the most common tests used:

  1. Fluorescence in situ hybridization (FISH): This test uses fluorescent markers to detect gene fusions. The markers will light up in a specific pattern under the microscope if a fusion is present.
  2. Polymerase chain reaction (PCR): This test looks for specific fusion genes by copying segments of DNA or RNA to see if a known fusion is present.
  3. Next-generation sequencing (NGS): This advanced test looks at many genes at once to detect fusions and other mutations. It provides a detailed view of the genetic changes in a cancer cell.
  4. Chromosomal analysis (karyotyping): This older technique examines the structure of chromosomes to identify large rearrangements, including gene fusions.

The results of these tests will be included in the pathology report, either confirming the presence of a fusion or stating that no fusion was found. The report will name the genes involved if a specific fusion is detected.

Here is an example of how a fusion result might appear in a molecular pathology report

Test: Fluorescence In Situ Hybridization (FISH)
Result: Positive for BCR::ABL1 fusion

Interpretation: A fusion was detected between the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. This fusion results in the formation of an abnormal protein that drives uncontrolled cell growth. The BCR::ABL1 fusion is characteristic of chronic myeloid leukemia (CML) and some types of acute lymphoblastic leukemia (ALL). This finding confirms the diagnosis and indicates that the patient may benefit from targeted therapy with a tyrosine kinase inhibitor, such as imatinib or dasatinib.

In this example, the report identifies the BCR::ABL1 fusion commonly associated with chronic myeloid leukemia (CML). This fusion produces a protein that causes cancer cells to grow uncontrollably. Detecting this fusion helps confirm the diagnosis and guides treatment, as tyrosine kinase inhibitors (TKIs) like imatinib or dasatinib are highly effective against cancers with this specific genetic change.

What are the most common gene fusions?

Here is a list of some of the most common gene fusions and the associated cancers:

  • BCR::ABL1 – Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL)
  • ETV6::RUNX1 – Acute lymphoblastic leukemia (ALL)
  • PML::RARA – Acute promyelocytic leukemia (APL)
  • EWSR1::FLI1 – Ewing sarcoma
  • TMPRSS2::ERG – Prostate cancer
  • ALK::EML4 – Non-small cell lung cancer (NSCLC)
  • CBFB::MYH11 – Acute myeloid leukemia (AML)
  • RUNX1::RUNX1T1 – Acute myeloid leukemia (AML)
  • FUS::DDIT3 – Myxoid liposarcoma
  • SS18::SSX1/SSX2 – Synovial sarcoma
  • ETV6::NTRK3 – Infantile fibrosarcoma and secretory breast cancer
  • KMT2A (MLL)::AF4 – Acute lymphoblastic leukemia (ALL)
  • ROS1 fusions – Non-small cell lung cancer (NSCLC)
  • RET::PTC – Thyroid cancer
  • PDGFRB fusions – Chronic myelomonocytic leukemia (CMML)
  • BCOR::CCNB3 – Clear cell sarcoma of the kidney
  • NUP98::NSD1 – Acute myeloid leukemia (AML)
  • EWSR1::ATF1 – Clear cell sarcoma
  • TCF3::PBX1 – Acute lymphoblastic leukemia (ALL)
  • BRAF::KIAA1549 – Pilocytic astrocytoma
  • NTRK1 fusions – Thyroid cancer and pediatric gliomas
  • NTRK2 fusions – Pediatric high-grade gliomas
  • NTRK3 fusions – Secretory breast cancer and congenital mesoblastic nephroma
  • FGFR1::TACC1 – Glioblastoma and other gliomas
  • FGFR2 fusions – Cholangiocarcinoma and endometrial cancer
  • FGFR3::TACC3 – Bladder cancer and lung squamous cell carcinoma
  • ETV6::ABL1 – Acute lymphoblastic leukemia (ALL)
  • ABL1::NUP214 – Acute lymphoblastic leukemia (ALL)
  • PAX3::FOXO1 – Alveolar rhabdomyosarcoma
  • PAX7::FOXO1 – Alveolar rhabdomyosarcoma
  • EWSR1::WT1 – Desmoplastic small round cell tumor
  • TFE3 fusions – Xp11 translocation renal cell carcinoma
  • FUS::ERG – Ewing-like sarcoma
  • CD74::ROS1 – Non-small cell lung cancer (NSCLC)
  • STRN::ALK – Non-small cell lung cancer (NSCLC)
  • KMT2A (MLL)::ELL – Acute myeloid leukemia (AML)
  • NUP98::KDM5A – Acute myeloid leukemia (AML)
  • CREB1::ATF1 – Angiomatoid fibrous histiocytoma
  • PRCC::TFE3 – Renal cell carcinoma
  • EWSR1::POU5F1 – Small round cell sarcoma

Each gene fusion 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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