Interpretation

Background Information for UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping:
Characteristics: UGT1A1 is responsible for the clearance of drugs (e.g., irinotecan) and endbiotic compounds (e.g., bilirubin). Irinotecan’s major active and toxic metabolite (SN-38) is inactivated by the UGT1A1 enzyme and then eliminated via the bile. UGT1A1 gene mutations cause accumulation of SN-38, which may lead to irinotecan-related toxicities (neutropenia, diarrhea).
Cause: Variations in TA repeat number in the TATAAA element of the 5’ UGT1A1-promoter affects transcription efficiency. The common number of repeats is six [(TA)6, 1 allele], while seven repeats [(TA)7, *28 allele] is associated with reduced transcription activity. Homozygosity for the (TA)7 allele is also associated with Gilbert Syndrome (benign familial hyperbilirubinemia).
Alleles Tested: *36 allele, (TA)5; *1 allele, (TA)6; *28 allele, (TA)7 and *37 allele, (TA)8.
Clinical Sensitivity/Specificity: Risk of irinotecan toxicity by genotype (Br J Cancer (2004) 91:678-82).
6/6 (1/1): diarrhea 17 percent; neutropenia 15 percent.
6/7 (1/28): diarrhea 33 percent; neutropenia 27 percent.
7/7 (28/*28): diarrhea 70 percent; neutropenia 40 percent.
Allelic Frequency: *1 (TA)6: Caucasians 0.61, Asians 0.84, African Americans 0.47.
*28 (TA)7: Caucasians 0.39, Asians 0.16, African Americans 0.43.
Methodology: Polymerase chain reaction followed by size analysis using capillary electrophoresis.
Analytical Sensitivity: Greater than 99 percent.
Limitations: Variations in the UGT1A1 gene, other than those targeted, will not be detected. Clinical significance of the rare *36, (TA)5 and *37, (TA)8 alleles in predicting irinotecan toxicities is not well established. Genetic and non-genetic factors other than UGT1A1, may contribute to irinotecan toxicity and efficacy. Diagnostic errors can occur due to rare sequence variations.

Counseling and informed consent are recommended for genetic testing.