UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity, Saliva
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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.(3,4)
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 polymorphisms and mutations in this assay.(5) More than 100 mutations have been described in the UGT1A1 gene; 42 of the described mutations have decreased enzyme activity.
Identifying individuals who are at increased risk of adverse drug reactions with irinotecan and who should be considered for decreased dosing of the drug.
Genotyping patients who prefer not to have venipuncture done
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Note that in patients who have received heterologous blood transfusions before a saliva sample was acquired, the saliva samples may contain donor DNA. Return to recipient genotype usually occurs after 6 weeks. Similarly, saliva samples obtained from patients after allogeneic blood or marrow transplantation can contain donor DNA. In both cases, this may result in genotyping results that reflect the genotype of the recipient, the donor, or a blend of the donor and recipient. Results obtained under these circumstances may not accurately reflect the recipient’s genotype.
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 on 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 polymorphisms 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.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158
2. 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
3. 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
4. NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. July 21, 2005. Pfizer.
5. 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