广西地区人群DNA修复基因XPF基因RS#744154多态性与胃腺癌发病风险及临床病理特征的关联性研究
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摘要
背景和目的胃腺癌在广西是一种较为常见的恶性肿瘤,最近的研究显示其发病可能与人体的DNA损伤修复能力相关,而DNA修复基因着色性干皮病基因F(Xeroderma pigmentosum group F,XPF)为核苷酸切除修复(nucleotide excision repair, NER)途径中至关重要的成分,已有研究表明XPF基因富含多个单核苷酸多态性(Single nucleotide polymorphism,SNP)位点,XPF基因多态性可能是引起疾病易感性的分子基础。目前已有报道XPF基因RS#744154多态性可能与一些恶性肿瘤如膀胱癌、乳腺癌、肺癌等有关,但该多态性是否影响广西人群胃腺癌的发病风险至今国内外未见报道,故我们设计并研究了该多态性与胃腺癌发病风险的关系,与此同时,通过观察不同基因型的胃腺癌的临床病理特征和幽门螺杆菌感染状况,进一步探讨和分析XPF基因多态性在胃腺癌发生、发展各个环节中所起的作用。
方法以广西地区人群为研究对象,胃腺癌疾病组与对照组按频数匹配方式,采用以医院为基础的病例-对照研究方式进行研究,其中疾病组99例,均为来自广西医科大学第一附属医院的经外科手术切除病理确诊的胃腺癌住院病人,每例患者分别采集外周血提取基因组DNA,以及收集手术标本进行临床病理特征和幽门螺杆菌检查;对照组(共284例)为来自同一医院的志愿者,其本人及家属均无肿瘤史;所有研究对象均为广西地区人群。两组在年龄、性别及民族等混杂因素进行频数匹配。采用TaqMan-PCR方法对XPF基因RS#744154 C357G基因型进行检测。采用以χ2检验进行哈代-温伯格平衡(Hardy-Weinberg equilibrium, HWE)分析,用χ2检验检验组间分布的差异,以非条件Logistic回归分析计算相对风险度的比值比(odds ratio,OR)和95%可信区间(confidence interval,CI),评价XPF基因多态性与胃腺癌发生风险及临床病理特征的关联性。
结果(1)XPF基因RS#744154多态性在研究对象中的分布符合Hard-Weinberg遗传平衡定律(P > 0.05)。
(2)XPF基因三种基因型(即XPF-GG、-GC和-CC)在疾病组与对照组中的分布差异具有统计学意义(P < 0.05)。
(3)XPF基因RS#744154 C357G多态性与胃腺癌的发病有关,以XPF-GG基因型为参照,携带XPF-CC基因型的个体患胃腺癌的风险增加2.60倍(95%CI:1.24-5.43)。
(4)在男性人群中,带有风险基因型(即XPF-GC/CC)的男性患胃腺癌风险是不带者的2.25倍(95%CI = 1.27-3.98,P < 0.05)。
(5)在民族分层分析中,带有风险基因型(即XPF-GC/CC)的汉族者患胃腺癌风险是不带者的1.95倍(95%CI = 1.02-3.72,P < 0.05)。
(6)在年龄分层分析中,带有风险基因型(即XPF-GC/CC)的高年龄者(> 54岁)患胃腺癌风险是不带者的3.00倍(95%CI = 1.45-6.20,P < 0.01)。
(7)XPF-GG、GC/CC基因型在肿瘤直径≤5 cm和> 5 cm患者中的频率分别为43.75%、71.64%和56.25%、28.36%,二者差异有统计学意义(χ2 = 7.198,P = 0.007,OR = 3.69)。
(8)XPF基因多态性对胃腺癌患者肿瘤发生部位、浸润深度、病理分级、Laurén分类、淋巴结转移和TNM分期均无影响。
(9)HP感染在不同基因型胃腺癌患者中分布的差异无统计学意义。
结论XPF基因RS#744154多态性与广西人群胃腺癌发病风险相关,这种风险在男性及高年龄者中更为明显。癌旁胃黏膜HP感染与XPF基因RS#744154多态性之间无显著的相关性,同时该多态性也与影响胃腺癌预后的临床病理特征无相关性。XPF功能下降所引起DNA损伤修复障碍可能主要影响胃癌的启动阶段,而非肿瘤浸润和转移相关基因。其具体的靶基因以及其与环境致癌因素的相互作用方式等,都值得进一步深入研究。
Objective Recent studies have demonstrated that gastric adenocarcinoma (GAC), a kind of common malignancy in Guangxi, is possibly related to DNA damage repair ability (DRC), while DNA repair gene XPF is very important ingredient in the nucleotide excision repair (NER) and the polymorphism of this gene (RS#744154) has been reported to relate to the risk of some malignant tumors such as breast cancer, the carcinoma of urinary bladder, lung cancer, and so on. However, it has not been elucidated whether XPF RS#744154 polymorphism modifies the risk of GAC among Guangxi population. Here, we specifically conducted a hospital-based case-control study to investigate the relation between this polymorphism and GAC risk, at the same time, by observing these polymorphism sites in the clinico-pathologic feature of gastric adenocarcinoma and the status of Helicobactor Pyiori( HP ) infection, for further analyze the role of XPF gene polymorphism in pathogenesis of gastric adenocarcinoma.
Methods This study, including 99 patients with GAC diagnosed by pathological examination , collecte the genomic DNA from peripheral blood for each patients, and examine the clinico-pathologic feature and HP status,284 controls without any evidence of tumors or family history of tumors, is a hospital-based case-control study. All subjects are Guangxiese. To control possible confounders, cases were frequently matched to controls based on age, gender, and race. XPF RS#744154 polymorphism was testified using TaqMan-PCR method. Hardy-Weinberg analysis was performed via comparing the observed and expected genotype frequencies by using Chi-square test. The distribution of the intergroup was analyzed by using Chi-square test. The odds ratio(OR) and relative 95% confidence interval(CI) were calculated by using anunconditional logistic regression model as appraise risk between the DNA repair gene XPF RS#744154 polymorphism on risk and clinico-pathologic feature of GAC.
Results (1)XPF RS#744154 polymorphism among the subjects did not significantly deviate from the expected Hardy-Weinberg equilibrium(p > 0.05).
(2)The distribution of three XPF genotypes (namely XPF-GG, -GC, and -CC) among cases was significantly dissimilar to among controls (P < 0.05).
(3)These results suggest that XPF RS#744154 polymorphism might associate with the risk of GAC. Compared with GG genotype, CC can increase the risk of GAC (corresponding OR was 2.60 for XPF-CC).
(4)Male individuals having genotypes with GC/CC, compared with those without risk genotypes, would face significantly higher risk of GAC(OR = 2.25,95%Cl = 1.27-3.98,P < 0.05).
(5)The Han Chinese individuals having genotypes with GC/CC, compared with those without risk genotypes, would face significantly higher risk of the gastric adenocarcinoma (OR = 1.95,95%Cl = 1.02-3.72,P < 0.05).
(6)Elders individuals having genotypes with GC/CC, compared with those without risk genotypes, would face significantly higher risk of the gastric adenocarcinoma (OR = 3.00,95%Cl = 1.45-6.20,P < 0.05)。
(7)The frequencies of the XPF-GG, GC/CC genotypes were 43.75%, 71.64% in patients with tumor diameter(≤5 cm),and 56.25%、28.36% in patients with tumor diameter(> 5 cm), respectively. The difference was statistical significance(χ2 = 7.198,P = 0.007, OR = 3.69).
(8)No relationship was found between XPF gene polymorphisms and tumor sites, pathology grade, Laurén classification,, lymph nodemetastasis, TNM stage.
(9) The distribution of HP infection among three XPF genotypes (namely XPF-GG, -GC, and -CC) was not significantly dissimilar in GAC(P > 0.05).
Conclusions These results suggest that XPF RS#744154 polymorphism might associate with the risk of gastric adenocarcinoma among Guangxi population, especially among males and elders. The distribution of HP infection and the XPF gene RS#744154 polymorphism was not significantly dissimilar to among juxtacacerous, at the same time , XPF gene polymorphism also was not significantly dissimilar with the clinico-pathologic feature. XPF function decline caused the DNA damage repair disorders may mainly affect start-up phase of gastric cancer, rather than tumor invasion and metastasis-associated genes. Its specific target genes and interaction modes with environment carcinogenic factors, etc, all deserve further study.
方法以广西地区人群为研究对象,胃腺癌疾病组与对照组按频数匹配方式,采用以医院为基础的病例-对照研究方式进行研究,其中疾病组99例,均为来自广西医科大学第一附属医院的经外科手术切除病理确诊的胃腺癌住院病人,每例患者分别采集外周血提取基因组DNA,以及收集手术标本进行临床病理特征和幽门螺杆菌检查;对照组(共284例)为来自同一医院的志愿者,其本人及家属均无肿瘤史;所有研究对象均为广西地区人群。两组在年龄、性别及民族等混杂因素进行频数匹配。采用TaqMan-PCR方法对XPF基因RS#744154 C357G基因型进行检测。采用以χ2检验进行哈代-温伯格平衡(Hardy-Weinberg equilibrium, HWE)分析,用χ2检验检验组间分布的差异,以非条件Logistic回归分析计算相对风险度的比值比(odds ratio,OR)和95%可信区间(confidence interval,CI),评价XPF基因多态性与胃腺癌发生风险及临床病理特征的关联性。
结果(1)XPF基因RS#744154多态性在研究对象中的分布符合Hard-Weinberg遗传平衡定律(P > 0.05)。
(2)XPF基因三种基因型(即XPF-GG、-GC和-CC)在疾病组与对照组中的分布差异具有统计学意义(P < 0.05)。
(3)XPF基因RS#744154 C357G多态性与胃腺癌的发病有关,以XPF-GG基因型为参照,携带XPF-CC基因型的个体患胃腺癌的风险增加2.60倍(95%CI:1.24-5.43)。
(4)在男性人群中,带有风险基因型(即XPF-GC/CC)的男性患胃腺癌风险是不带者的2.25倍(95%CI = 1.27-3.98,P < 0.05)。
(5)在民族分层分析中,带有风险基因型(即XPF-GC/CC)的汉族者患胃腺癌风险是不带者的1.95倍(95%CI = 1.02-3.72,P < 0.05)。
(6)在年龄分层分析中,带有风险基因型(即XPF-GC/CC)的高年龄者(> 54岁)患胃腺癌风险是不带者的3.00倍(95%CI = 1.45-6.20,P < 0.01)。
(7)XPF-GG、GC/CC基因型在肿瘤直径≤5 cm和> 5 cm患者中的频率分别为43.75%、71.64%和56.25%、28.36%,二者差异有统计学意义(χ2 = 7.198,P = 0.007,OR = 3.69)。
(8)XPF基因多态性对胃腺癌患者肿瘤发生部位、浸润深度、病理分级、Laurén分类、淋巴结转移和TNM分期均无影响。
(9)HP感染在不同基因型胃腺癌患者中分布的差异无统计学意义。
结论XPF基因RS#744154多态性与广西人群胃腺癌发病风险相关,这种风险在男性及高年龄者中更为明显。癌旁胃黏膜HP感染与XPF基因RS#744154多态性之间无显著的相关性,同时该多态性也与影响胃腺癌预后的临床病理特征无相关性。XPF功能下降所引起DNA损伤修复障碍可能主要影响胃癌的启动阶段,而非肿瘤浸润和转移相关基因。其具体的靶基因以及其与环境致癌因素的相互作用方式等,都值得进一步深入研究。
Objective Recent studies have demonstrated that gastric adenocarcinoma (GAC), a kind of common malignancy in Guangxi, is possibly related to DNA damage repair ability (DRC), while DNA repair gene XPF is very important ingredient in the nucleotide excision repair (NER) and the polymorphism of this gene (RS#744154) has been reported to relate to the risk of some malignant tumors such as breast cancer, the carcinoma of urinary bladder, lung cancer, and so on. However, it has not been elucidated whether XPF RS#744154 polymorphism modifies the risk of GAC among Guangxi population. Here, we specifically conducted a hospital-based case-control study to investigate the relation between this polymorphism and GAC risk, at the same time, by observing these polymorphism sites in the clinico-pathologic feature of gastric adenocarcinoma and the status of Helicobactor Pyiori( HP ) infection, for further analyze the role of XPF gene polymorphism in pathogenesis of gastric adenocarcinoma.
Methods This study, including 99 patients with GAC diagnosed by pathological examination , collecte the genomic DNA from peripheral blood for each patients, and examine the clinico-pathologic feature and HP status,284 controls without any evidence of tumors or family history of tumors, is a hospital-based case-control study. All subjects are Guangxiese. To control possible confounders, cases were frequently matched to controls based on age, gender, and race. XPF RS#744154 polymorphism was testified using TaqMan-PCR method. Hardy-Weinberg analysis was performed via comparing the observed and expected genotype frequencies by using Chi-square test. The distribution of the intergroup was analyzed by using Chi-square test. The odds ratio(OR) and relative 95% confidence interval(CI) were calculated by using anunconditional logistic regression model as appraise risk between the DNA repair gene XPF RS#744154 polymorphism on risk and clinico-pathologic feature of GAC.
Results (1)XPF RS#744154 polymorphism among the subjects did not significantly deviate from the expected Hardy-Weinberg equilibrium(p > 0.05).
(2)The distribution of three XPF genotypes (namely XPF-GG, -GC, and -CC) among cases was significantly dissimilar to among controls (P < 0.05).
(3)These results suggest that XPF RS#744154 polymorphism might associate with the risk of GAC. Compared with GG genotype, CC can increase the risk of GAC (corresponding OR was 2.60 for XPF-CC).
(4)Male individuals having genotypes with GC/CC, compared with those without risk genotypes, would face significantly higher risk of GAC(OR = 2.25,95%Cl = 1.27-3.98,P < 0.05).
(5)The Han Chinese individuals having genotypes with GC/CC, compared with those without risk genotypes, would face significantly higher risk of the gastric adenocarcinoma (OR = 1.95,95%Cl = 1.02-3.72,P < 0.05).
(6)Elders individuals having genotypes with GC/CC, compared with those without risk genotypes, would face significantly higher risk of the gastric adenocarcinoma (OR = 3.00,95%Cl = 1.45-6.20,P < 0.05)。
(7)The frequencies of the XPF-GG, GC/CC genotypes were 43.75%, 71.64% in patients with tumor diameter(≤5 cm),and 56.25%、28.36% in patients with tumor diameter(> 5 cm), respectively. The difference was statistical significance(χ2 = 7.198,P = 0.007, OR = 3.69).
(8)No relationship was found between XPF gene polymorphisms and tumor sites, pathology grade, Laurén classification,, lymph nodemetastasis, TNM stage.
(9) The distribution of HP infection among three XPF genotypes (namely XPF-GG, -GC, and -CC) was not significantly dissimilar in GAC(P > 0.05).
Conclusions These results suggest that XPF RS#744154 polymorphism might associate with the risk of gastric adenocarcinoma among Guangxi population, especially among males and elders. The distribution of HP infection and the XPF gene RS#744154 polymorphism was not significantly dissimilar to among juxtacacerous, at the same time , XPF gene polymorphism also was not significantly dissimilar with the clinico-pathologic feature. XPF function decline caused the DNA damage repair disorders may mainly affect start-up phase of gastric cancer, rather than tumor invasion and metastasis-associated genes. Its specific target genes and interaction modes with environment carcinogenic factors, etc, all deserve further study.
引文
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