A population study on the UGT1A1*28 variant associated to Irinotecan tolerance

Roman R,1 Colomer A,1 Erill N,1 Verdú M,2 Ibáñez R,1 Cordon-Cardo C,1 Puig X.1,2

1BIOPAT. Biopatologia Molecular, Grup Assistència & 2HISTOPAT Laboratoris, Barcelona, Catalonia, Spain.

Background: Irinotecan (CPT-11) is currently used as first- or second-line treatment for colorectal cancer, either alone or in combination with 5-fluorouracil based regimens. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the inactivation of SN-38, the active metabolite of irinotecan, through glucuronidation. UGT1A1*28, a polymorphic variant of this enzyme displaying an additional TA dinucleotide in the promoter TATA box, has been related to a reduction of its transcriptional activity. Patients presenting this variant are prone to increased severe toxicities, mainly neutropenia and diarrhea. In fact, a reduction of the initial dose of irinotecan has been recommended for individuals presenting the UGT1A1*28 homozygous genotype.

Aim and Design: The objective of our study was to evaluate the presence of the UGT1A1*28 variant in a series of 106 samples collected from the area of Barcelona, Catalonia, Spain. This series included a set of 54 normal mucosa samples collected from patients surgically treated for colorectal cancer, and a collection of 52 tonsillectomy samples from healthy children. All tissues were routinely formalin fixed and embedded in paraffin. The study was carried out by PCR amplification of extracted genomic DNA, followed by direct sequencing. Genotypes were assigned as follows: 6/6 describes cases homozygous for the common allele with six TA repetitions, 7/7 describes cases homozygous for the UGT1A1*28 variant with seven TA repetitions, and 6/7 represent heterozygous cases.

Results: We observed an UGT1A1*28 allelic frequency of 0.32 in the population studied. The 6/6 genotype was detected in 46.2% of cases, while 43.4% and 10.4% of the individuals presented with 6/7 and 7/7 genotypes, respectively. These results are in agreement with those reported for other European populations. Looking at our two different sets of samples separately, a higher allelic frequency was found in the colorectal cancer patients when compare to that found in the tonsils group (0.36 vs. 0.28), though it did not reach statistic significance.

Conclusions: Based on these data and other reports, together with the potential severe toxicities and the benefit of a reduced initial dose of irinotecan, it seems logical to perform a UGT1A1 genotype in colon cancer patients prior to irinotecan treatment. The putative increase in the frequency of the UGT1A1*28 variant in a population with colorectal cancer needs to be further assessed and validated using a larger and well characterized cohort.

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Abstract exhibited at the:

International Academy of Pathology Centennial Congress

Montreal, Québec, Canada

September 16-21, 2006

Abstract in:

Modern Pathology 2006; 19 (suppl. 3): 142.