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UGT1A1 Gene Polymorphism (TA Repeat)

UGT1A1 Gene Polymorphism (TA Repeat)

Test Summary

UGT1A1 Gene Polymorphism (TA Repeat)

  

Clinical Use

  • Predict toxicity from irinotecan therapy

  • Assist in selection of initial irinotecan dosage

  • Support diagnosis of Gilbert’s syndrome

Clinical Background

Irinotecan (Campostar®, Pfizer Inc, New York, NY) is a topoisomerase-I inhibitor widely used for treatment of metastatic and recurrent colorectal cancer. The most common dose-limiting adverse effects of irinotecan are neutropenia, diarrhea, and asthenia. Variations in the gene encoding uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) may help predict which patients are most likely to develop these adverse effects.

UGT1A1 is a hepatic enzyme primarily responsible for conjugation of bilirubin. UGT1A1 also catalyzes the glucuronidation of SN-38, the active metabolite of irinotecan and the main source of treatment-related toxicity. Glucuronidation is thought to protect against the toxicity of SN-38.1 However, the presence of an additional TA repeat in the TATA region of the UGT1A1 promoter (ie, 7 TA repeats; UGT1A1*28) markedly decreases UGT1A1 production, leading to reduced glucuronidation.2,3 Patients homozygous for the UGT1A1*28 allele therefore accumulate higher levels of SN-38 and are more likely to experience severe adverse effects during irinotecan chemotherapy.4-6 Thus, knowledge of the UGT1A1 polymorphism status could help guide the selection of appropriate starting dosages, reducing the risk of severe toxicity and improving the chances that therapy could be maintained. Homozygosity for this allele is also associated with Gilbert’s syndrome, a mild form of unconjugated hyperbilirubinemia.

Roughly 10% of the US population is homozygous for UGT1A1*28. The frequency of the UGT1A1*28 allele varies among ethnicities,7 being highest in those of African (43%) or European (39%) descent and lowest in those of Asian (16%) descent.8 Variants with 5 or 8 repeats occur at much lower frequencies, primarily in individuals of African descent. The presence of 8 TA repeats has been associated with Gilbert’s syndrome and with decreased glucuronidation in vitro.8 Other variations in the genes encoding UGT1A1 and other uridine diphosphate glucuronosyltransferases may also influence glucuronidation and have been reported at varying frequencies across ethnicities.

Individuals Suitable for Testing

  • Patients being considered for treatment with irinotecan

  • Individuals with suspected Gilbert’s syndrome

Method

  • Fluorescent polymerase chain reaction (PCR) with primers specific for the 5′ untranslated region of UGT1A1

  • Automated detection of PCR products

  • Results reported as negative, heterozygous, or homozygous for the UGT1A1*28 allele

Interpretive Information

Absence of the UGT1A1*28 allele usually indicates a wild-type genotype, although some individuals—especially those of African descent—may have 5 or 8 TA repeats. Patients with a wild-type UGT1A1 genotype have a low risk of severe toxicity from standard starting dosages of irinotecan. Similarly, in patients with 1 copy of the UGT1A1*28 allele (heterozygous), the other copy is most likely wild-type. These patients are at increased risk of irinotecan toxicity but may still tolerate normal initial dosages. Individuals with 2 copies of the UGT1A1*28 allele (homozygous) are at increased risk of severe toxicity from irinotecan. Irinotecan product information indicates that a reduced initial dosage should be considered for such patients.9 Other chemotherapeutic options may also be considered.

This assay does not detect other polymorphisms or mutations in the UGT1A1 gene that may impair irinotecan detoxification, nor does it examine other modifiers of irinotecan metabolism such as CYP3A4 activity. Since genetic variation can affect the accuracy of direct mutation testing, the results should be interpreted in light of other clinical and laboratory findings.

In symptomatic patients, homozygosity for UGT1A1*28 is consistent with a diagnosis of Gilbert’s syndrome. Because other UGT variants have been associated with Gilbert’s syndrome, absence of the UGT1A1*28 allele does not rule out this condition.

References

  1. Gupta E, Lestingi TM, Mick R, et al. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res. 1994;54:3723-3725.

  2. Iyer L, King CD, Whitington PF, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest. 1998;101:847-854.

  3. Iyer L, Das S, Janisch L, et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J. 2002;2:43–47.

  4. Massacesi C, Terrazzino S, Marcucci F, et al. Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Cancer. 2006; [Epub ahead of print]

  5. Rouits E, Boisdron-Celle M, Dumont A, et al. Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res. 2004;10:5151-5159.

  6. Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22:1382-1388.

  7. 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. Erratum in: Pharmacogenetics. 2003;13:183.

  8. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 1998;95:8170-8174.

  9. Campostar® [package insert]. New York, NY: Pfizer Inc; 2005.
     

This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

Content reviewed 12/2012
 
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