The UGT1A9*22 genotype identifies a high-risk group for irinotecan toxicity among gastric cancer patients.

Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A16, UGT1A127, UGT1A128, UGT1A160, UGT1A72, UGT1A73, and UGT1A922 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A16 and UGT1A922 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A128 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A16, UGT1A73, and UGT1A922 polymorphisms than in controls. The presence of the UGT1A16 allele also showed a significant association with grade III-IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A16 or UGT1A73 variant also had the UGT1A922 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A922 polymorphism. By genotyping UGT1A922 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A922 polymorphism, clinicians should closely monitor them for signs of severe toxicity such as intense diarrhea or neutropenia.