Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients

Abstract

BACKGROUND: Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase-I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant. METHODS: The study included 329 colorectal cancer patients from the Israeli population-based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3-4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene. RESULTS: The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3-4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity-related hospitalization (45.8%, 25.3%, and 14.4% respectively; P ¼ .001). Both short-term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P ¼ .01) were significantly worse in the 7/7 carriers. The age/stage-adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1-2.3). CONCLUSIONS: The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan.

UGT1A1*28 Polymorphism in Chronic Lymphocytic Leukemia: The First Investigation of the Polymorphism in Disease Susceptibility and Its Specific Cytogenetic Abnormalities

“…In particular, studies have implicated UGT1A1*28 polymorphism with the occurrence of colorectal and breast cancer, while Lacko et al [6] proved its contribution to laryngeal and head and neck cancer [17,24]. Moreover, the incidence of Gilbert's syndrome, an autosomal recessive trait, the genetic basis of which is UGT1A1*28 polymorphism, has been estimated to affect 3-10% of the general population, prevailing in Caucasians over eastern populations, such as Asians and Japanese [6,9].…”

Correlation of UGT1A1 and ERCC1 gene polymorphisms with the outcome of combined irinotecan plus cisplatin treatment in recurrent ovarian cancer

“…In the promoter region, differences in numbers of TA repeats yield the wild-type 6-repeat allele variant UGT1A1*1 and the mutant 7-repeat variant UGT1A1*28, giving rise to the genotypes WW (TA6/TA6 or *1/*1), MM (TA7/TA7 or *28/*28), and WM (TA6/TA7 or *1/*2). The polymorphism in ERCC1 is found in the fourth exon at codon 118 and is synonymous (Asn118Asn) (Martinez-Balibrea et al, 2010;Shulman et al, 2011). The frequency distributions of the UGT1A1 and ERCC1 alleles in the 89 patients with recurrent ovarian cancer can be seen in Table 1 …”

Correlation of UGT1A1 * 28 and * 6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients

“…The frequency of UGT1A1 * 28 is high in Caucasians (about 39%) and is considered as a major predictive pharmacogenetic marker of severe hematological toxicity [9,10]. Previous studies reported that the polymorphism of UGT1A1 * 28 is associated with irinotecan-induced severe neutropenia [11,12]. Therefore, in 2005, the U.S. Food and Drug Administration (FDA) suggested that homozygous UGT1A1 * 28 patients should receive an irinotecan dose-reduction by at least one level [13].…”