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Genetic polymorphisms in xenobiotic metabolism enzyme genes and their associations with colorectal cancer and breast cancer in Han Chinese population

Authors Liao, Linghong
Issue Date 2008
Summary Cancer is a major cause of death worldwide. Recently, polymorphisms of xenobiotic metabolizing enzymes (XMEs) and their associations with cancers attracted considerable attentions due to the fact that xenobiotic metabolism can either potentiate or detoxify most chemical carcinogens. The aim of my study is to investigate the genetic polymorphisms in some XME genes and evaluate their associations with colorectal cancer (CRC) and breast cancer for Han Chinese. Genes coding for CYP1A1, CYP2C9, CYP2E1, CYP3A4 and NAT2 were selected based on their potential role(s) in carcinogen activation and detoxification. The genetic polymorphisms for the promoters, exons, exon-flanking introns and 3’ flanking regions of CYP1A1, CYP2C9, CYP2E1, CYP3A4 and NAT2, were screened by resequencing the appropriate PCR amplified fragments from the genomic DNA isolated from 41 subjects. I identified 151 polymorphisms (including SNPs and deletions/insertions) in the 44.47kb region investigated. A two-stage case-control investigation was conducted in a study population consisted of 468 controls and 277 CRC patients to detect the associations between these polymorphisms and CRC. During the stage I investigation, I genotyped all common polymorphisms (with minor allele frequency >5%) in 81 patients and 104 controls and selected 20 tagSNPs based on the LD patterns. During the stage II study, all 20 tagSNPs were genotyped in the remaining samples to assess CRC associations and for the construction of the haplotype for each gene. Among the 20 tagSNPs, CYP2C9 S135 and CYP3A4 S042, were detected with significant association with CRC in this study population (P = 0.0007 and 0.0008). Haplotype association revealed that the two haplotypes GGCCT (OR= 0.761) and GAACA (OR= 2.256) (S130-S134-S135-S138-S140) of CYP2C9 gene and a haplotype TGCA (OR= 0.714) (S042-S046-S047-S048) of CYP3A4 were related to CRC (P=0.033, 0.006 and 0.003 respectively) but the associations did not reach the significance level. The associations of these XME genes in the developing of breast cancer were studied in a female Han Chinese study population containing 322 controls and 346 breast cancer patients. SNP S081 of NAT2 gene showed the strongest association at both allelic (P = 0.005) and genotypic level (P = 0.0002). The genotype S081 “A/A” carriers have 3.6-fold reduced breast cancer risk compared with “G/G” and “G/A” carriers (OR = 0.275). A marginal association with breast cancer was detected for CYP2E1 S178 (P = 0.005). In addition, two haplotypes of NAT2: CTGG (OR=1.382) and TTAG (OR=0.753) (S078-S079-S081-S083), were detected with marginal associations with breast cancer (P = 0.032 and 0.006). SNP-SNP interactions in breast cancer and CRC cancer susceptibility were estimated by using three different statistical methods: logistic regression model (LRM), the classification and regression trees (CART), and the multifactor dimensionality reduction (MDR). The results from all three methods concluded that the interactions among SNPs NAT2 S081, CYP2E1 S151 and S178 significantly affected individual breast cancer risk. In terms of CRC risk, all three methods identified the single major effect of CYP3A4 S042.
Note Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2008
Language English
Format Thesis
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