Polymorphism in The UGT1A1 Gene and its Association with Small Cell Lung Cancer in North Indian Population

Abstract

In the number of studies done so far among different populations Irinotecan unexpectedly has shown severe Gastrointestinal and Haematological toxicities. Studies have shown that polymorphism within UGT1A1 gene plays an important role in determining the severity of toxicity caused by Irinotecan. Gene polymorphisms and mutations in various types of cancer may predict clinical response to chemotherapy and related toxicity. Irinotecan is metabolised to form an active SN-38, which is further broken down by UDP-glucuronosyltransferase(UGT)1A1 enzyme. There will be alterations in bioavailability of SN-38 because of genetic polymorphisms of the UGT1A1 which would affect inter individual variation of the toxicity by irinotecan. Objectives: Our aim is to study UGT1A1 gene polymorphisms amongst the SCLC patients in North Indian population and to investigate the influence of these polymorphic variants on overall survival and Irinotecan induced toxicities. Methods: A total of 129 subjects were evaluated for polymorphisms in UGT1A1*28, *7, *6, *27 and *29 allele. Genotyping for UGTA1*28 was done using SSCP analysis and for UGT1A1*6, *7, *27, *29 PCR-RFLP method was followed. Results: For UGT1A1*6, the allelic frequency in case of mutant (A/A) genotype was 3.07%, heterozygous (G/A) was 6.15% and for the wild type it was found to be 90.7%. The genotypic frequencies for UGT1A1*28 were 44% (TA6/6), 40% (TA6/7) and 16% (TA7/7). For patients with heterozygous genotype (TA6/7) there was a 3 folds risk (OR=3.067) for diarrhoea, slight risk (OR=1.66) for thrombocytopenia and anaemia (OR=1.7032). The patients with homozygous genotype (TA7/7) had a slight risk (OR= 1.310) towards Leucopoenia. In case of UGT1A1*6, 45.5% patients had grade 2 and 5.02% patients had grade 3-4 leucopoenia, Grade 3-4 diarrhoea was diagnosed in 21.09% of the patients. And 6.8% had grade 3-4 thrmbocytopenia. Conclusion: Polymorphisms in UGT1A1*28 and UGT1A1*6 gene seems to be important for toxicological studies related with Irinotecan. But on the other hand no polymorphism was reported in case of UGT1A1*27, *7 and *29. Thus, suggesting that these polymorphisms do not significantly predict severe irinotecan toxicities in small cell lung cancer patients of Indian population.