Rearrangement

In a molecular pathology report, the word rearrangement refers to a change in the DNA structure within a cell. DNA is usually organized into long strands called chromosomes, each containing many genes. A rearrangement happens when a piece of a chromosome breaks off and attaches somewhere else, either on the same chromosome or another chromosome. This change can affect how genes work and sometimes contribute to cancer development.

Why do rearrangements happen?

Rearrangements can occur for many reasons. Some happen by chance when a cell makes a mistake while copying its DNA. Environmental factors, such as exposure to radiation or harmful chemicals, cause others. Sometimes, people may inherit genetic tendencies that make their cells more prone to rearrangements. However, most rearrangements that occur in cancer are not inherited but develop over time in specific cells, known as somatic rearrangements.

What happens to a cell after a rearrangement takes place?

When a rearrangement occurs, it can alter how specific genes function. Sometimes, this causes a gene to become more active than it should be, while other times, it can silence a gene needed to control the cell. If the rearrangement involves a gene that controls cell growth, the affected cell may divide uncontrollably, eventually leading to a tumour. However, not all rearrangements cause harm; some do not affect the cell.

How do rearrangements cause cancer?

Rearrangements can bring together two different genes, creating a fusion gene. The fusion gene can produce an abnormal protein that promotes uncontrolled cell growth. In other cases, rearrangements might disrupt tumour-suppressing genes that normally keep cell division in check. Without these controls, the cell can multiply unchecked, forming a tumour.

Do rearrangements always cause cancer?

Not all rearrangements lead to cancer. Many occur without any impact on how cells function. These are sometimes referred to as passenger rearrangements because they are present but do not affect tumour growth. A rearrangement can contribute to cancer only when it involves specific genes that control how cells grow and divide. Even then, the rearrangement needs to affect the cell in a way that helps it grow out of control.

How do pathologists test for rearrangements?

Pathologists use several techniques to detect rearrangements in tumour cells:

• Fluorescence in situ hybridization (FISH): This test uses fluorescent probes to detect specific DNA changes. It helps identify larger rearrangements or fusion events involving known genes.
• Polymerase Chain Reaction (PCR): PCR amplifies small segments of DNA to detect specific known rearrangements, such as those involving fusion genes.
• Next-Generation Sequencing (NGS): NGS allows pathologists to sequence large DNA regions to find a wide range of rearrangements, including ones that are hard to detect with other methods.
• Karyotyping: This test examines the structure of chromosomes under a microscope to identify large-scale rearrangements. It is often used to study blood cancers, such as leukemia.

Results from these tests will indicate whether any rearrangements were found and whether they are likely to affect treatment.

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

Test: Fluorescence In Situ Hybridization (FISH)
Result: Positive for ALK-EML4 fusion

Interpretation: The presence of an ALK-EML4 fusion was detected in tumour cells. This rearrangement is commonly seen in non-small cell lung cancer (NSCLC) and suggests that the tumour may respond well to ALK inhibitors, such as crizotinib or alectinib.

In this example, the report confirms that the patient’s cancer cells contain the ALK-EML4 fusion, meaning part of the ALK gene on chromosome 2 has fused with the EML4 gene. This fusion creates an abnormal protein that drives cancer growth. A positive result suggests that targeted therapies—drugs specifically designed to block the abnormal ALK protein—are likely to be effective in treating the tumour.

What are the most common gene rearrangements and their associated cancers?

Below is a list of common gene rearrangements and the cancers in which they are frequently found:

• BCR-ABL1: Chronic myeloid leukaemia and acute lymphoblastic leukaemia
• ETV6-RUNX1: Acute lymphoblastic leukaemia
• PML-RARA: Acute promyelocytic leukaemia
• ALK-EML4: Non-small cell lung cancer
• TMPRSS2-ERG: Prostate cancer
• EWSR1-FLI1: Ewing sarcoma
• CCND1-IGH: Mantle cell lymphoma
• BCL2-IGH: Follicular lymphoma
• BCL6-IGH: Diffuse large B-cell lymphoma
• NPM1-ALK: Anaplastic large cell lymphoma
• MYC-IGH: Burkitt lymphoma
• SS18-SSX1: Synovial sarcoma
• RET-PTC: Thyroid cancer
• ROS1-CD74: Non-small cell lung cancer
• CBFB-MYH11: Acute myeloid leukaemia
• RUNX1-RUNX1T1: Acute myeloid leukaemia
• MLL-AF9: Acute myeloid leukaemia
• EWSR1-ATF1: Clear cell sarcoma
• TFE3-ASPSCR1: Alveolar soft part sarcoma
• FGFR3-TACC3: Bladder cancer
• NTRK1-TPM3: Thyroid cancer
• NTRK3-ETV6: Secretory breast carcinoma
• KMT2A-ELL: Acute myeloid leukaemia
• FGFR1-ZMYM2: Myeloid/lymphoid neoplasms
• PDGFRA-FIP1L1: Gastrointestinal stromal tumour (GIST)
• TBL1XR1-PLAG1: Salivary gland carcinoma
• PRKAR1A-RET: Thyroid cancer
• BRAF-KIAA1549: Pilocytic astrocytoma
• EWSR1-WT1: Desmoplastic small round cell tumour
• FOXO1-PAX3: Alveolar rhabdomyosarcoma
• FGFR2-BICC1: Cholangiocarcinoma
• CDK4-MDM2: Liposarcoma
• NUP98-HOXA9: Acute myeloid leukaemia
• ETV1-ELK4: Prostate cancer
• TCF3-HLF: Acute lymphoblastic leukaemia
• ZRSR2-MLL: Acute myeloid leukaemia
• PAX8-PPARγ: Thyroid cancer
• BCOR-CCNB3: Sarcoma
• CIC-DUX4: Ewing-like sarcoma
• ERBB2-MLL: Breast cancer

Each rearrangement 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.