【作者】 李芳；

【导师】 钟美佐；

【作者基本信息】 中南大学 ， 肿瘤学， 2012， 博士

【摘要】 背景：胃癌是世界第四大常见恶性肿瘤,居肿瘤相关死因的第二位。流行病学研究发现了胃癌的许多危险因素,如：幽门螺杆菌感染,纤维素摄入量少,吸烟等,但仅有少部分暴露于这些危险因素的人患病的事实表明胃癌的遗传易感性在胃癌发病中起至关重要的作用。研究报道前列腺干细胞抗原(prostate stem cell antigen, PSCA)、粘蛋白(mucin1, MUC1)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、Selenoprotein S(SEPS1)基因多态性与胃癌的发生相关,mothers against decapentaplegic homolog7(SMAD7)基因多态性与西方人群结肠癌的发生相关。目的：(1)分析300例湖南地区胃癌病例的临床及其病理类型资料,了解目前本地区胃癌发病的特征；(2)研究PSCA rs2294008、MUC1rs2070803、SMAD7rs12953717、TNF-αrs361525、SEPS1rs28665122单核苷酸多态性与湖南地区人群胃癌易感性的关系。方法：收集300例2011年6月-2011年11月中南大学湘雅医院、中南大学湘雅二医院、湖南省肿瘤医院病理确诊的胃癌病例和300例相同地区同期健康对照的血液标本,分析胃癌病例的临床及其病理类型资料。采用基质辅助激光解吸附电离-飞行时间质谱技术(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, MALDI-TOF-MS)对300例胃癌病例及300例健康对照者的血液标本进行基因分型,胃癌组与对照组之间年龄、性别及临床病理学特征的差异采用X2检验进行比较确定有无显著性意义。采用X2检验分析5个SNP位点基因型分布在胃癌组和对照组是否符合Hardy-Weinberg遗传平衡。采用非条件Logistic回归分析PSCA rs2294008、MUC1rs2070803、SMAD7rs12953717、TNF-ars361525、 SEPS1rs28665122胃癌组和对照组间等位基因和基因型频率差别及各基因型频率与胃癌的相关性,计算OR值(Odds ratio OR)和95%可信区间(95%Confidence interval,95%CI), OR值经性别和年龄校正,统计学分析通过SPSS13.0统计软件完成(SPSS, Chicago, IL), P<0.05为差异有统计学意义。结果：(1)本组胃癌的临床病理学特点为：在300例胃癌中,贲门癌79例,占全部胃癌的26.3%,非贲门癌221例,占73.7%。性别构成比：胃癌的男/女性别构成比为1.8/1,责门癌男/女构成比显著高于非贲门癌(2.7/1vs1.5/1,P=0.04)。年龄：平均年龄为52.2±11.8岁,贲门癌患者的平均年龄(51.0±12.2岁)与非贲门癌患者相近(52.5±11.4岁)。贲门癌组65岁以上患者所占的比例显著高于非贲门癌组(24.1%vs12.7%,P=0.020)。Lauren病理分型：本组胃癌以肠型为主,占70.3%,贲门癌患者肠型胃癌比例显著高于非责门胃癌(82.4%vs70.1%,P=0.035)。分化程度：本组胃癌病例以低分化为主,占69.6%,其中贲门癌低分化类型所占的比例显著低于非贲门胃癌(56.0%vs74.5%,P<0.001)。TNM分期：本组胃癌以中晚期为主,III、IV期患者占69.1%；贲门癌及非贲门癌两组患者TNM分期无统计学差别。与国内外研究结果相比较：本研究贲门癌占胃癌的比例与陕西、沈阳及葡萄牙、英国的研究结果接近(21.5%-29.5%),但高于韩国及日本(低于10%)；本研究在性别构成比及发病年龄等方面与这些地区的较为一致(2.7/1VS1.66-3.7/1,平均年龄51.0-63.0岁)：本研究与葡萄牙、英国的结果在Lauren病理分型上较一致,均以肠型为主。TNM分期均以中晚期(Ⅲ+Ⅳ)患者为主,显著高于沈阳、韩国和日本(62.1%vs41.3%-56.4%)。(2)PSCA rs2294008多态性与胃癌发病风险增加有关。与CC基因型相比,携带rs2294008TT、TC基因型显著增加胃癌发病风险,OR值分别为2.26(95%CI1.25-4.07,P=0.007)、1.72(95%CI1.23-2.42,P=0.002),进一步分析发现：携带TT及TC基因型者显著增加肠型和弥漫型胃癌的发病风险的作用一致。(3) MUC1rs2070803多态性与胃癌的遗传易感性有关：等位基因A对胃癌的发生有保护性作用。与GG基因型相比,携带rs2070803GA基因型显著降低胃癌发病风险,OR值为0.42(95%CI0.28-0.62,P<0.0011,进一步分析发现：携带GA基因型降低胃癌发病风险的作用在肠型和弥漫型胃癌中是一致的。(4)胃癌组和对照组SMAD7rsl2953717等位基因、各基因型的分布差异无统计学意义,各基因型分布差异在肠型胃癌组和弥漫型胃癌组无统计学意义。(5)携带TNF-a rs361525AA基因型显著增加胃癌的发病风险,OR值为2.15(95%CI:1.06-4.37,P=0.035),携带AA基因型显著降低肠型胃癌发病风险(OR=0.42,95%CI:0.20-0.89,P=0.023),而弥漫型胃癌组与对照组相比较,基因型频率无统计学意义差异。(6)携带SEPS1rs28665122GA基因型显著降低胃癌的发病风险,OR值为0.63(95%CI:0.40-0.99,P=0.044)。携带AA基因型显著增加肠型胃癌发病风险(OR=1.71,95%CI:1.02-2.84,P=0.041),而弥漫型胃癌组与对照组相比较,基因型频率无统计学意义差异。结论：(1)本组胃癌的临床病理学特点为：男性多于女性、发病年龄晚、病理类型以肠型胃癌为主、低分化多见、TNM分期多为中晚期；与非贲门胃癌相比,贲门癌具有以男性比例更高、更倾向于肠型及高分化的特点。(2) PSCA rs2294008和MUC1rs2070803多态性与胃癌发生有关,PSCA rs2294008TT、TC基因型是胃癌的危险因素,而MUC1rs2070803GA基因型是胃癌的保护性因素。(3) SMAD7rsl2953717多态性与胃癌发病无关。(4)携带TNF-α rs361525AA基因型显著增加胃癌的发病风险,携带AA基因型显著增加降低肠型胃癌发病风险。(5)携带SEPS1rs28665122GA基因型显著降低胃癌的发病风险,携带AA基因型显著增加肠型胃癌发病风险。更多还原

【Abstract】 Background Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death worldwide. Epidemiological studies have identified many risk factors for gastric cancer, such as Helicobacter pylori (H. pylori) infection, low fiber intake, and tobacco smoking, however, only a fraction of individuals exposed to these factors develop gastric cancer during their lifetime, which suggests that genetic susceptibility plays an important role in gastric carcinogenesis. It has been reported that polymorphisms in prostate stem cell antigen (PSCA), mucin1gene(MUC1), Selenoprotein S(SEPS1) and tumor necrosis factor-a(TNF-a)genes were associated with the risk of gastric cancer, and polymorphism in mothers against decapentaplegic homolog7(SMAD7)gene was associated with colorectal cancer in a Western population.Objective (1) Analyzed the clinical and pathological data of300gastric cancers by comparing the cardia and non-cardia gastric cancers in clinicopathological profiles, in order to give a better understanding of the profiles of gastric cancer in our region.(2) Analyzed the relationship of single nucleotide polymorphisms in PSCA rs2294008, MUC1rs2070803, SMAD7rsl2953717, TNF-a rs361525, SEPS1rs28665122and susceptibility to gastric cancer with different clinic pathological profiles in a population from Hunan province.Methods300pathologically confirmed gastric cancer patients were enrolled at the Xiangya Hospital of Central South University, The Second-Xiangya Hospital of Central South University and Tumor Hospital of Hunan Province, between June2011and November2011.300healthy controls were selected randomly from the same geographic region as the patients with gastric cancer. First analyze the clinical and pathological data of gastric cancer, then300cases of gastric cancer and300controls were genetyped for PSCA rs2294008, MUC1rs2070803, SMAD7rsl2953717, TNF-a rs361525, SEPS1rs28665122by means of Matrix-assisted laser desorptionionization time-of-flight mass spectrometry(MALDI-TOF-MS). Chi-square test was used to compare demographic distributions and pathological profiles between cases and controls. Hardy-Weinberg equilibrium was checked for controls using the goodness-of-fit χ2test. The associations between the genotypes and risk of gastric cancer were estimated by calculating the odds ratios (ORs) with95%confidence intervals (CIs) using unconditional logistic regression analyses adjusted for age and gender. All tests were conducted at the P=0.05level of significance, using SPSS13.0software package (SPSS, Chicago, IL).Results (1) The main clinicopathological profiles of gastric cancer in our region:gastric cardia canceraccounted for26.3%, while non-cardia cancer accounted for73.7%of total300patients. There was a significant difference in the gender composition between cardia and non-cardia cancer, the male/female ratio was significantly higher in cardia cancer than that of non-cardia gastric cancer (2.7/1vsl.5/1, P=0.04). There was no significant difference on average age between cardia cancer patients (51.2±12.2years) and non-cardia gastric cancer group(52.5±11.4years). The proportion of patients over65years of age in cardia cancer group was significantly higher than that of non-cardia gastric cancer group (24.1%vs12.7%, P=0.020). According to Lauren classification, the proportion of intestinal-type gastric cancer in cardia cancer was significantly higher than that of non-cardia gastric cancer(82.4%vs70.1%, P=0.035). Classification according to the degree of differentiation, the proportion of poorly differentiated type in cardia cancer was significantly lower than that of non-cardia gastriccancer (56.0%vs74.5%, P<0.001). The cases are mostly advanced gastric cancer and TNM staging were not significant different between cardia and non-cardia gastric cancer(P=0.160). To compare the findings with other studies in othe countries or regions, we found that the proportion of gastric cardia cancer was consistent with the results from Shanxi, Shenyang, Portugal and England (21.5%-29.5%), but higher than results from SouthKorea and Japan, which was reported to be less than10%. Consistent results in gender composition and age of onset were observed in them(2.7/1VS1.66-3.7/1, the average age of onset:52.1-63.0y). This study was more consistent with Portugal and England with respect to the Lauren classification and TNM staging, as both were mainly intestinal type and with advanced TNM stages(Ⅲ-Ⅳ), whose proportions were significantly higher than Shenyang, SouthKorea and Japan (62.1%VS41.3%-56.4%).Conclusion (1) The main clinic pathological profiles of gastric cancer in our region were susceptible with men, late age of onset, intestinal type, poorly differentiated and late TNM staging; compared with non-cardia gastric cancer, cardia cancer tends to be male-dominated, more inclined to well-differentiated and intestinal type.(2) PSCA rs2294008was associated with increased risk of gastric cancer. TT genotype increased gastric cancer risk to an odd of2.26(95%CI1.25-4.07, P=0.007), TC to1.72(95%CI1.23-2.42, P=0.002) compared with CC genetype. Further stratification analysis revealed that rs2294008TT and TC genotypes had a consistently increased risk on both intestinal and diffuse-type gastric cancer.(3) MUC1rs2070803was associated with the susceptibility to gastric cancer. GA genotype was associated with decreased gastric cancer risk to an odd of0.42(95%CI0.28-0.62) compared with GG genetype. Further stratification analysis revealed that the effect of rs2070803in MUC1was consistent in both intestinal and diffuse-subtypes.(4) There were no statistical differences on SMAD7 rs12953717genotypes frequencies between gastric cancer cases and controls, and between the two pathologic subtypes of gastric cancer.(5) TNF-a rs361525AA genotype was significantly associated with increased gastric cancer risk (OR=2.15,95%CI1.06-4.37, P=0.035). AA genotype was significantly associated with decreased intestinal-type gastric cancer risk (OR=0.42,95%CI:0.20-0.89, P=0.023), however, there were no statistical differences on TNF-a rs361525genotype frequencies between intestinal gastric cancer and controls.(6) SEPS1rs28665122GA genotype was significantly associated with decreased gastric cancer risk (OR=0.63,95%CI:0.40-0.99, P=0.044). AA genotype was significantly associated with increased intestinal-type gastric cancer risk (OR=1.71,95%CI:1.02-2.84, P=0.041), however, there were no statistical differences on genotypes frequencies between intestinal gastric cancer and controls.更多还原