Polymorphisms in Xenobiotic Genes and Risk of Developing Diffuse Large B-Cell Lymphoma in Saudi Population.

Abstract Diffuse large B-Cell Lymphoma (DLBCL) is one of the most common types of non-Hodgkin lymphoma (NHL) and an increased incidence has been reported during the past 30 years. The cause of this remains unknown but population-based studies suggest a relationship with exposure to certain environment carcinogens. Particularly, exposure to asbestos, benzene, industrial and agricultural toxins has been implicated as possible cause of the disease. The xenobiotic enzyme system that enables us to detoxify these types of carcinogens exhibits identifiable genetic polymorphisms that are associated with variations in functional activity. These genetic differences are highly race specific and have never been screened in the Saudi DLBCL patients. We propose that individuals with certain xenobiotic gene polymorphisms may modify the risk to develop DLBCL than other individuals exposed to similar environmental conditions. Furthermore, the demonstration of a relationship between identifiable xenobiotic systems and the development of DLBCL would contribute to our understanding of the pathogenesis of this and related disorder. We have therefore investigated the association between polymorphisms in genes encoding xenobiotics-metabolizing enzymes, including CYP1A1, GSTT1, GSTM1, GSTP1, MTHFR and NQO1, using PCR-RELP, and risk to develop DLBCL in a population-based study (513 Saudi controls and 182 Saudi DLBCL patients). MTHFR 1298 CC (OR=4.23) and C allele (OR = 1.73) showed an increased risk, and combined genotype CCCC among intermediate MTHFR activity group was associated with 3.489 fold increase and CTCC among low MTHFR activity group was related to 9.515 fold higher risk to develop DLBCL compared with full MTHFR enzyme activity. The genotype of NQO1 TT was associated with 1.86 fold while CYP1A 4887 AA showed 2.34 fold higher risk to develop DLBCL compared with wild type. GSTP1 1578 GG genotype (OR=0.368) was shown to be protective against DLBLC. Although the GSTT1 null was found to be a risk factor (OR=11.948) to develop DLBCL but double null of GSTT1 and GSTM1 also showed 3.087 fold higher risk to develop DLBCL. Our findings suggest that polymorphisms of xenobiotic metabolizing enzyme genes modify the individual susceptibility to develop DLBCL in the Saudi population. Although no dose-response relationship was found for multiple genes, future large-scale study is called for to confirm the role of polymorphisms of above genes and their combination on modification of susceptibility to DLBCL in Saudi Arabia. Distribution of polymorphisms in healthy population and lymphoma patients. Polymorphism Genotype Control Patients P OR MTHFR A1298C AA 239(46.8%) 38(33.6%) AC 220(43.1%) 40(35.4%) CC 52(10.2%) 35(31%) <0.001 4.23 AC+CC 272(53.2%) 75(66.4%) 0.012 1.73 MTHFR C677T+A1298C Intermediate Activity CCCC 45(8.8%) 22(27.8%) <0.001 3.48 Low Activity CTCC 6(1.2%) 8(10%) <0.001 9.51 TTAC 0 2(2.5%) 0.017 NQO1 C609T CC 295(58.5%) 94(62.7%) CT 177(35.1%) 37(24.7%) 0.051 0.65 TT 32(6.4%) 19(8.7%) 0.059 1.86 CT+TT 209(41.5%) 56(37.3%) GSTP1 A1578G AA 170(33.5%) 56(35%) AG 271(53.5%) 96(60%) GG 66(13%) 8(5%) 0.013 0.37 AG+GG 337(66.5%) 104(65%) GSTT1 P 385(75%) 36(20.1%) D 128(25%) 143(79.9%) <0.001 11.95 GSTT1+GSTM1 Present 423(82.8%) 109(60.9%) Double Null 88(17.2%) 70(39.1%) <0.001 3.09 CYP1A1 C4887A CC 331(64.8%) 102(63%) CA 162(31.7%) 47(29%) AA 18(3.5%) 13(8%) 0.030 2.34