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Test Code UGTI UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity

Performing Laboratory

Mayo Medical Laboratories in Rochester

Reporting Name

UGT1A1 Gene Sequence, Irinotecan

Specimen Type

Whole Blood EDTA


Specimen Required


Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.


Reject Due To

Hemolysis

NA

Lipemia

NA

Icterus

NA

Other

NA

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)
  Refrigerated 

Specimen Minimum Volume

0.3 mL

Day(s) and Time(s) Performed

Tuesday; Varies

Specimen Retention Time

Whole Blood: 2 weeks Extracted DNA: 2 months

Analytic Time

7 days

Reference Values

An interpretive report will be provided.

Useful For

Identifying individuals who are at increased risk of adverse drug reactions with drugs that are metabolized by UGT1A1, including irinotecan, atazanavir, nilotinib, pazopanib, and belinostat

Testing Algorithm

See UGT1A1 Test-Ordering Algorithm in Special Instructions.

Method Name

Polymerase Chain Reaction (PCR) Followed by Gene Sequencing

Test Classification

See Individual Test IDs

CPT Code Information

81350-UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide AI) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
UGTI UGT1A1 Gene Sequence, Irinotecan In Process

 

Result ID Test Result Name Result LOINC Value
UGTSQ UGT, Full Gene Sequencing In Process
89397 UGT1A1 Irinotecan Result 34509-0
29339 UGT1A1 Irinotecan Interp 69047-9
29340 Reviewed by No LOINC Needed

Clinical Information

Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1)

 

UGT1A1 is involved in the metabolism of irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38 is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the gastrointestinal tract. If UGT1A1 activity is impaired or deficient due to mutations in the coding region or promoter TA (thymine, adenine) repeat polymorphisms, SN-38 fails to become conjugated with glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The combination of neutropenia with diarrhea can be life-threatening.(2,3)

 

Additional drugs have also been associated with an increased risk for adverse outcomes if the patient has reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).

 

The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. The promoter, exons, exon-intron boundaries, and a region in the distal promoter called the "phenobarbital response enhancer module," which is associated with transcriptional activity of the gene, are assessed for variants in this assay.(4)

Interpretation

An interpretive report will be provided.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Cautions

Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient’s genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.

 

UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's UGT1A1 status.

 

An alternative splice site for exon 5 (referred to as exon 5b) has been discovered and described in the literature. This new exon is described to have a decrease in enzymatic activity (compared to exon 5a [previously known as exon 5]), but little is known about the frequency of exon 5b or how it impacts irinotecan therapy. Currently, we are not testing or sequencing exon 5b. We will continue to monitor the literature for new information on exon 5b.

 

Rare variants exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

Clinical Reference

1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyl-transferase enzymes. Pharmacogenomics J 2003;3:136-158

2. Goetz MP, Safgren S, Goldberg RM, et al: A phase I dose escalation study of irinotecan (CPT-11), oxaliplatin (Oxal), and capecitabine (Cap) within three UGT1A1 TA promoter cohorts (6/6, 6/7, and 7/7). ASCO 2005 ASCO Annual Meeting Abstract No: 2014

3. NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. July 21, 2005. Pfizer

4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the Phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41

5. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733

6. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther 2015 doi: 10.1002/cpt.269. (Epub ahead of print)

7. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396

8. US Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Accessed November 2015. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

9. UDP-Glucuronosyltransferase Alleles Nomenclature page. Accessed November 2015. Available at: http://www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles

Method Description

Genomic DNA is extracted from whole blood. The UGT1A1 gene is amplified by PCR. The PCR product is then purified and sequenced in both directions using fluorescent dye-terminator chemistry. Sequencing products are separated on an automated sequencer and trace files analyzed for variations in the exons and intron/exon boundaries of the all exons and a region in the distal promoter called the "phenobarbital response enhancer module" using mutation detection software and visual inspection.(Skierka J, O'Kane D: UDP-glucuronosyltransferase 1A1 and the glucuronidation in oncology applications and hyperbilirubinemia. In Molecular Diagnostics: Techniques and Applications for the Clinical Laboratory. Edited by WW Grody, RM Nakamura, FL Kiechle, CM. Strom Academic Press. 2010, pp 409-420)

Profile Information

Test ID Reporting Name Available Separately Always Performed
UGT1 UGT1A1 Gene Sequence, Irinotecan No Yes
UGTSQ UGT, Full Gene Sequencing No Yes

Genetics Test Information

This test includes gene sequencing of UGT1A1 and the results are interpreted for the purposes of UGT1A1 drug metabolism. If UGT1A1 gene sequencing is desired for interpretation related to hyperbilirubinemia syndromes including Gilbert syndrome and Crigler-Najjar syndrome, order UGT2 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia.

Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

Oncology Test Request Form (T729) (http://www.mayomedicallaboratories.com/it-mmfiles/oncology-request-form.pdf)

Pharmacogenomics Test Request Form (T797) (https://www.mayomedicallaboratories.com/it-mmfiles/pharmacogenomics-test-request-form-mc0767-15.pdf)