The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users

Cytochrome P450 2D6 (CYP2D6) plays an important role in the formation of endoxifen, the active metabolite of tamoxifen. In this study the association between the most prevalent CYP2D6 null-allele in Caucasians (CYP2D6*4) and breast cancer mortality was examined among all incident users of tamoxifen in a population-based cohort study. Breast cancer mortality was significantly increased in patients with the * 4/*4 genotype (HR = 4.1, CI 95% 1.1–15.9, P = 0.041) compared to wild type patients. The breast cancer mortality increased with a hazard ratio of 2.0 (CI 95% 1.1–3.4, P = 0.015) with each additional variant allele. No increased risk of all-cause mortality or all-cancer mortality was found in tamoxifen users carrying a CYP2D6*4 allele. The risk of breast cancer mortality is increased in tamoxifen users with decreased CYP2D6 activity, consistent with the model in which endoxifen formation is dependent on CYP2D6 activity.     

Genetic polymorphism of GSTM1, CYP2E1 and CYP2D6 in Egyptian bladder cancer patients

Polymorphic changes in the GSTM1, CYP2E1 and the CYP2D6 geneshave been reported to be individually associated with increasedsusceptibility to certain cancers. In the present study, therelationship between genetic polymorphism for these genes anddevelopment of urinary bladder cancer among Egyptian patientswas investigated. Our results indicate that the frequency ofbladder cancer patients with the GSTM1 null genotype is significantlyhigher than that of the normal controls (86.3 and 47.6%, respectively)with an odds ratio (OR) of 6.97 (95% CL = 1.59–30.57,Fisher's exact P = 0.008). In contrast, our investigation failedto demonstrate any difference in the distribution of CYP2E1polymorphism between bladder cancer patients and controls asdetected by PstI restriction fragment length polymorphism (RFLP)analysis. RFLP analysis of the CYP2D6 gene revealed a non-significantincrease in the number of extensive metabolizers (EM) amongthe patients compared to the controls (68 versus 48%). However,the EM genotypes enhances the risk further for individuals harboringthe GSTM1 null genotype as individuals harboring both the EMand the GSTM1 null genotypes have an odds ratio of 14.0 (95%CL = 1.3–151.4, Fisher's exact P = 0.02) compared to individualsharboring the EM and the GSTM1+/+ genotypes. In conclusion,our results indicate that genetic polymorphism, especially inGSTM1 and CYP2D6 could play an important role as host risk factorsfor development of urinary bladder cancer among Egyptians.     

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.     

CYP2D6、GSTM1遗传多态性与肺癌易感性关系

目的探讨中国汉族广东籍人群中ＣＹＰ２Ｄ６、ＧＳＴＭ１的遗传多态性与肺癌易感性关系。方法采用病例—对照研究方法,用ＰＣＲ检测ＣＹＰ２Ｄ６、ＧＳＴＭ１的基因型,限制性酶切电泳鉴定ＣＹＰ２Ｄ６点突变。结果病例组与对照组间未发现ＣＹＰ２Ｄ６多态性分布差异,而ＧＳＴＭ１多态性存在分布差异,病例组为５８．７％,对照组为３５．７％（Ｐ＜０．０５）,ＯＲ值为２．５６（１．１１－２．４４）。结论ＣＹＰ２Ｄ６Ｇ－Ａ突变与肺癌易感性未见有联系,ＧＳＴＭ１－／－型个体患肺癌易感性增高     

CYP2D6遗传多态性与肺癌易感性关系的研究

目的探讨CYP2D6Ch基因多态性的频率分布,以及与肺癌的遗传易感性关系.方法应用病例-对照研究及PCR-RFLP等技术,检测肺癌及正常对照各50例的CYP2D6Ch基因型,并应用Logistic回归分析基因多态性与肺癌易感性的关系.结果(1)CYP2D6Ch T/T型(突变型)频率在病例组中为36.0%,在对照组中为50.0%;非T/T型(即C/C合并C/T基因型)与肺癌风险临界升高相关(OR=3.06;95%CI=0.94～9.92).(2)对病例组进行相关变量的分层分析后发现,在肺鳞癌,或轻度吸烟组中,CYP2D6Ch非T/T型与肺癌风险升高显著相关(分别为:OR=3.20,CI=1.04～9.85;OR=7.07,CI=1.16～42.85).结论本文提示CYP2D6Ch基因型分布规律与欧美人群差异较大,且T/T型在肺鳞癌或轻度吸烟者中可作为保护因素而降低肺癌的易感性.     

The CYP2D6 extensive metabolizer genotype is associated with increased risk for bladder cancer

Inheritance of certain polymorphic metabolizing genes is associated with the development of a number of environmental cancers and may also influence the clinicopathological tumor outcome. We have investigated the association between the inheritance of the polymorphic cytochrome P-450 2D6 (CYP2D6) gene and the development of transitional and squamous cell carcinomas (TCC and SCC) of the bladder in 37 Egyptian cancer patients and 27 matched controls. Genotypic analysis using the polymerase chain reaction (PCR) and the restriction fragment length polymorphism (RFLP) assays revealed that the CYP2D6 extensive metabolizer genotype (CYP2D6*1A) is over represented in bladder cancer patients compared to controls (79 versus 44%, respectively) and is significantly associated with increased risk for bladder cancer (odds ratio (OR) = 4.5, 95% confidence limit (CL) = 1.3-15.7, P = 0.006). Our results also indicate that individuals who have inherited this genotype are more likely to develop TCC (OR = 5.9, 95% CL = 1.4-27.9, P = 0.006) rather than SCC (OR = 3.1, 95% CL = 0.7-15.9; P = 0.09). When the relative risk associated with this genotype was estimated among subjects who were smokers or schistosoma infected, the same tendency towards the development of TCC was observed. These data suggest that the predisposing CYP2D6 gene may not only increase the risk for bladder cancer among Egyptians, but may also influence the clinicopathological tumor outcome.     

Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment

BackgroundHuman cytochrome P450 2D6 (CYP2D6) genotype may affect the efficacy of tamoxifen treatment in Caucasian women with breast cancer. The most common polymorphism of CYP2D6 in Chinese women is variant 10 (188 C to T).Patients and methodsTamoxifen and 4-hydroxytamoxifen (4OHtam) were measured in the serum of 37 women with breast cancer who were receiving tamoxifen treatment. The association between CYP2D6 *10 genotype and survival was determined in a cohort of 293 women with breast cancer who received tamoxifen (n = 152) or who did not (n = 141).ResultsThe serum 4OHtam concentrations were significantly lower in women with the CYP2D6 *10 homozygous variant T/T genotype than in those with the homozygous wild-type C/C genotype (P = 0.04). Among tamoxifen-treated women, women with the T/T genotype had a significantly worse disease-free survival (DFS) than those with the C/C or C/T genotype, and the T/T genotype remained an independent prognostic factor of DFS in multivariate analysis (hazard ratio = 4.7; 95% confidence interval = 1.1–20.0; P = 0.04). Among women who did not receive tamoxifen, there was no significant association between CYP2D6 *10 genotype and survival.ConclusionIn tamoxifen-treated patients, women with the CYP2D6 *10 T/T genotype have a lower 4OHtam level in the serum and a worse clinical outcome.     

Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy

The clinical outcomes of breast cancer patients treated with tamoxifen may be influenced by the activity of cytochrome P450 2D6 (CYP2D6) enzyme because tamixifen is metabolized by CYP2D6 to its active forms of antiestrogenic metabolite, 4-hydroxytamoxifen and endoxifen. We investigated the predictive value of the CYP2D6 * 10 allele, which decreased CYP2D6 activity, for clinical outcomes of patients that received adjuvant tamoxifen monotherapy after surgical operation on breast cancer. Among 67 patients examined, those homozygous for the CYP2D6 * 10 alleles revealed a significantly higher incidence of recurrence within 10 years after the operation ( P =  0.0057; odds ratio, 16.63; 95% confidence interval, 1.75–158.12), compared with those homozygous for the wild-type CYP2D6 * 1 alleles. The elevated risk of recurrence seemed to be dependent on the number of CYP2D6 * 10 alleles ( P =  0.0031 for trend). Cox proportional hazard analysis demonstrated that the CYP2D6 genotype and tumor size were independent factors affecting recurrence-free survival. Patients with the CYP2D6 * 10/ * 10 genotype showed a significantly shorter recurrence-free survival period ( P =  0.036; adjusted hazard ratio, 10.04; 95% confidence interval, 1.17–86.27) compared to patients with CYP2D6 * 1/ * 1 after adjustment of other prognosis factors. The present study suggests that the CYP2D6 genotype should be considered when selecting adjuvant hormonal therapy for breast cancer patients. ( Cancer Sci 2008; 99: 995–999)     

CYP2D6 gene polymorphism in caucasian smokers: lung cancer susceptibility and phenotype-genotype relationships

Individual susceptibility to smoking-related cancers is proposed to partly depend on a genetically determined ability to metabolise tobacco carcinogens. We previously reported on the association between the activity of the xenobiotic-metabolising enzyme CYP2D6 and lung cancer risk in a hospital-based case-control study among French Caucasian smokers. Here we extended the study to address the effect of four gene-inactivating mutations (CYP2D6(*)3, (*)4, (*)5 and (*)16) and the gene duplication of the CYP2D6 gene (CYP2D6(*)2x2 or CYP2D6(*)1x2) on lung cancer risk in the same population (150 patients with primary lung carcinoma of squamous cell or small cell histology and 172 controls). The risk of lung cancer associated with the CYP2D6 poor metaboliser genotype (odds ratio 1.5, 95% confidence interval 0.5-4.3) did not differ from that in the reference category of extensive metaboliser and ultra-rapid metaboliser genotypes combined. Lung cancer risks for the CYP2D6 PM genotype amongst light smokers (tobacco consumption 20 g/day) were not significantly different. The present findings agree with the discrepancy between the phenotype-based and genotype-based studies indicated by the recent meta-analyses.     

CYP2D6

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Human CYP2D6 gene polymorphism in Slovene cancer patients and healthy controls

The polymorphic CYP2D6 gene encoding debrisoquine hydroxylasehas attracted much interest for its possible role in human pulmonarycarcinogenesis. The purpose of this work was to determine thefrequency of poor metabolizers (PM) and extensive metabolizers(EM) of debrisoquine in Slovene population of healthy individuals(n = 107), lung cancer patients (200) and melanoma patients(121). Polymorphism of CYP2D6 gene was studied by genotypingbased on PCR analysis of the intron 3 exon 4 junction containingG to A mutation and one base pair deletion in exon 5, whichare responsible for     

The association of CYP2D6 *10 polymorphism with breast cancer risk and clinico-pathologic characteristics in Chinese women

A relatively little is known of whether CYP2D6 *10 (188 C to T) polymorphism mediates susceptibility to breast cancer. In this study the CYP2D6 *10 polymorphism was detected in Chinese women (286 breast cancer patients and 305 healthy women) by a PCR-RFLP assay. We found that women with the 188T/T genotype displayed a slightly increased risk for breast cancer as compared with those with the 188C/C genotype (OR 1.36, CI 0.89-2.1), the association of the 188T/T genotype with breast cancer risk was more pronounced among postmenopausal women (OR 1.49, CI 0.8-2.76), but the association did not reach statistical significance. Furthermore, we found that patients carrying the 188T/T or T/C genotype were more likely to be a positive lymph node status than those with the 188C/C genotype (OR 2.12, CI 1.08-4.18, P = 0.019). Our results suggest that CYP2D6 *10 mutant 188T/T genotype displays a non-significant increased risk for breast cancer. Moreover, patients carrying 188T/T or T/C genotype might exhibit a more aggressive phenotype than those carrying 188C/C genotype, as the observation association of genotype with clinical outcome may be due to chance, therefore, further studies are required to confirm our present findings.     

CYP2D6 T188C variant is associated with lung cancer risk in the Chinese population

The CYP2D6 gene has been suggested to play an important role in the pathogenesis of lung cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of CYP2D6 T188C variant with lung cancer. Published literature from PubMed, Embase, Chinese National Knowledge Infrastructure and Wanfang data were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed- or random-effects model. A total of nine studies (1,516 lung cancer cases and 1,950 controls) for CYP2D6 T188C variant were included in the meta-analysis. The meta-analysis indicated that compared with CYP2D6 TT genotype, non-TT genotype (CC or CT) was significantly associated with lung cancer in the Chinese (OR?=?1.61, 95 % CI?=?1.38–1.87, p?<?0.001), with no evidence of between-study heterogeneity (I ²?=?0.0 %, p?=?0.991). The sensitivity analysis indicated that the association was stable and no publication bias was detected. The present meta-analysis supported the positive association of CYP2D6 T188C variant with lung cancer in the Chinese. Further large-scale studies with the consideration for gene–gene/gene–environment interactions should be conducted to investigate the association.     

甘肃地区乳腺癌患者的CYP2D6基因多态性及代谢表型特征分析

目的:分析乳腺癌患者的CYP2D6基因多态性和代谢表型,为乳腺癌患者进行他莫西芬（TAM）个体化临床治疗提供参考依据。方法:选取2018年1月至2019年1月于我院乳腺科确诊的170例乳腺癌患者外周血,通过Sanger测序技术对CYP2D6基因的9个外显子进行全面具体分析。结果:本研究主要发现有5个CYP2D6等位基因变异位点:CYP2D6*10、CYP2D6*4、CYP2D6*7、CYP2D6*41和CYP2D6*5,其对应的发生频率分别为66.5%、5.9%、2.4%、0.6%和0.6%;其中,CYP2D6*10/*10基因型在乳腺癌患者中占据主导地位,发生频率为60.6%。结论:中国甘肃地区乳腺癌患者,多以CYP2D6*10等位基因、CYP2D6*10/*10基因型、TAM中间代谢型为主,这可为乳腺癌患者选择相应的个体化药物治疗方案以及本地区乳腺癌患者今后大规模的药物遗传基因组学研究提供参考数据。     

The ethics of CYP2D6 testing for patients considering tamoxifen

The CYP2D6 gene is responsible for the majority of tamoxifen metabolism. Recent compelling, yet limited data have determined that postmenopausal women who carry a functional polymorphism in the CYP2D6 gene have a worse clinical outcome than women who have a wild-type genotype. In this commentary we discuss the level of evidence needed to change clinical practice and whether CYP2D6 genotyping is appropriate for all women considering tamoxifen as part of their adjuvant therapy.     

CYP2B6*6 is associated with increased breast cancer risk

The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6_516_G>T (rs3745274) and CYP2B6_785_A>G (rs2279343) and breast cancer risk, we established a specific matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry assay. The GENICA breast cancer case–control study showed associations between the variant genotypes CYP2B6_516_TT and CYP2B6_785_GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6_516_T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6_516_G and the CYP2B6_785_G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6_516_G and CYP2B6_785_G (designated CYP2B6*6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk.     

乳腺癌患者CYP2D6基因多态性与他莫昔芬代谢相关性研究

目的 探究乳腺癌患者CYP2D6基因多态性与他莫昔芬药物代谢产物浓度之间的关系。方法 收集2010年1月—2012年12月我院乳腺癌患者的外周血样本,检测CYP2D6基因上rs16947,rs1065852和rs28371725三种单核苷酸多态性(Single nucleotide polymorphism,SNP)位点的基因型及他莫昔芬代谢产物在血液中的浓度。应用非参数检验中的独立样本Kruskal-Wallis检验进行统计学分析。结果 CYP2D6基因上rs16947位点不同基因型携带者间他莫昔芬代谢产物4-OH-N-D-TAM和4'OH-N-D-TAM在血液中的浓度具有统计学差异(P=0.049),表明CYP2D6基因上的rs16947位点影响他莫昔芬药物在人体内的代谢。结论 乳腺癌患者CYP2D6基因rs16947位点的基因型与部分他莫昔芬代谢产物的血液浓度有关。