UGT1A1 Genotyping - Irinotecan

Diagnosis

Indications for Testing

• Patient who will receive irinotecan (in doses >150 mg/m²), who has a history of irinotecan sensitivity, or who experiences neutropenia while receiving irinotecan
• Patient suspected to have Gilbert syndrome

Laboratory Testing

• UGT1A1 (TA) polymorphism test
  • Risk of irinotecan toxicity by genotype

    Risk of irinotecan toxicity by genotype*
    TA genotype	Diarrhea risk	Neutropenia risk
    6/6 (*1/*1)	17%	15%
    6/7 (*1/*28)	33%	27%
    7/7 (*28/*28)	70%	40%
    *Based on data from Br J Cancer 2004; 91:678-82.

• UGT1A1 genotype does not significantly influence risk of irinotecan toxicity when low dose therapy with irinotecan (eg, 15-75 mg/m² daily for five days for two consecutive weeks) is employed

Clinical Background

Irinotecan (CPT-11) is a common chemotherapeutic drug used for the treatment of advanced colorectal and gastric cancer. Allelic variance of UGT1A1 may be associated with increased drug toxicity and with syndromes such as Gilbert syndrome (benign familial hyperbilirubinemia) and Crigler-Najjar (rare form of nonhemolytic jaundice).

Epidemiology

• Ethnicity
  • Caucasian
    • (TA)6 – 61%
    • (TA)7 – 39%
  • Asian
    • (TA)6 – 84%
    • (TA)7 – 16%
  • African
    • (TA)6 – 47%
    • (TA)7 – 43%

Genetics

• UGT1A1 is located on chromosome 2q37
• The polymorphic TA repeat in the TATA element of the 5’-promoter region of UGT1A1 may consist of 5, 6, 7, or 8 repeats [(TA)5, (TA)6, (TA)7, (TA)8]
  • (TA)6 (also known as UGT1A1*1)  – most common number of repeats
  • (TA)7 (also known as UGT1A1*28)  – important genotype for risk of severe drug-induced toxicity
    • Increase in number of TA repeats may reduce transcription efficiency, lower enzyme concentrations, and lead to accumulation of SN-38 and risk for toxicities
  • (TA)5 and (TA)8 alleles are rare but may also be clinically significant
    • Number of TA repeats thought to be inversely related to expression of UGT1A1 protein, such that (TA)8 would be associated with the most impaired transcription efficiency

Pathophysiology

• UGT1A1 is responsible for the clearance, by glucuronidation, of drugs (eg, irinotecan) and endogenous substances (eg, bilirubin)
  • >150 functional polymorphisms on UGT1A1 locus
• SN-38 – primary active and toxic metabolite of irinotecan
  • SN-38 is inactivated by UGT1A1 to form SN-38G, which is eliminated via bile
• Variations of the TA repeat length in the UGT1A1 promoter TATA element may lead to decreased gene expression, accumulation of SN-38, and irinotecan-related toxicities
  • Variations of the TA region are associated with Gilbert syndrome
• Presence of UGT1A1*28 also may affect treatment with the following agents
  • Raloxifene
  • Raltegravir
  • Indinavir
  • Atazanavir
  • Sorafenib

Clinical Presentation

• Irinotecan toxicity-related symptoms
  • Typically severe (grade 3/4) diarrhea and neutropenia
• Other related symptoms
  • Nausea, fever, alopecia

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory