叶酸及其代谢酶基因多态与子宫内膜癌发生和预后
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摘要
[背景]
子宫内膜癌是一种常见的妇科恶性肿瘤,好发于中老年女性。降低子宫内膜癌的发生和死亡对提高女性健康具有重要意义。叶酸因其在核苷酸合成中的重要作用,可能在子宫内膜癌形成的不同阶段产生不同的效应:肿瘤形成前,高水平的叶酸可防止正常细胞发生突变,降低肿瘤的发生危险,而对已发生的癌前病变或肿瘤生长可能有促进作用。亚甲基四氢叶酸还原酶(5,10-methylenetetrahydrofolatereductase,MTHFR)和胸苷合酶(Thymidylate synthase,TYMS)是叶酸代谢通路中的关键酶,其活性可影响体内叶酸和同型半胱氨酸水平,造成个体间肿瘤易感性和对化疗药物敏感性的差异。MTHFR和TYMS基因多态决定了这些酶活性的高低,因而可能在子宫内膜癌的发生和预后中起一定的作用。
[目的]
研究叶酸及其代谢酶基因多态在子宫内膜癌发生和预后中的作用。具体而言:
1.利用以人群为基础的病例对照研究收集的现场调查资料和生物标本,分析膳食来源的叶酸等甲基营养素及维生素补充剂与子宫内膜癌的关联,并分析MTHFR和TYMS基因多态及单体型与子宫内膜癌的关联及修饰效应。
2.利用子宫内膜癌病例随访资料,评估膳食叶酸、维生素补充剂、MTHFR和TYMS基因多态及单体型对子宫内膜癌生存率的影响。
[方法]
上海子宫内膜癌研究(Shanghai endometrial cancer study,SECS)是一项以人群为基础的病例对照研究,共收集1997年1月-2003年12月确诊、年龄为30-69岁、有上海市区常住户口的子宫内膜癌新发病例1,454例,其中1,204例完成了问卷调查。人群对照为1,212例与病例进行年龄频数配对的有上海市区常住户口的健康女性。膳食叶酸、核黄素(维生素B2)、维生素B6、维生素B12和甲硫氨酸的摄入水平根据膳食频率调查表数据计算,维生素补充剂的使用亦通过问卷调查而得。共检测了1,041例病例和1,030例对照MTHFR 677C＞T(rs1801133),1298A＞C(rs1801131)和1793 G＞A(rs2274976)三个多态位点的基因型以及1,037例病例和1,018例对照TYMS基因及其上、下游各5kb区域11个单体型标签单核苷酸多态(Haplotype tagging single nucleotide polymorphisms,htSNPs)。单体型的估计使用Phase软件。比值比(Odds ratio,OR)和95%可信区间(Confidence interval,CI)的计算采用Logistic回归模型,用于估计营养素和基因多态与子宫内膜癌的关联。单体型与子宫内膜癌的关联及其与环境因素的交互作用使用HapSTAT软件分析。
上海子宫内膜癌随访调查(Shanghai endometrial cancer follow-up survey,SECFS)以1997-2003年上海市区30-69岁所有新发子宫内膜癌病例共1,454例为研究对象。2007年1-3月期间对其中参加SECS的1,204例病例进行跟踪随访,收集确诊后维生素补充剂的使用和疾病结局等信息,共1,032例病例或家属接受面访,完成了随访表的填写。2007年4月,将所有1,454例病例的个人信息与上海市疾病预防和控制中心死因登记数据库进行记录联动查询,以核查和补充病例的死亡日期及死亡原因等信息。子宫内膜癌的五年生存率使用Kaplan-Meier方法计算,Log-rank检验用于分析不同分组病例的生存率差异。Cox模型用于分析叶酸摄入以及相关基因多态对子宫内膜癌五年无瘤生存率的影响。
[结果]
病例对照研究中,膳食叶酸摄入水平与子宫内膜癌危险呈负向剂量反应关系(趋势检验P＜0.01)。与叶酸摄入量四分位最低组相比,四分位最高组的OR=0.6,95%CI:0.4-0.7。这种关联模式在从未摄入B族维生素补充剂的亚组中更显著(四分位最高组较最低组的OR=0.5,95%CI:0.4-0.7)。无论在全部对象或未摄入B族维生素补充剂的女性中,均未见核黄素、维生素B6、维生素B12和甲硫氨酸的摄入水平与子宫内膜癌有显著关联。摄入维生素补充剂对子宫内膜癌有显著保护作用。与从未服用者相比,服用任何维生素补充剂可降低30%子宫内膜癌的发病危险。而且随着使用频率和时间的增加,子宫内膜癌的危险呈下降趋势(趋势检验P＜0.01)。在部分只服用单种维生素补充剂的研究对象中,服用B族维生素补充剂相比于从未服用任何维生素补充剂者可显著降低子宫内膜癌的发病危险(OR=0.3,95%CI:0.1-0.8)。未见MTHFR 677C＞T、1298 A＞C和1793G＞A多态与子宫内膜癌的危险相关联。但是,在从未摄入B族维生素补充剂的人群中,MTHFR 1298C和1793A等位基因携带者摄入低水平叶酸时与子宫内膜癌的高发病危险关联更强,交互作用检验P值分别为0.08和0.03。进一步分析发现,危险最低组见于1298AC/CC基因型且摄入高叶酸和高核黄素的女性(OR=0.6,95%CI:0.3-1.0),而危险最高组见于有同样基因型但摄入高叶酸和低核黄素的女性(OR=2.2,95%CI:0.9-5.7),交互作用检验P值为0.04。MTHFR 1793A等位基因与叶酸和核黄素也有同样的关联模式(交互作用检验P=0.03)。所选TYMS基因及上、下游各5kb区域的11个htSNPs中,rs3819102多态与子宫内膜癌的发生有显著关联。与rs3819102TT基因型相比,CC基因型的OR=1.5,95%CI=1.0-2.2。这种关联在绝经后女性中更为明显(OR=1.7,95%CI=1.1-2.8)。TYMSblock 2 TTG单体型在显性和相加模式下对子宫内膜癌有一定的保护作用,且与绝经状况在子宫内膜癌的发生中有显著的交互作用,交互作用检验P值为0.0008。
病例随访研究中,截止至2006年12月31日,通过对1,454例子宫内膜癌病例平均5.2年的随访,观察到子宫内膜癌的总五年生存率为86.31%,五年无瘤生存率为90.78%。上海女性子宫内膜癌的临床预后因子包括病理类型、临床病理分期、分化程度、雌激素受体(Estrogen receptor,ER)和孕激素受体(Progesteronereceptor,PGR)状况等。年龄、文化程度和月经状况也与子宫内膜癌的预后有关。未发现膳食叶酸摄入水平的高低及MTHFR和TYMS基因多态对子宫内膜癌的总五年生存率及五年无瘤生存率有显著影响,但发现隐性遗传模式下,MTHFR ACC单体型显著增加子宫内膜癌死亡、复发或转移的风险,年龄调整风险比(Hazardratio,HR)为4.36,95%CI:1.07-17.76。进一步调整文化程度、是否绝经、病理类型、临床病理分期、分化程度、ER和PGR状况、化疗和放疗等预后因子后关联加强(HR=7.95,95%CI:1.78-35.49)。确诊后维生素补充剂使用者的子宫内膜癌无瘤生存率显著高于从未使用者,但该结果可能因存活偏倚所致。
[结论]
膳食叶酸摄入可能降低子宫内膜癌的发病危险,尤其在未服用B族维生素补充剂的人群中,但对子宫内膜癌的预后无显著影响;维生素补充剂的使用可显著降低子宫内膜癌的发病危险,且不增加子宫内膜癌的死亡风险;MTHFR基因多态在子宫内膜癌的发生和预后中无显著主效应,但可能修饰叶酸与子宫内膜癌发生的负向关联;MTHFR单体型可能与子宫内膜癌的预后有关;TYMSrs3819102变异等位基因增加子宫内膜癌的发病危险,但与预后无直接关联;TYMS单体型在子宫内膜癌发生中存在主效应,并与绝经状况有交互作用。
[BACKGROUND]
Endometrial cancer,one of the most common gynecologic malignant tumors, usually occurs in the middle and elderly aged women.Reducing incidence and mortality of endometrial cancer,thus,has significant public health implication in women.
Due to the important role of folate in production of nucleuids,the nutrient may have duel effect in carcinogenesis and progression of endometrial cancer,namely,high folate intake may decrease the risk of endometrial cancer by preventing the mutation of normal cells,but may stimulate the growth of pre-cancerous lesions or existing tumors.
5,10-methylenetetrahydrofolate reductase(MTHFR) and thymidylate synthase (TYMS) are key enzymes in folate metabolism.Activities of the two enzymes have been suggested to affect serum levels of folic acid and homocysteine and predispose individuals to cancer susceptibility and chemotherapy sensitivity.Therefore,genetic variants in MTHFR and TYMS genes,which may alter the activities of MTHFR and TYMS,may be involved in the etiology and progression of endometrial cancer.
[OBJECTIVES]
To evaluate the effect of folate intake and polymorphisms of folate metabolic enzyme genes in the development and progression of endometrial cancer among Chinese women in Shanghai.Specifically,
1.To investigate the independent and joint effects of dietary folate intake and genetic polymorphisms of MTHFR and TYMS genes on endometrial cancer risk in a population-based case-control study-the Shanghai Endometrial Cancer Study(SECS).
2.To evaluate the role of dietary folate intake,vitamin supplement use and polymorphisms of MTHFR and TYMS genes in the progression of endometrial cancer by using data collected in the Shanghai Endometrial Cancer Follow-up Survey (SECFS).
[METHODS]
During 1997 to 2003,1,204 newly diagnosed endometrial cancer cases and 1,212 controls were recruited from women between the ages of 30 and 69 in urban Shanghai, China.Dietary intakes of folate and other methyl-related nutrients,including riboflavin (vitamin B2),vitamin B6,vitamin B12,and methionine,were derived from a validated food frequency questionnaire(FFQ).Use of vitamin supplement was also obtained through in-person interview using a structured questionnaire.Genotyping was performed on 1,041 cases and 1,030 controls for MTHFR 677C＞T(rs1801133), 1298A＞C(rs1801131) and 1793G＞A(rs2274976) and on 1,037 cases and 1,018 controls for htSNPs located in the TYMS gene or within the 5 kb region flanking the gene(rs502396,rs2244500,rs3786362,rs2853532,rs3744962,rs11081251,rs9948583, rs3819102,rs10502289,rs2298583 and rs2298581).Haplotype estimation of the SNPs was performed using Phase software.Odds ratios(ORs) and 95%confidence intervals (CIs) were calculated to evaluate associations of nutrients and genotypes with endometrial cancer.Associations of haplotypes with the cancer and possible interactions between haplotypes and environmental exposure factors in endometrial cancer were analyzed using HapSTAT software.
1,454 endometrial cancer patients were followed-up with a combination of active survey and record linkage to the death certificates kept by the Vital Statistics Unit of the Shanghai Center for Disease Control and Prevention.Of the 1,204 patients included in the original study,1,032(85.7%) were successfully contacted from January to March, 2007 and information on vitamin supplement use and outcome of these patients was obtained.In April 2007,a record linkage with Shanghai Resident Vital Registry was operated for all 1,454 endometrial cancer cases in order to obtain or confirm the information of date of death and cause of death.The Kaplan-Meier method was used to compute 5-year survival rates and the log-rank test was applied to test the differences in survival across different groups.The multivariate Cox proportional hazards regression model was applied to evaluate the effect of dietary folate intake,vitamin supplement use,MTHFR or TYMS genotypes and haplotypes on overall survival and disease-free survival with adjustment for age and known prognostic factors for endometrial cancer.
[RESULTS]
In SECS,a significant inverse association between dietary folate intake and endometrial cancer risk was observed among all subjects and non-B vitamin supplement users.The greatest reduction in endometrial cancer risk was observed among non-B vitamin supplement users in the highest quartile of dietary folate intake (OR=0.5,95%CI:0.4-0.7) as compared with those in the lowest quartile.Dietary intake of folate cofactors(methionine,riboflavin,vitamin B6,and vitamin B12) was not related to the risk of endometrial cancer.Use of any vitamin supplement decreased 30%risk of endometrial cancer,and the risk decreased with increasing dose and period of use(P for trend＜0.01).Compared to non-supplement users,use of only B vitamins was inversely associated with the risk of endometrial cancer(OR=0.3,95%CI:0.1-0.8). No association was observed between endometrial cancer and the MTHFR 677C＞T, 1298 A＞C,and 1793G＞A polymorphisms.Among non- B vitamin supplement users, however,the 1298C and the 1793A alleles were associated with a lower risk of endometrial cancer among women with high dietary folate intake,but related to a higher risk among those with low dietary folate intake(P for interactions were 0.08 and 0.03,respectively).Further analysis observed a lowest risk(OR=0.6,95%CI:0.4-1.1) among women with the 1298C allele and highest intakes of both folate and riboflavin and a highest risk(OR=2.2,95%CI:0.9-5.7) among 1298C allele carriers with highest intake of folate but lowest intake of riboflavin(P for interaction=0.04).A similar association was observed for the 1793A allele(P for interaction=0.03).Of eleven TYMS htSNPs identified,polymorphism of rs3819102 in the 3'flanking region of the TYMS gene was associated with the risk of endometrial cancer.Compared with the TT genotype at SNP rs3819102,genotype CC was associated with increased risk of endometrial cancer(OR=1.5,95%CI=1.0-2.2),particularly among postmenopausal women(OR=1.7,95%CI=1.1-2.8).Haplotype TTG at block 2 of TYMS gene,which included three htSNPs in the 3' flanking region,rs10502289,rs2298583 and rs2298581, was inversely associated with the risk of endometrial cancer under dominant(OR=0.8, 95%CI=0.6-1.0) and additive(OR=0.8,95%CI=0.7-1.0) but not recessive(OR=1.2, 95%CI=0.4-3.9) models.A significant multiplicative interaction was found for TYMS haplotypes at block 2 with postmenopausal status in endometrial cancer risk(P for interaction=0.0008).
In SECFS,the median follow-up time for 1,454 endometrial cancer cases was 5.2 years after cancer diagnosis by the end of 2006.Overall 5-year survival rate of 86.31% and 5-year disease-fiee survival rate of 90.78%were observed for the case cohort.The important clinically prognostic factors of endometrial cancer in this population included pathological type and stage,cancer cell differentiation and status of estrogen receptor (ER) and progesterone receptor(PGR).Age,education level and postmenopausal status were also associated with endometrial cancer survival.While no association was observed for folate intake,MTHFR and TYMS genetic polymorphisms with endometrial cancer survival,a significant increased risk of endometrial cancer death was observed for MTHFR haplotype ACC under recessive model,with age-adjusted hazard ratio(HR) being 4.36(95%CI:1.07-17.76).Further adjusting for the known prognostic factors mentioned above strengthened the association(HR=7.95,95%CI:1.78-35.49).Use of any vitamin supplement after diagnosis was observed to decrease the risk of endometrial cancer death.The protective effect,however,was due to survival bias.
[CONCLUSION]
Our findings suggest that dietary folate intake may decrease the risk of endometrial cancer,but has no effect on endometrial cancer survival;use of vitamin supplement decreases the risk of endometrial cancer and is not detrimental to the prognosis of the disease;while MTHFR genetic variants have no main effect in the development and progression of endometrial cancer,MTHFR polymorphisms modify the effect of folate intake on the risk of endometrial cancer and MTHFR haplotypes are associated with endometrial cancer survival;TYMS polymorphisms and haplotypes may affect or modify the risk of endometrial cancer.
子宫内膜癌是一种常见的妇科恶性肿瘤,好发于中老年女性。降低子宫内膜癌的发生和死亡对提高女性健康具有重要意义。叶酸因其在核苷酸合成中的重要作用,可能在子宫内膜癌形成的不同阶段产生不同的效应:肿瘤形成前,高水平的叶酸可防止正常细胞发生突变,降低肿瘤的发生危险,而对已发生的癌前病变或肿瘤生长可能有促进作用。亚甲基四氢叶酸还原酶(5,10-methylenetetrahydrofolatereductase,MTHFR)和胸苷合酶(Thymidylate synthase,TYMS)是叶酸代谢通路中的关键酶,其活性可影响体内叶酸和同型半胱氨酸水平,造成个体间肿瘤易感性和对化疗药物敏感性的差异。MTHFR和TYMS基因多态决定了这些酶活性的高低,因而可能在子宫内膜癌的发生和预后中起一定的作用。
[目的]
研究叶酸及其代谢酶基因多态在子宫内膜癌发生和预后中的作用。具体而言:
1.利用以人群为基础的病例对照研究收集的现场调查资料和生物标本,分析膳食来源的叶酸等甲基营养素及维生素补充剂与子宫内膜癌的关联,并分析MTHFR和TYMS基因多态及单体型与子宫内膜癌的关联及修饰效应。
2.利用子宫内膜癌病例随访资料,评估膳食叶酸、维生素补充剂、MTHFR和TYMS基因多态及单体型对子宫内膜癌生存率的影响。
[方法]
上海子宫内膜癌研究(Shanghai endometrial cancer study,SECS)是一项以人群为基础的病例对照研究,共收集1997年1月-2003年12月确诊、年龄为30-69岁、有上海市区常住户口的子宫内膜癌新发病例1,454例,其中1,204例完成了问卷调查。人群对照为1,212例与病例进行年龄频数配对的有上海市区常住户口的健康女性。膳食叶酸、核黄素(维生素B2)、维生素B6、维生素B12和甲硫氨酸的摄入水平根据膳食频率调查表数据计算,维生素补充剂的使用亦通过问卷调查而得。共检测了1,041例病例和1,030例对照MTHFR 677C＞T(rs1801133),1298A＞C(rs1801131)和1793 G＞A(rs2274976)三个多态位点的基因型以及1,037例病例和1,018例对照TYMS基因及其上、下游各5kb区域11个单体型标签单核苷酸多态(Haplotype tagging single nucleotide polymorphisms,htSNPs)。单体型的估计使用Phase软件。比值比(Odds ratio,OR)和95%可信区间(Confidence interval,CI)的计算采用Logistic回归模型,用于估计营养素和基因多态与子宫内膜癌的关联。单体型与子宫内膜癌的关联及其与环境因素的交互作用使用HapSTAT软件分析。
上海子宫内膜癌随访调查(Shanghai endometrial cancer follow-up survey,SECFS)以1997-2003年上海市区30-69岁所有新发子宫内膜癌病例共1,454例为研究对象。2007年1-3月期间对其中参加SECS的1,204例病例进行跟踪随访,收集确诊后维生素补充剂的使用和疾病结局等信息,共1,032例病例或家属接受面访,完成了随访表的填写。2007年4月,将所有1,454例病例的个人信息与上海市疾病预防和控制中心死因登记数据库进行记录联动查询,以核查和补充病例的死亡日期及死亡原因等信息。子宫内膜癌的五年生存率使用Kaplan-Meier方法计算,Log-rank检验用于分析不同分组病例的生存率差异。Cox模型用于分析叶酸摄入以及相关基因多态对子宫内膜癌五年无瘤生存率的影响。
[结果]
病例对照研究中,膳食叶酸摄入水平与子宫内膜癌危险呈负向剂量反应关系(趋势检验P＜0.01)。与叶酸摄入量四分位最低组相比,四分位最高组的OR=0.6,95%CI:0.4-0.7。这种关联模式在从未摄入B族维生素补充剂的亚组中更显著(四分位最高组较最低组的OR=0.5,95%CI:0.4-0.7)。无论在全部对象或未摄入B族维生素补充剂的女性中,均未见核黄素、维生素B6、维生素B12和甲硫氨酸的摄入水平与子宫内膜癌有显著关联。摄入维生素补充剂对子宫内膜癌有显著保护作用。与从未服用者相比,服用任何维生素补充剂可降低30%子宫内膜癌的发病危险。而且随着使用频率和时间的增加,子宫内膜癌的危险呈下降趋势(趋势检验P＜0.01)。在部分只服用单种维生素补充剂的研究对象中,服用B族维生素补充剂相比于从未服用任何维生素补充剂者可显著降低子宫内膜癌的发病危险(OR=0.3,95%CI:0.1-0.8)。未见MTHFR 677C＞T、1298 A＞C和1793G＞A多态与子宫内膜癌的危险相关联。但是,在从未摄入B族维生素补充剂的人群中,MTHFR 1298C和1793A等位基因携带者摄入低水平叶酸时与子宫内膜癌的高发病危险关联更强,交互作用检验P值分别为0.08和0.03。进一步分析发现,危险最低组见于1298AC/CC基因型且摄入高叶酸和高核黄素的女性(OR=0.6,95%CI:0.3-1.0),而危险最高组见于有同样基因型但摄入高叶酸和低核黄素的女性(OR=2.2,95%CI:0.9-5.7),交互作用检验P值为0.04。MTHFR 1793A等位基因与叶酸和核黄素也有同样的关联模式(交互作用检验P=0.03)。所选TYMS基因及上、下游各5kb区域的11个htSNPs中,rs3819102多态与子宫内膜癌的发生有显著关联。与rs3819102TT基因型相比,CC基因型的OR=1.5,95%CI=1.0-2.2。这种关联在绝经后女性中更为明显(OR=1.7,95%CI=1.1-2.8)。TYMSblock 2 TTG单体型在显性和相加模式下对子宫内膜癌有一定的保护作用,且与绝经状况在子宫内膜癌的发生中有显著的交互作用,交互作用检验P值为0.0008。
病例随访研究中,截止至2006年12月31日,通过对1,454例子宫内膜癌病例平均5.2年的随访,观察到子宫内膜癌的总五年生存率为86.31%,五年无瘤生存率为90.78%。上海女性子宫内膜癌的临床预后因子包括病理类型、临床病理分期、分化程度、雌激素受体(Estrogen receptor,ER)和孕激素受体(Progesteronereceptor,PGR)状况等。年龄、文化程度和月经状况也与子宫内膜癌的预后有关。未发现膳食叶酸摄入水平的高低及MTHFR和TYMS基因多态对子宫内膜癌的总五年生存率及五年无瘤生存率有显著影响,但发现隐性遗传模式下,MTHFR ACC单体型显著增加子宫内膜癌死亡、复发或转移的风险,年龄调整风险比(Hazardratio,HR)为4.36,95%CI:1.07-17.76。进一步调整文化程度、是否绝经、病理类型、临床病理分期、分化程度、ER和PGR状况、化疗和放疗等预后因子后关联加强(HR=7.95,95%CI:1.78-35.49)。确诊后维生素补充剂使用者的子宫内膜癌无瘤生存率显著高于从未使用者,但该结果可能因存活偏倚所致。
[结论]
膳食叶酸摄入可能降低子宫内膜癌的发病危险,尤其在未服用B族维生素补充剂的人群中,但对子宫内膜癌的预后无显著影响;维生素补充剂的使用可显著降低子宫内膜癌的发病危险,且不增加子宫内膜癌的死亡风险;MTHFR基因多态在子宫内膜癌的发生和预后中无显著主效应,但可能修饰叶酸与子宫内膜癌发生的负向关联;MTHFR单体型可能与子宫内膜癌的预后有关;TYMSrs3819102变异等位基因增加子宫内膜癌的发病危险,但与预后无直接关联;TYMS单体型在子宫内膜癌发生中存在主效应,并与绝经状况有交互作用。
[BACKGROUND]
Endometrial cancer,one of the most common gynecologic malignant tumors, usually occurs in the middle and elderly aged women.Reducing incidence and mortality of endometrial cancer,thus,has significant public health implication in women.
Due to the important role of folate in production of nucleuids,the nutrient may have duel effect in carcinogenesis and progression of endometrial cancer,namely,high folate intake may decrease the risk of endometrial cancer by preventing the mutation of normal cells,but may stimulate the growth of pre-cancerous lesions or existing tumors.
5,10-methylenetetrahydrofolate reductase(MTHFR) and thymidylate synthase (TYMS) are key enzymes in folate metabolism.Activities of the two enzymes have been suggested to affect serum levels of folic acid and homocysteine and predispose individuals to cancer susceptibility and chemotherapy sensitivity.Therefore,genetic variants in MTHFR and TYMS genes,which may alter the activities of MTHFR and TYMS,may be involved in the etiology and progression of endometrial cancer.
[OBJECTIVES]
To evaluate the effect of folate intake and polymorphisms of folate metabolic enzyme genes in the development and progression of endometrial cancer among Chinese women in Shanghai.Specifically,
1.To investigate the independent and joint effects of dietary folate intake and genetic polymorphisms of MTHFR and TYMS genes on endometrial cancer risk in a population-based case-control study-the Shanghai Endometrial Cancer Study(SECS).
2.To evaluate the role of dietary folate intake,vitamin supplement use and polymorphisms of MTHFR and TYMS genes in the progression of endometrial cancer by using data collected in the Shanghai Endometrial Cancer Follow-up Survey (SECFS).
[METHODS]
During 1997 to 2003,1,204 newly diagnosed endometrial cancer cases and 1,212 controls were recruited from women between the ages of 30 and 69 in urban Shanghai, China.Dietary intakes of folate and other methyl-related nutrients,including riboflavin (vitamin B2),vitamin B6,vitamin B12,and methionine,were derived from a validated food frequency questionnaire(FFQ).Use of vitamin supplement was also obtained through in-person interview using a structured questionnaire.Genotyping was performed on 1,041 cases and 1,030 controls for MTHFR 677C＞T(rs1801133), 1298A＞C(rs1801131) and 1793G＞A(rs2274976) and on 1,037 cases and 1,018 controls for htSNPs located in the TYMS gene or within the 5 kb region flanking the gene(rs502396,rs2244500,rs3786362,rs2853532,rs3744962,rs11081251,rs9948583, rs3819102,rs10502289,rs2298583 and rs2298581).Haplotype estimation of the SNPs was performed using Phase software.Odds ratios(ORs) and 95%confidence intervals (CIs) were calculated to evaluate associations of nutrients and genotypes with endometrial cancer.Associations of haplotypes with the cancer and possible interactions between haplotypes and environmental exposure factors in endometrial cancer were analyzed using HapSTAT software.
1,454 endometrial cancer patients were followed-up with a combination of active survey and record linkage to the death certificates kept by the Vital Statistics Unit of the Shanghai Center for Disease Control and Prevention.Of the 1,204 patients included in the original study,1,032(85.7%) were successfully contacted from January to March, 2007 and information on vitamin supplement use and outcome of these patients was obtained.In April 2007,a record linkage with Shanghai Resident Vital Registry was operated for all 1,454 endometrial cancer cases in order to obtain or confirm the information of date of death and cause of death.The Kaplan-Meier method was used to compute 5-year survival rates and the log-rank test was applied to test the differences in survival across different groups.The multivariate Cox proportional hazards regression model was applied to evaluate the effect of dietary folate intake,vitamin supplement use,MTHFR or TYMS genotypes and haplotypes on overall survival and disease-free survival with adjustment for age and known prognostic factors for endometrial cancer.
[RESULTS]
In SECS,a significant inverse association between dietary folate intake and endometrial cancer risk was observed among all subjects and non-B vitamin supplement users.The greatest reduction in endometrial cancer risk was observed among non-B vitamin supplement users in the highest quartile of dietary folate intake (OR=0.5,95%CI:0.4-0.7) as compared with those in the lowest quartile.Dietary intake of folate cofactors(methionine,riboflavin,vitamin B6,and vitamin B12) was not related to the risk of endometrial cancer.Use of any vitamin supplement decreased 30%risk of endometrial cancer,and the risk decreased with increasing dose and period of use(P for trend＜0.01).Compared to non-supplement users,use of only B vitamins was inversely associated with the risk of endometrial cancer(OR=0.3,95%CI:0.1-0.8). No association was observed between endometrial cancer and the MTHFR 677C＞T, 1298 A＞C,and 1793G＞A polymorphisms.Among non- B vitamin supplement users, however,the 1298C and the 1793A alleles were associated with a lower risk of endometrial cancer among women with high dietary folate intake,but related to a higher risk among those with low dietary folate intake(P for interactions were 0.08 and 0.03,respectively).Further analysis observed a lowest risk(OR=0.6,95%CI:0.4-1.1) among women with the 1298C allele and highest intakes of both folate and riboflavin and a highest risk(OR=2.2,95%CI:0.9-5.7) among 1298C allele carriers with highest intake of folate but lowest intake of riboflavin(P for interaction=0.04).A similar association was observed for the 1793A allele(P for interaction=0.03).Of eleven TYMS htSNPs identified,polymorphism of rs3819102 in the 3'flanking region of the TYMS gene was associated with the risk of endometrial cancer.Compared with the TT genotype at SNP rs3819102,genotype CC was associated with increased risk of endometrial cancer(OR=1.5,95%CI=1.0-2.2),particularly among postmenopausal women(OR=1.7,95%CI=1.1-2.8).Haplotype TTG at block 2 of TYMS gene,which included three htSNPs in the 3' flanking region,rs10502289,rs2298583 and rs2298581, was inversely associated with the risk of endometrial cancer under dominant(OR=0.8, 95%CI=0.6-1.0) and additive(OR=0.8,95%CI=0.7-1.0) but not recessive(OR=1.2, 95%CI=0.4-3.9) models.A significant multiplicative interaction was found for TYMS haplotypes at block 2 with postmenopausal status in endometrial cancer risk(P for interaction=0.0008).
In SECFS,the median follow-up time for 1,454 endometrial cancer cases was 5.2 years after cancer diagnosis by the end of 2006.Overall 5-year survival rate of 86.31% and 5-year disease-fiee survival rate of 90.78%were observed for the case cohort.The important clinically prognostic factors of endometrial cancer in this population included pathological type and stage,cancer cell differentiation and status of estrogen receptor (ER) and progesterone receptor(PGR).Age,education level and postmenopausal status were also associated with endometrial cancer survival.While no association was observed for folate intake,MTHFR and TYMS genetic polymorphisms with endometrial cancer survival,a significant increased risk of endometrial cancer death was observed for MTHFR haplotype ACC under recessive model,with age-adjusted hazard ratio(HR) being 4.36(95%CI:1.07-17.76).Further adjusting for the known prognostic factors mentioned above strengthened the association(HR=7.95,95%CI:1.78-35.49).Use of any vitamin supplement after diagnosis was observed to decrease the risk of endometrial cancer death.The protective effect,however,was due to survival bias.
[CONCLUSION]
Our findings suggest that dietary folate intake may decrease the risk of endometrial cancer,but has no effect on endometrial cancer survival;use of vitamin supplement decreases the risk of endometrial cancer and is not detrimental to the prognosis of the disease;while MTHFR genetic variants have no main effect in the development and progression of endometrial cancer,MTHFR polymorphisms modify the effect of folate intake on the risk of endometrial cancer and MTHFR haplotypes are associated with endometrial cancer survival;TYMS polymorphisms and haplotypes may affect or modify the risk of endometrial cancer.
引文
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