候选基因及miRNA基因多态性与肺癌遗传易感性的关联研究
发布时间：2018-08-13 08:37
【摘要】：背景肺癌是最常见的恶性肿瘤。除了吸烟等环境因素的影响外,遗传因素也在肺癌的发生中起到很重要的作用,个体遗传易感性的差异与肺癌发生风险显著相关。在过去的20多年里,候选基因关联研究(candidate-gene association studies)是肺癌遗传易感性研究的主要方法之一,已经有1000多篇文献基于候选基因策略研究遗传多态性与肺癌易感性的关联。尽管这些候选基因关联研究发现了许多与肺癌发病风险相关的遗传变异位点,但是许多研究之间报道的结果并不一致,很难明确所发现的位点是否与肺癌发生风险之间存在真实的病因关联。目前缺乏对这些大量的研究证据的整合系统评价、meta分析和总体流行病学证据可靠性的分级评估。此外,目前报道的这些肺癌遗传关联研究,主要关注的是位于DNA剪切修复基因、代谢酶基因、免疫通路相关基因、细胞凋亡通路基因等蛋白编码基因上的遗传变异位点与肺癌易感性的关系,很少关注位于非蛋白编码基因上的遗传变异位点。然而,人类基因组中存在大量的非编码RNAs(non-coding RNAs,nc RNAs)。且许多nc RNAs在肺癌及其他多种肿瘤发生发展中的重要作用已逐渐被证实,尤其是miRNAs在肿瘤中的功能作用。近年来,研究发现位于miRNA基因上的单核苷酸多态性(single nucleotide polymorphisms,SNPs)位点也与某些肿瘤的发生风险相关联。然而目前有关miRNA基因上的SNPs与肺癌易感性的关联研究还很少,有待进一步发掘更多新的肺癌易感性相关的miRNA SNPs位点,为肺癌病因学研究提供更多新的线索。目的1.采用整合系统评价、meta分析以及流行病学证据质量分级的方法对目前发表的所有与肺癌发生风险相关的候选基因关联研究进行分析,全面识别、验证和解释以往报道的遗传变异位点与肺癌发生风险之间的关联。2.通过生物信息学分析,筛选位于miRNA基因序列上的潜在功能性SNPs,并基于病例-对照研究的关联分析,探讨miRNA基因上的SNPs位点与肺癌发生风险的关联,进而发掘新的与肺癌易感性相关的位于miRNA基因上的SNPs位点方法1.对截止2015年11月1日发表的全部关于肺癌易感性的候选基因关联研究,进行系统性地文献检索和文献评估。对至少被三个独立研究报道的遗传变异位点,采用meta分析的方法评估其与肺癌易感性之间的关联。此外我们还根据种族、病理分型以及吸烟状态进行亚组分析。根据meta分析的结果,采用威尼斯标准评估具有统计学意义的关联位点的流行病学证据可靠性。进一步采用生物信息学分析,对与肺癌易感性之间存在显著性关联且关联具有强流行病学证据可靠性的位点进行功能注释。对于meta分析发现的与肺癌发生风险之间不具有统计学意义的关联位点,也对其证据质量进行评估,评估方法基于纳入研究之间的异质性、潜在偏倚以及meta分析结果的统计学效能三个方面。2.通过生物信息学分析,筛选了13个具有潜在生物学功能的位于不同miRNA上的SNPs位点。在626例肺癌患者和年龄、性别与病例相匹配的736例正常对照中,采用SNPscanTM分型技术对筛选的13个SNPs位点进行基因分型。多因素Logistic回归分析不同基因型与肺癌易感性之间的关联;并基于肺癌的病理学类型和个体的吸烟状态进行分层分析,在不同的亚组中评估各SNP位点与肺癌发生风险之间的关联。结果第一部分:1.经过系统性的文献检索和文献筛选,最终我们纳入了1018篇符合标准的文献,这些文献总共报道了位于754个不同基因或染色体位点上的2910个遗传变异位点。2.采用meta分析的方法评估其中的246个遗传变异位点(位于138个不同的基因)与肺癌易感性之间的关联。基于meta分析结果和威尼斯标准评估发现,22个位点(位于21个不同的基因)与肺癌发生风险显著相关,且关联具有强的流行病学证据可靠性,这22个遗传变异位点分别是APEX1 rs1130409、APEX1 rs1760944、ATM rs664677、AXIN2 rs2240308、CHRNA3 rs6495309、CHRNA5 rs16969968、CLPTM1L rs402710、CXCR2 rs1126579、CYP1A1 rs4646903、CYP2E1 rs6413432、ERCC1 rs11615、ERCC2rs13181、FGFR4 rs351855、HYKK rs931794、MIR146A rs2910164、MIR196A2 rs11614913、OGG1 rs1052133、PON1 rs662、REV3L rs462779、SOD2 rs4880、TERT rs2736098和TP53rs1042522位点。3.生物信息学分析表明,在这22个遗传变异位点中,大部分位点可以通过改变蛋白质编码序列或者影响DNA调控元件,来影响其所在基因的表达和/或功能。4.Meta分析发现150个遗传变异位点(来自98个不同的基因)与肺癌发生风险之间的关联无统计学意义,证据质量评估发现其中7个位点(ERCC1 rs16979802、ERCC1rs2298881、ERCC1 rs735482、POLI rs3730668、PPARG rs1801282、PTGS2 rs20417和TNF rs1799724)的meta分析结果的流行病学证据质量高,具有较高的可靠性。第二部分:1.通过生物信息学分析筛选了13个位于不同miRNAs基因上的潜在功能性的SNPs位点(rs11597888 G/A、rs12803915 G/A、rs16867808 T/C、rs2292879 A/G、rs45530340 C/T、rs5997893 G/A、rs61747536 C/T、rs62085660 C/G、rs6464546 G/A、rs6717413 A/G、rs7247237 C/T、rs745666 G/C和rs999665 G/A),进一步关联分析发现这些SNPs位点总体上与肺癌发生风险之间的关联不具有统计学意义(P值均大于0.05)。2.基于肺癌病理类型的亚组分析发现,rs11597888(GA)位点的杂合子GA基因型可以显著增加肺腺癌的发生风险(共显性模型:校正OR=1.34,95%CI=1.00-1.79,P=0.046);rs62085660(CG)位点的变异型等位基因G和变异基因型(CG+GG)都可以显著降低肺鳞癌的发生风险(加性模型:校正OR=0.79,95%CI=0.62-1.00,P=0.049;显性模型:校正OR=0.72,95%CI=0.53-0.98,P=0.035)。3.基于吸烟状态的亚组分析发现,rs11597888(GA)位点的变异基因型(GA+AA)可以显著增加吸烟人群发生肺癌的风险(共显性模型:校正OR=1.44,95%CI=1.02-2.02,P=0.037;显性模型:校正OR=1.42,95%CI=1.03-1.96,P=0.033);rs16867808(TC)位点在多种假设遗传模型下与吸烟人群发生肺癌的风险显著相关(加性模型:校正OR=0.58,95%CI=0.40-0.84,P=0.004;共显性模型:校正OR=0.55,95%CI=0.35-0.85,P=0.007;显性模型:校正OR=0.53,95%CI=0.35-0.81,P=0.004)。4.Haplo Reg数据库功能注释表明,亚组分析中识别的与肺癌易感性显著相关的3个位点(rs11597888 G/A、rs62085660 C/G和rs16867808 T/C)都位于肺癌组织及其他多种组织细胞中的DNA调控元件区域(启动子区域和/或增强子区域)、Dnase I高敏感区、相关转录因子结合位点以及可以改变相关模体(motif),其中rs62085660 C/G和rs16867808 T/C位点还是多种基因的的表达数量性状位点(expression quantitative trait locus,e QTLs)。结论1.基于整合系统评价、meta分析、流行病学证据质量分级的方法发现,目前在所有报道的肺癌遗传易感性候选基因关联研究中,约有9%(22/246)遗传变异位点与肺癌的易感性显著相关,且流行病学证据评估具有较强可靠性。相关研究以及生物信息学分析表明,在这些位点中,大部分位点可以通过改变蛋白质编码序列或者影响调控元件,来影响其所在的基因的表达和/或功能。2.基于病例-对照研究设计的关联分析发现,rs11597888 G/A(miRNA AL391839.1)、rs62085660 C/G(miRNA AC145343.1)以及rs16867808 T/C(miRNA AL021918.2)位点分别与肺癌的发生风险存在显著性关联,但是这3个SNPs位点与肺癌易感性的关联效应只能在特定的亚组人群中观察到,具体包括:rs11597888(GA)位点与肺腺癌发生风险以及吸烟人群中肺癌发生风险显著相关;rs62085660(CG)位点与肺鳞癌发生风险显著相关;rs16867808(TC)位点与吸烟人群中肺癌发生风险显著相关。本研究结果为肺癌遗传风险效应相关的研究提供了最新且全面的证据,同时发现了与肺癌易感性相关的新的miRNA SNPs位点,将为后续肺癌风险相关的研究提供有力的线索,为肺癌的个体化防治提供理论依据。
[Abstract]:Background Lung cancer is the most common malignancy. In addition to environmental factors such as smoking, genetic factors play an important role in the development of lung cancer. Differences in individual genetic susceptibility are significantly associated with the risk of lung cancer. One of the main methods of genetic susceptibility research, more than 1000 papers have studied the association between genetic polymorphism and lung cancer susceptibility based on candidate gene strategies. There is a lack of integrated systematic evaluation of the large number of studies, meta-analysis, and hierarchical evaluation of the reliability of overall epidemiological evidence. In addition, the reported genetic association studies of lung cancer focus on DNA splicing. The genetic variation sites of repair genes, metabolic enzymes genes, immune pathway related genes, apoptosis pathway genes and other protein coding genes are rarely concerned with the susceptibility to lung cancer. However, a large number of non-coding RNAs (nc RNAs) exist in the human genome. Many of the important roles of NC RNAs in lung cancer and many other tumors have been gradually confirmed, especially the role of microRNAs in tumors. In recent years, studies have found that single nucleotide polymorphisms (SNPs) sites in the microRNA gene are also associated with the risk of some tumors. Previous studies on the association of microRNAs with lung cancer susceptibility are rare. More novel sites of microRNAs associated with lung cancer susceptibility need to be explored to provide new clues for the etiological study of lung cancer. Objective 1. The current publication is based on integrated system assessment, meta-analysis and epidemiological evidence quality grading. All candidate genes associated with lung cancer risk were analyzed to identify, validate and explain the association between previously reported genetic variation sites and lung cancer risk. To explore the association between SNPs on the microRNAs and the risk of lung cancer, and to explore new SNPs on the microRNAs associated with lung cancer susceptibility. 1. Systematic literature search and evaluation of all candidate gene association studies on lung cancer susceptibility published as of November 1, 2015. Meta-analysis was used to assess the association between genetic variants and susceptibility to lung cancer. Subgroup analysis was also performed based on race, pathological typing, and smoking status. Evidence reliability. Further, bioinformatics analysis was used to annotate functional sites that were significantly associated with lung cancer susceptibility and were associated with strong epidemiological evidence reliability. The quality of evidence was assessed for sites that were not statistically relevant to the risk of lung cancer detected by meta-analysis. Based on the heterogeneity of the included studies, potential bias, and statistical efficacy of meta-analysis results, 13 SNPs with potential biological functions on different microRNAs were screened by bioinformatics analysis. In 626 lung cancer patients and 736 age-matched normal controls, sex matched with the case. Multivariate logistic regression analysis was used to analyze the association between different genotypes and susceptibility to lung cancer, and stratified analysis was performed based on pathological types of lung cancer and smoking status of individuals to assess the relationship between SNP loci and lung cancer risk in different subgroups. Result Part I: 1. After systematic literature search and literature screening, we finally included 1018 eligible literatures, which reported 2910 genetic variation sites on 754 different genes or chromosome loci. 2. 246 genetic variation loci (sites) were evaluated by meta-analysis. Based on meta-analysis and Venice Standard Assessment, 22 loci (located in 21 different genes) were found to be significantly associated with the risk of lung cancer, and the association had strong epidemiological evidence reliability. The 22 genetic variation loci were APEX1 rs1130409, APEX1 rs176094. 4, ATM rs66464677, AXIN2 rs66464777, AXIN2 rs2240308, CHRNA 3 rs64646495309, CHRNA 5 rs1696969968, CHRNA 5 rs1696969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1rs46464646903, CYP2E1rs6413413432, ERCC1 rs11611611611611611611615, ERCC2 rs131811 181, FGFR4 rs351855 rs351855, HYKrs93931794 rs931794 rs2910164 19164, MIR1196196A211619119113 11611611619113 11311311311311311311311311311321313, OGG11052132132133, OGG12132132132132133, G11 1 1 SOD2 rs4880, TERT rs2736098 and TP Bioinformatics analysis showed that most of the 22 genetic variants could affect the gene expression and/or function by altering protein coding sequences or influencing DNA regulatory elements. 4. Meta analysis revealed 150 genetic variants (from 98 different genes) associated with lung cancer. There was no significant correlation between risks. Evidence quality assessment found that meta-analysis of 7 sites (ERCC1 rs16979802, ERCC1 rs2298881, ERCC1 rs735482, POLI rs3730668, PPARG rs1801282, PTGS2 rs2041 7 and TNF rs1799724) had high quality and reliability of epidemiological evidence. Thirteen potential functional SNPs loci (rs11597888 G/A, rs12803915 G/A, rs16867808 T/C, rs2292879 A/G, rs45530340 C/T, rs5997893 G/A, rs61747536 C/T, rs62085660 C/G, rs64546 G/A, rs6717413 A/G, rs7247237 C/T, rs745666/C and rs999665 G/A) were analyzed and screened. The association between some SNPs loci and the risk of lung cancer was not statistically significant (P > 0.05). 2. Subgroup analysis based on pathological types of lung cancer revealed that the heterozygote GA genotype at rs11597888 (GA) locus significantly increased the risk of lung adenocarcinoma (co-dominant model: corrected OR = 1.34, 95% CI = 1.00-1.79, P = 0.046); Both variant allele G and variant genotype (CG + GG) at 60 (CG) locus significantly reduced the risk of lung squamous cell carcinoma (additive model: corrected OR = 0.79, 95% CI = 0.62-1.00, P = 0.049; dominant model: corrected OR = 0.72, 95% CI = 0.53-0.98, P = 0.035). 3. Subgroup analysis based on smoking status revealed that variant genotype (GA + AA) at rs11597888 (GA) locus. The risk of lung cancer in smokers was significantly increased (co-dominant model: corrected OR = 1.44, 95% CI = 1.02-2.02, P = 0.037; dominant model: corrected OR = 1.42, 95% CI = 1.03-1.96, P = 0.033); rs16867808 (TC) locus was significantly correlated with the risk of lung cancer in smokers under multiple hypothetical genetic models (additive model: corrected OR = 0.58, 95% CI = 0.40-0.84). Co-dominance model: Corrected OR = 0.55, 95% CI = 0.35-0.85, P = 0.007; Dominant model: Corrected OR = 0.53, 95% CI = 0.35-0.81, P = 0.004). Functional annotations of Haplo Reg database showed that three loci (rs11597888 G/A, rs62085660 C/G and rs16867808 T/C) identified by subgroup analysis were significantly associated with lung cancer susceptibility in lung cancer tissues and other tissues. DNA regulatory element regions (promoter region and/or enhancer region), Dnase I hypersensitive region, related transcription factor binding sites and motifs that can be altered in a variety of tissues and cells. Among them, rs62085660 C/G and rs16867808 T/C loci are quantitative trait loci for expression of multiple genes. Based on the integrated system assessment, meta-analysis and epidemiological evidence quality grading, it was found that about 9% (22/246) of the genetic variant loci were significantly associated with the susceptibility of lung cancer in all the reported association studies of candidate genes for lung cancer genetic susceptibility, and the evaluation of epidemiological evidence was highly reliable. The study and bioinformatics analysis showed that most of these loci could affect the gene expression and/or function by altering the protein coding sequence or influencing regulatory elements. 2. Case-control study design-based association analysis revealed that rs11597888 G/A (microNA AL391839.1), rs62085660 C/G (microNA AC145). 343.1 and rs16867808 T/C (microNA AL021918.2) loci were significantly associated with the risk of lung cancer, respectively. However, the association between these three SNPs and lung cancer susceptibility could only be observed in a specific subgroup of people, including: rs11597888 (GA) locus and the risk of lung adenocarcinoma, and the risk of lung cancer in smokers. The results of this study provide the latest and comprehensive evidence for the study of genetic risk effects of lung cancer. At the same time, we found a new microRNA SNPs locus associated with lung cancer susceptibility. It provides a powerful clue for the follow-up study of lung cancer risk, and provides a theoretical basis for the individual prevention and treatment of lung cancer.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2
本文编号：2180446
[Abstract]:Background Lung cancer is the most common malignancy. In addition to environmental factors such as smoking, genetic factors play an important role in the development of lung cancer. Differences in individual genetic susceptibility are significantly associated with the risk of lung cancer. One of the main methods of genetic susceptibility research, more than 1000 papers have studied the association between genetic polymorphism and lung cancer susceptibility based on candidate gene strategies. There is a lack of integrated systematic evaluation of the large number of studies, meta-analysis, and hierarchical evaluation of the reliability of overall epidemiological evidence. In addition, the reported genetic association studies of lung cancer focus on DNA splicing. The genetic variation sites of repair genes, metabolic enzymes genes, immune pathway related genes, apoptosis pathway genes and other protein coding genes are rarely concerned with the susceptibility to lung cancer. However, a large number of non-coding RNAs (nc RNAs) exist in the human genome. Many of the important roles of NC RNAs in lung cancer and many other tumors have been gradually confirmed, especially the role of microRNAs in tumors. In recent years, studies have found that single nucleotide polymorphisms (SNPs) sites in the microRNA gene are also associated with the risk of some tumors. Previous studies on the association of microRNAs with lung cancer susceptibility are rare. More novel sites of microRNAs associated with lung cancer susceptibility need to be explored to provide new clues for the etiological study of lung cancer. Objective 1. The current publication is based on integrated system assessment, meta-analysis and epidemiological evidence quality grading. All candidate genes associated with lung cancer risk were analyzed to identify, validate and explain the association between previously reported genetic variation sites and lung cancer risk. To explore the association between SNPs on the microRNAs and the risk of lung cancer, and to explore new SNPs on the microRNAs associated with lung cancer susceptibility. 1. Systematic literature search and evaluation of all candidate gene association studies on lung cancer susceptibility published as of November 1, 2015. Meta-analysis was used to assess the association between genetic variants and susceptibility to lung cancer. Subgroup analysis was also performed based on race, pathological typing, and smoking status. Evidence reliability. Further, bioinformatics analysis was used to annotate functional sites that were significantly associated with lung cancer susceptibility and were associated with strong epidemiological evidence reliability. The quality of evidence was assessed for sites that were not statistically relevant to the risk of lung cancer detected by meta-analysis. Based on the heterogeneity of the included studies, potential bias, and statistical efficacy of meta-analysis results, 13 SNPs with potential biological functions on different microRNAs were screened by bioinformatics analysis. In 626 lung cancer patients and 736 age-matched normal controls, sex matched with the case. Multivariate logistic regression analysis was used to analyze the association between different genotypes and susceptibility to lung cancer, and stratified analysis was performed based on pathological types of lung cancer and smoking status of individuals to assess the relationship between SNP loci and lung cancer risk in different subgroups. Result Part I: 1. After systematic literature search and literature screening, we finally included 1018 eligible literatures, which reported 2910 genetic variation sites on 754 different genes or chromosome loci. 2. 246 genetic variation loci (sites) were evaluated by meta-analysis. Based on meta-analysis and Venice Standard Assessment, 22 loci (located in 21 different genes) were found to be significantly associated with the risk of lung cancer, and the association had strong epidemiological evidence reliability. The 22 genetic variation loci were APEX1 rs1130409, APEX1 rs176094. 4, ATM rs66464677, AXIN2 rs66464777, AXIN2 rs2240308, CHRNA 3 rs64646495309, CHRNA 5 rs1696969968, CHRNA 5 rs1696969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1rs46464646903, CYP2E1rs6413413432, ERCC1 rs11611611611611611611615, ERCC2 rs131811 181, FGFR4 rs351855 rs351855, HYKrs93931794 rs931794 rs2910164 19164, MIR1196196A211619119113 11611611619113 11311311311311311311311311311321313, OGG11052132132133, OGG12132132132132133, G11 1 1 SOD2 rs4880, TERT rs2736098 and TP Bioinformatics analysis showed that most of the 22 genetic variants could affect the gene expression and/or function by altering protein coding sequences or influencing DNA regulatory elements. 4. Meta analysis revealed 150 genetic variants (from 98 different genes) associated with lung cancer. There was no significant correlation between risks. Evidence quality assessment found that meta-analysis of 7 sites (ERCC1 rs16979802, ERCC1 rs2298881, ERCC1 rs735482, POLI rs3730668, PPARG rs1801282, PTGS2 rs2041 7 and TNF rs1799724) had high quality and reliability of epidemiological evidence. Thirteen potential functional SNPs loci (rs11597888 G/A, rs12803915 G/A, rs16867808 T/C, rs2292879 A/G, rs45530340 C/T, rs5997893 G/A, rs61747536 C/T, rs62085660 C/G, rs64546 G/A, rs6717413 A/G, rs7247237 C/T, rs745666/C and rs999665 G/A) were analyzed and screened. The association between some SNPs loci and the risk of lung cancer was not statistically significant (P > 0.05). 2. Subgroup analysis based on pathological types of lung cancer revealed that the heterozygote GA genotype at rs11597888 (GA) locus significantly increased the risk of lung adenocarcinoma (co-dominant model: corrected OR = 1.34, 95% CI = 1.00-1.79, P = 0.046); Both variant allele G and variant genotype (CG + GG) at 60 (CG) locus significantly reduced the risk of lung squamous cell carcinoma (additive model: corrected OR = 0.79, 95% CI = 0.62-1.00, P = 0.049; dominant model: corrected OR = 0.72, 95% CI = 0.53-0.98, P = 0.035). 3. Subgroup analysis based on smoking status revealed that variant genotype (GA + AA) at rs11597888 (GA) locus. The risk of lung cancer in smokers was significantly increased (co-dominant model: corrected OR = 1.44, 95% CI = 1.02-2.02, P = 0.037; dominant model: corrected OR = 1.42, 95% CI = 1.03-1.96, P = 0.033); rs16867808 (TC) locus was significantly correlated with the risk of lung cancer in smokers under multiple hypothetical genetic models (additive model: corrected OR = 0.58, 95% CI = 0.40-0.84). Co-dominance model: Corrected OR = 0.55, 95% CI = 0.35-0.85, P = 0.007; Dominant model: Corrected OR = 0.53, 95% CI = 0.35-0.81, P = 0.004). Functional annotations of Haplo Reg database showed that three loci (rs11597888 G/A, rs62085660 C/G and rs16867808 T/C) identified by subgroup analysis were significantly associated with lung cancer susceptibility in lung cancer tissues and other tissues. DNA regulatory element regions (promoter region and/or enhancer region), Dnase I hypersensitive region, related transcription factor binding sites and motifs that can be altered in a variety of tissues and cells. Among them, rs62085660 C/G and rs16867808 T/C loci are quantitative trait loci for expression of multiple genes. Based on the integrated system assessment, meta-analysis and epidemiological evidence quality grading, it was found that about 9% (22/246) of the genetic variant loci were significantly associated with the susceptibility of lung cancer in all the reported association studies of candidate genes for lung cancer genetic susceptibility, and the evaluation of epidemiological evidence was highly reliable. The study and bioinformatics analysis showed that most of these loci could affect the gene expression and/or function by altering the protein coding sequence or influencing regulatory elements. 2. Case-control study design-based association analysis revealed that rs11597888 G/A (microNA AL391839.1), rs62085660 C/G (microNA AC145). 343.1 and rs16867808 T/C (microNA AL021918.2) loci were significantly associated with the risk of lung cancer, respectively. However, the association between these three SNPs and lung cancer susceptibility could only be observed in a specific subgroup of people, including: rs11597888 (GA) locus and the risk of lung adenocarcinoma, and the risk of lung cancer in smokers. The results of this study provide the latest and comprehensive evidence for the study of genetic risk effects of lung cancer. At the same time, we found a new microRNA SNPs locus associated with lung cancer susceptibility. It provides a powerful clue for the follow-up study of lung cancer risk, and provides a theoretical basis for the individual prevention and treatment of lung cancer.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2
【参考文献】
相关期刊论文 前1条
1 陈万青;张思维;邹小农;;中国肺癌发病死亡的估计和流行趋势研究[J];中国肺癌杂志;2010年05期
，本文编号：2180446
本文链接：https://www.wllwen.com/kejilunwen/jiyingongcheng/2180446.html
最近更新
教材专著
