Study of polymorphisms of UGT1A1 and DPYD genes in chemotherapy for colorectal cancer

Abstract

Background. The personalized approach implies an individual choice of medicines and their doses for the patient, providing the most effective and safe pharmacotherapy. Objective: analysis of the frequencies of UGT1A1 and DPYD polymorphisms and comparison of genotyping data with irinotecan and 5-fluorouracil-induced toxicity, respectively.Materials and Methods. Venous blood of 94 Caucasian patients (46 men and 48 women, median age 61 years). The *6 and *28 UGT1A1 alleles were identified by pyrosequencing, and the *2А DPYD allele was identified by Real-time PCR.Results. The genotyping of 94 patients with colon cancer did not reveal the *2A SNP in the DPYD gene. The frequency rate of the *6 and *28 alleles of the UGT1A1 gene was 0.346 and 0.016, respectively. 24 % of patients receiving chemotherapy with 5-fluorouracil developed side effects associated with the circulatory system and the gastrointestinal tract. Hematological and nonhematological toxic reactions were noted in 48 % and 50 % of patients receiving irinotecan. Severe bilirubinemia was associated with the *28/*28 UGT1A1 genotype. The presence of a high-risk genotype (*28/*1, *28/*28 UGT1A1) correlated with the development of side effects (p=0.040).Conclusion. The absence of carriers of the *2А DPYD allele in the sample with a significant proportion of pronounced adverse toxic reactions to 5-fluorouracil causes the need for the inclusion of new polymorphisms of the DPYD gene in pharmacogenetic testing. The inclusion of genotyping of UGT1A1 polymorphisms into a complex of preliminary examination is advisable when planning treatment with irinotecan.

UGT1A1 gene mutation as a marker indicating there is a high risk of Gilbert's syndrome: Theoretical and applied aspects

“…Data on population and genetic peculiarities of UGT1A1 gene in population in Russia are scarce. Recently some research results have been published on UGT1A1 polymorphism in a sampling which included people living in the south of Russia (Rostov-on-Don) [14]. According to the obtained results, *28/*28 genotype fraction amounted to 9.6%, and allele *28 frequency was even higher than we detected in our research.…”

“…There are very scarce data on UGT1A1 genetic polymorphism as well as on its physiological and biochemical signs in population in Russia [14,15]. Besides, Gilbert's syndrome frequency is unknown and there are no data on how many people or what specific population groups run risks of this pathology.…”

Population genetic research of the mutation in ugt1a1 gene associated with reduced activity of liver UDP-glucuronosyltransferase A1

“…Учитывая сказанное, становится очевидным, что данные о распространенности мутаций в гене UGT1A1 позволят косвенно оценить долю населения, подверженного гипербилирубинемиям и склонным к нежелательным лекарственным реакциям при приеме препаратов, подвергающихся в организме глюкуронированию. По нашим данным, популяционно-генетические исследования UGT1A1 среди жителей России единичны, при этом они обычно охватывают специфические контингенты обследованных, что затрудняет экстраполяцию данных на обычное население [10].…”

UGT1A1 gene mutation as a marker indicating there is a high risk of Gilbert's syndrome: Theoretical and applied aspects

“…Данных о генетическом полиморфизме UGT1A1, а также о его физиолого-биохимических проявлениях у населения России крайне мало [14,15]. Кроме того, неизвестна частота синдрома Жильбера и объем группы риска по данной патологии у населения нашей страны.…”

“…Данных о популяционно-генетических особенностях UGT1A1 у жителей России крайне мало. Недавно были опубликованы результаты исследования полиморфизма UGT1A1 в выборке жителей Юга России (г. Ростов-на-Дону) [14]. Согласно полученным результатам, доля генотипа *28/*28 составила 9,6 %, а частота аллеля *28 даже превышала установленное нами значение.…”