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Diagnosis and tests

Cytogenetics: karyotype and FISH

Changes inside the leukemia cell, in its chromosomes, often shape the type of disease, its course and its treatment more strongly than anything else. This topic explains the two main chromosome tests — the karyotype and FISH: how they are done, what entries such as t(9;22) or del(17p) on your report mean and how the results affect the treatment plan.

Last updated: ~6 min read
Several translucent X-shaped chromosomes floating in soft light on a dark navy background, with faint bands across them and a fine DNA helix behind.
Figure 1.Concept: chromosomes are the tightly packed “volumes” of DNA.

01Short answer

Cytogenetics is the study of a cell’s chromosomes. A human cell normally has 23 pairs, or 46 chromosomes. In leukemia cells, pieces of chromosomes can swap places (translocation), flip around (inversion), be lost (deletion) or be present in extra copies. In a karyotype test, bone marrow or blood cells are grown in the laboratory, their chromosomes are stained at the moment of division and the whole set is examined under the microscope; this can take about a week or longer. FISH looks for a specific change using fluorescent probes that attach to a particular gene or part of a chromosome; it can find small changes that a karyotype misses and often gives results sooner. These tests reveal important changes such as the Philadelphia chromosome in CML, t(15;17) in APL, the risk group in AML, the subtypes of ALL and del(17p) in CLL. The changes in leukemia cells are usually not inherited. Your hematologist will explain what the results mean for you.

02Simple explanation

Chromosomes are the tightly packed “volumes” of DNA — like books in which the genes are written. Each cell has 46 chromosomes, or 23 pairs: one of each pair comes from the mother and one from the father.

In a leukemia cell, the pages of these “books” can get mixed up: two chromosomes swap pieces, a piece is lost or an extra copy appears. Such changes can make the cell grow out of control.

A karyotype is a photograph of the whole library: the laboratory grows the cells, stains the chromosomes, arranges them by size and looks at them all at once. This can reveal unexpected changes too, but it takes time.

FISH is more like a torch searching for a particular page: bright coloured probes attach only to a specific gene. Because the cells do not need to be grown, the result often comes back sooner.

These changes arise in leukemia cells during life and are usually not passed on to your children. They help the doctor determine the type of leukemia, the risk group and the most suitable treatment.

03Scientific explanation

How is a karyotype done? The NCI describes cytogenetic analysis as checking the chromosomes in a blood or bone marrow sample for changes such as broken, missing, rearranged or extra chromosomes. The ACS notes that the cells must first grow in the laboratory, which can take about a week. Chromosomes become visible at the moment of division (metaphase) after a special banding stain; for a reliable result, usually 20 or more dividing cells are analysed. Small changes may not be visible under the microscope.

The language of the report (ACS): t stands for translocation — for example, t(8;21) means chromosomes 8 and 21 have swapped pieces; inv for inversion, such as inv(16); del for deletion, such as del(7) or del(5q) — loss of part of the long q arm; “+8” means an extra copy of chromosome 8, and “−7” the loss of one chromosome 7. A normal karyotype is written “46,XY” in men and “46,XX” in women. ELN 2022 calls three or more unrelated abnormalities a “complex karyotype”.

FISH: according to the NHGRI, short probes matching the part of DNA being looked for are labelled with a fluorescent dye and bind to the matching place on the chromosome. According to the ACS, FISH can find both translocations visible under the microscope and some small changes that standard cytogenetics misses; it is done on ordinary blood or marrow samples, and results are often available sooner. In CLL, according to the NCI, the standard FISH panel covers del(11q), del(13q), del(17p), trisomy 12 and t(11;14).

Typical findings and what they mean: CML is diagnosed when the Philadelphia chromosome — t(9;22) — or the BCR::ABL1 gene is found (ACS). In APL, t(15;17) creates the PML::RARA fusion gene. Under ELN 2022, t(8;21) and inv(16) in AML fall into the favourable group, while −5/del(5q), −7, 17p abnormalities and a complex karyotype fall into the adverse group. For B-ALL, the ACS lists genetic subtypes such as high hyperdiploidy (more than 50 chromosomes), hypodiploidy (fewer than 44), ETV6::RUNX1, KMT2A rearrangement and BCR::ABL1.

04What happens in the body?

Sample and timing

Cytogenetic tests are usually done on bone marrow aspirate and sometimes on blood. For a karyotype the cells must be alive and divide in the laboratory, so the result often takes not a few days but closer to one or two weeks. FISH can answer urgent questions faster — for example, when APL or a Philadelphia chromosome is suspected.

Translocation: when chromosomes swap pieces

In a translocation, two chromosomes exchange pieces. At the break points, parts of two genes can join to form a new, abnormal “fusion gene”. This is how BCR::ABL1 arises on the Philadelphia chromosome and PML::RARA in APL — and both have dedicated targeted treatments.

Two chromosomes in different colours — blue and orange — on a dark navy background; their end pieces trade places, and a warm light flares where they join.
Figure 2.In a translocation two chromosomes swap pieces, and a new fusion gene can form.

FISH: glowing signals

In FISH, the probe for one gene of interest might glow red and the probe for another green. In a normal cell the signals appear separately; when a fusion gene is present, they sit side by side or merge. A specialist counts hundreds of cells to decide whether the change is present and in what percentage of cells.

A translucent cell nucleus on a dark navy background; inside are several small bright red and green dots, two of which have merged side by side into a yellowish glow.
Figure 3.In FISH, coloured probes attach to the gene of interest and appear as bright dots.

How does the result affect treatment?

Chromosome findings help define the risk group and the intensity of treatment, and sometimes guide the decision about a stem cell transplant. Some changes open the way to targeted drugs. The meaning of each finding depends on the type of leukemia, so discuss your results with your doctor.

05Chromosome tests step by step

Four steps — from the marrow sample to the risk group.

Sample — Bone marrow aspirate or blood.1SampleBone marrow aspirate or blood.
Karyotype — Cells are grown and all chromosomes checked.2KaryotypeCells are grown and all chromosomes checked.
FISH — Probes search for a specific change.3FISHProbes search for a specific change.
Interpretation — Findings are linked to type and risk group.4InterpretationFindings are linked to type and risk group.
Precise typeFor example, CML, APL or an ALL subtype.
Risk groupFavourable, intermediate or adverse.
Targeted treatmentFor example, for BCR::ABL1 and PML::RARA.

06Some important chromosome changes (simplified)

ChangeWhere is it found?What does it mean?
t(9;22) — Philadelphia, BCR::ABL1CML, some ALLDiagnosis of CML; targeted treatment with TKIs
t(15;17) — PML::RARAAPLTreatment with ATRA and arsenic trioxide
t(8;21), inv(16)AMLFavourable group under ELN 2022
−5/del(5q), −7, 17p, complex karyotypeAMLAdverse group under ELN 2022
High hyperdiploidy, ETV6::RUNX1B-ALL (especially in children)Genetic subtype; part of the risk assessment
del(17p), del(11q), del(13q), trisomy 12CLL (FISH)Outlook and choice of treatment

* This table is a simplified summary; the meaning of a finding depends on other genetic results, the type of leukemia and the response to treatment. Discuss your results with your hematologist.

07Key terms

Cytogenetics
The study of chromosomes and their changes.
Karyotype
A cell’s complete set of chromosomes, and the picture of it.
FISH
A test that finds a specific gene or chromosome change using fluorescent probes.
Translocation (t)
An exchange of pieces between two chromosomes.
Inversion (inv)
A piece of a chromosome flipped the other way round.
Deletion (del)
Loss of part of a chromosome.
Trisomy
An extra (third) copy of a chromosome.
Fusion gene
An abnormal gene formed when parts of two genes join.
Complex karyotype
Three or more unrelated chromosome abnormalities.
Germline change
A change present from birth in every cell, which can be inherited.

08Key points

  • A normal cell has 46 chromosomes (23 pairs).
  • In leukemia, chromosomes can swap pieces, lose them or gain copies.
  • A karyotype looks at all chromosomes but takes time.
  • FISH finds a specific change faster and more sensitively.
  • The Philadelphia chromosome is the basis of a CML diagnosis.
  • In AML, chromosome findings define the risk group.
  • Changes in leukemia cells are usually not inherited.
  • The meaning of findings is always interpreted with your doctor.

09Frequently asked questions

My karyotype is “normal”. Is that good?

A normal karyotype means no changes visible at the chromosome level were found. In AML this is often linked with the intermediate risk group, but the final assessment also depends on molecular test results (for example, NPM1 and FLT3).

Why does the result take so long?

For a karyotype, the cells first have to be grown in the laboratory, which can take about a week. FISH answers urgent questions faster. Treatment sometimes starts before all the results are in and is then refined.

Could these changes be passed on to my family?

Chromosome changes found in leukemia cells are usually acquired during life and are not inherited. If an inherited predisposition is suspected, a separate test and genetic counselling may be offered.

What does “complex karyotype” mean?

It means the leukemia cells have three or more unrelated chromosome changes. In AML this is placed in the adverse risk group and is taken into account in the treatment plan — for example, in the decision about a transplant.

Is the test repeated during treatment?

Yes, sometimes. Cytogenetics or FISH may be repeated to check remission; for example, in CML the response to treatment used to be assessed by the percentage of Philadelphia-positive cells in the marrow, whereas today it is mainly tracked by PCR on blood.

How do I make sense of the abbreviations on my report?

The key letters are: t for translocation, inv for inversion, del for deletion, “+” for an extra and “−” for a missing chromosome. But the full meaning of the entry, and what it means for you, is best explained by your hematologist.

10Questions for your doctor

Take these questions to your appointment. The ones you save are collected on the “My questions” page and stay on this device only.

  1. What do my karyotype and FISH results show?

  2. How do the results affect my risk group?

  3. What happens if the karyotype test fails?

  4. When do we expect these results?

My questions

12Sources

  1. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: cytogenetic analysis
  2. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: karyotype
  3. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: FISH
  4. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: translocation
  5. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: Philadelphia chromosome
  6. National Human Genome Research Institute (NHGRI). Talking Glossary of Genomic and Genetic Terms: Karyotype
  7. National Human Genome Research Institute (NHGRI). Fluorescence In Situ Hybridization Fact Sheet
  8. American Cancer Society. Tests for Acute Myeloid Leukemia (AML)
  9. American Cancer Society. Tests for CML
  10. American Cancer Society. Acute Lymphocytic Leukemia Subtypes and Prognostic Factors
  11. National Cancer Institute (NCI). Chronic Lymphocytic Leukemia Treatment (PDQ®) — Health Professional Version
  12. Testing.com. Karyotyping Test: What It Measures and How It Works
  13. Blood (American Society of Hematology), 2022. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN
  14. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: germline mutation
Medical disclaimerThis information is for educational purposes only and does not replace medical advice.
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