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PML-RARA Mutation Analysis Test

Last updated May 29, 2017

Approved by: Maulik P. Purohit MD MPH

The PML-RARA Mutation Analysis Test detects the PML-RARA fusion gene. It is used to diagnose acute promyelocytic leukemia.


What are other Names for this Test? (Equivalent Terms)

  • PML/RARA t(15;17) Mutation Analysis Test
  • PML/RARA Translocation Mutation Analysis Test

What is PML-RARA Mutation Analysis Test? (Background Information)

  • PML-RARA mutation refers to a problematic fusion between two genes. It is associated with acute promyelocytic leukemia, the most dangerous type of myeloid leukemia
  • The PML gene gives instructions for a protein that helps prevent a cell from becoming cancerous by controlling its growth and division, while the RARA gene encodes a protein necessary for proper development of a cell
  • Fusion of the PML and RARA genes in white blood cells results in a loss of function of both the PML tumor suppressing protein and the RARA maturation protein. This leads to the development of white blood cell cancer (leukemia)
  • The PML-RARA Mutation Analysis Test detects the PML-RARA fusion gene. It is used to diagnose acute promyelocytic leukemia

The molecular testing, in general, can be performed using a variety of methods. Some of these methods include:

  • In situ hybridization technique, such as fluorescence in situ hybridization (FISH)
  • Immunohistochemistry (IHC)
  • Next-generation sequencing (NGS)
  • Polymerase chain reaction (PCR)
  • Comparative genomic hybridization (CGH)
  • Karyotyping including spectral karyotyping
  • mRNA analysis
  • Tissue microarrays (TMAs)
  • Southern blot test
  • Northern blot test
  • Western blot test
  • Eastern blot test

The methodology used for the test may vary from one laboratory to another. 

Note: Molecular testing has limitations due to the molecular method and genetic mutational abnormalities being tested. This can affect the results on a case-by-case basis. Consultation with your healthcare provider will help in determining the right test and right molecular method, based on individual circumstances.

What are the Clinical Indications for performing the PML-RARA Mutation Analysis Test?

Following are the clinical indications for performing the PML-RARA Mutation Analysis Test: 

  • Bleeding that is hard to stop, even from a small cut
  • Blood in the urine
  • Heavy nosebleeds
  • Bleeding gums and easy bruising
  • Fever and infections
  • Low red blood cell count
  • Paleness
  • Tiring easily
  • Poor appetite
  • Unexplained weight loss

In general, the molecular genetic testing is undertaken in the following situations: 

  • To assist (and in some cases, confirm) the initial diagnosis
  • To distinguish other tumors/conditions that have similar histological features, when examined by a pathologist under the microscope
  • To help in determining treatment options
  • To confirm recurrence of the tumor: Tumor recurrence can either be at the original tumor site, or at a distant location (away from the initial site)

How is the Specimen Collected for PML-RARA Mutation Analysis Test?

Following is the specimen collection process for PML-RARA Mutation Analysis Test

The specimen sample requirements may vary from lab to lab. Hence, it is important to contact the testing lab for exact specimen requirements, before initiating the testing process.

  • Sample on which the test is performed may include:
    • Fresh tumor tissue during biopsy
    • Formalin-fixed paraffin-embedded solid tumor tissue (FFPE tumor tissue), often referred to as paraffin block of the tumor
    • Unstained tissue slides
  • Process of obtaining the sample: As outlined by the laboratory testing facility
  • Preparation required: As outlined by the laboratory testing facility

Note:

  • In some cases, a different source of specimen (such as peripheral blood, bone marrow biopsy specimen, or other body fluids) may be acceptable to the laboratory performing the test
  • Occasionally, additional samples may be required to either repeat the test or to perform follow-up testing
  • Depending on the location of testing, it may take up to 2 weeks’ turnaround time, to obtain the test results
  • Many hospitals preserve the paraffin blocks for at least 7 years. In general, older paraffin blocks (over 5 years) may affect the detection of specific mutations, due to degradation of the tumor specimen over time

Cost of PML-RARA Mutation Analysis Test:

  • The cost of the test procedure depends on a variety of factors, such as the type of your health insurance, annual deductibles, co-pay requirements, out-of-network and in-network of your healthcare providers and healthcare facilities
  • In many cases, an estimate may be provided before the test is conducted. The final amount may depend upon the findings during the test procedure and post-operative care that is necessary (if any)

What is the Significance of the PML-RARA Mutation Analysis Test Result?

  • A fusion between the PML and RARA genes indicates a positive result for the PML-RARA Mutation Analysis Test. This may point to a diagnosis of acute promyelocytic leukemia

The laboratory test results are NOT to be interpreted as results of a "stand-alone" test. The test results have to be interpreted after correlating with suitable clinical findings and additional supplemental tests/information. Your healthcare providers will explain the meaning of your tests results, based on the overall clinical scenario.

Additional and Relevant Useful Information:

  • 99% of individuals with acute promyelocytic leukemia possess the PML-RARA mutation
  • Many laboratories may not have the capability to perform this test. Only highly-specialized labs with advanced facilities and testing procedures may perform this test

Certain medications that you may be currently taking may influence the outcome of the test. Hence, it is important to inform your healthcare provider, the complete list of medications (including any herbal supplements) you are currently taking. This will help the healthcare provider interpret your test results more accurately and avoid unnecessary chances of a misdiagnosis.

What are some Useful Resources for Additional Information?

Please visit our Laboratory Procedures Center for more physician-approved health information:

http://www.dovemed.com/common-procedures/procedures-laboratory/

References and Information Sources used for the Article:

https://ghr.nlm.nih.gov/primer/testing/genetictesting (accessed on 05/10/2017)

https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5806a1.htm (accessed on 05/10/2017)

http://www.nature.com/gim/journal/v10/n5/full/gim200852a.html (accessed on 05/10/2017)

http://pediatrics.aappublications.org/content/106/6/1494 (accessed on 05/10/2017)

Acute Promyelocytic Leukemia (APL) - St. Jude Children’s Research Hospital. (n.d.). Retrieved from https://www.stjude.org/disease/acute-promyelocytic-leukemia.html

PML gene - Genetics Home Reference. (n.d.). Retrieved from https://ghr.nlm.nih.gov/gene/PML

PML/RARA t(15;17) Translocation, FISH and Quantitative Real-Time PCR. (n.d.). Retrieved from http://www.questdiagnostics.com/testcenter/testguide.action?dc=TH_PML_RARA

RARA gene - Genetics Home Reference. (n.d.). Retrieved from https://ghr.nlm.nih.gov/gene/RARA

Helpful Peer-Reviewed Medical Articles:

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Drets, M. E., & Shaw, M. W. Specific banding patterns of human chromosomes. Proceedings of the National Academy of Sciences 68, 2073–2077 (1971)

Druker, B. J. Perspectives on the development of a molecularly targeted agent. Cancer Cell 1, 31–36 (2002)

Parra, I., & Windle, B. High resolution visual mapping of stretched DNA by fluorescent hybridization. Nature Genetics 5, 17–21 (1993) doi:10.1038/ng0993-17

Pinkel, D., et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genetics 20, 207–211 (1998) doi:10.1038/2524

Speicher, M. R., et al. Karyotyping human chromosomes by combinatorial multi-fluor FISH. Nature Genetics 12, 368–375 (1996) doi:10.1038/ng0496-368

Schnittger, S., Bacher, U., Haferlach, C., Kern, W., Alpermann, T., & Haferlach, T. (2011). Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t (15; 17)/PML-RARA. Haematologica, 96(12), 1799-1807.

Pritchard, C. C., Salipante, S. J., Koehler, K., Smith, C., Scroggins, S., Wood, B., ... & Liu, Y. (2014). Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. The Journal of Molecular Diagnostics, 16(1), 56-67.

Ommen, H. B., Schnittger, S., Jovanovic, J. V., Ommen, I. B., Hasle, H., Østergaard, M., ... & Hokland, P. (2010). Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood, 115(2), 198-205.

Rabellino, A., Carter, B., Konstantinidou, G., Wu, S. Y., Rimessi, A., Byers, L. A., ... & Scaglioni, P. P. (2012). The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer research, 72(9), 2275-2284.

Figueroa, M. E., Lugthart, S., Li, Y., Erpelinck-Verschueren, C., Deng, X., Christos, P. J., ... & Campagne, F. (2010). DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer cell, 17(1), 13-27.

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Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: May 29, 2017
Last updated: May 29, 2017