孟德尔随机化揭示了细胞衰老相关基因与多种癌症风险之间的潜在因果关系-动脉网

Mendelian randomization reveals potential causal relationships between cellular senescence-related genes and multiple cancer risks

Nature 等信源发布 2024-08-31 08:36



可切换为仅中文







AbstractCellular senescence is widely acknowledged as having strong associations with cancer. However, the intricate relationships between cellular senescence-related (CSR) genes and cancer risk remain poorly explored, with insights on causality remaining elusive. In this study, Mendelian Randomization (MR) analyses were used to draw causal inferences from 866 CSR genes as exposures and summary statistics for 18 common cancers as outcomes.

摘要细胞衰老被广泛认为与癌症有很强的相关性。然而，细胞衰老相关（CSR）基因与癌症风险之间的复杂关系仍然没有得到很好的探索，关于因果关系的见解仍然难以捉摸。在这项研究中，使用孟德尔随机化（MR）分析从866个CSR基因中得出因果推论作为暴露，并将18种常见癌症的汇总统计作为结果。

We focused on genetic variants affecting gene expression, DNA methylation, and protein expression quantitative trait loci (cis-eQTL, cis-mQTL, and cis-pQTL, respectively), which were strongly linked to CSR genes alterations. Variants were selected as instrumental variables (IVs) and analyzed for causality with cancer using both summary-data-based MR (SMR) and two-sample MR (TSMR) approaches.

我们专注于影响基因表达，DNA甲基化和蛋白质表达数量性状基因座（分别为顺式eQTL，顺式mQTL和顺式pQTL）的遗传变异，这些变异与CSR基因改变密切相关。选择变体作为工具变量（IVs），并使用基于汇总数据的MR（SMR）和双样本MR（TSMR）方法分析与癌症的因果关系。

Bayesian colocalization was used to unravel potential regulatory mechanisms underpinning risk variants in cancer, and further validate the robustness of MR results. We identified five CSR genes (CNOT6, DNMT3B, MAP2K1, TBPL1, and SREBF1), 18 DNA methylation genes, and LAYN protein expression which were all causally associated with different cancer types.

贝叶斯共定位用于揭示支持癌症风险变异的潜在监管机制，并进一步验证MR结果的稳健性。我们鉴定了五个CSR基因（CNOT6，DNMT3B，MAP2K1，TBPL1和SREBF1），18个DNA甲基化基因和LAYN蛋白表达，它们都与不同的癌症类型有因果关系。

Beyond causality, a comprehensive analysis of gene function, pathways, and druggability values was also conducted. These findings provide a robust foundation for unravelling CSR genes molecular mechanisms and promoting clinical drug development for cancer..

除了因果关系之外，还对基因功能，途径和可药用性值进行了全面分析。这些发现为揭示CSR基因的分子机制和促进癌症的临床药物开发奠定了坚实的基础。。

IntroductionCellular senescence is a biological response to different external stimuli, encompassing microenvironmental stress, nutrient deprivation, DNA damage, cellular and organelle impairment, and cellular signaling network abnormalities. The process manifests with four characteristics: cell cycle arrest, a senescence-associated secretory phenotype (SASP), macromolecular damage, and metabolic disorder1,2.

引言细胞衰老是对不同外部刺激的生物反应，包括微环境压力，营养缺乏，DNA损伤，细胞和细胞器损伤以及细胞信号网络异常。该过程表现出四个特征：细胞周期停滞，衰老相关分泌表型（SASP），大分子损伤和代谢紊乱1,2。

Cellular senescence is a recently hypothesized molecular cancer hallmark and has important implications for age-related illnesses, carcinogenesis, and tissue repair3,4. In terms of carcinogenesis, cellular senescence functions as a “double-edged sword”; on the one hand, senescence exerts inhibitory effects toward tumorigenesis through cell-intrinsic mechanisms, fostering local anti-tumor immunity, contributing to wound healing, and enhancing host immunity5.

细胞衰老是最近假设的分子癌症标志，对年龄相关疾病，癌变和组织修复具有重要意义3,4。就致癌作用而言，细胞衰老是一把“双刃剑”；一方面，衰老通过细胞内在机制对肿瘤发生产生抑制作用，促进局部抗肿瘤免疫力，促进伤口愈合，增强宿主免疫力5。

Senescent cells, on the other hand, generate and secrete cytokines that stimulate tumor cell growth, ultimately contributing to tumorigenesis by facilitating chronic inflammation and associated degenerative and hyperplastic lesions6. Therefore, elucidating cellular senescence roles in tumorigenesis is critical.Currently, based on traditional observational studies, associations between specific cellular senescence-related (CSR) genes and diverse tumor risks have been identified.

另一方面，衰老细胞产生并分泌刺激肿瘤细胞生长的细胞因子，最终通过促进慢性炎症和相关的退行性和增生性病变促进肿瘤发生6。因此，阐明细胞衰老在肿瘤发生中的作用至关重要。。

For example, EZH2 and TOP2A knockdown inhibit hepatocarcinogenesis by inducing cellular senescence7. IL-1 is a key SASP component and promotes the malignant transformation of oral precursor lesions7. SOX6 suppresses cervical cell proliferation by inducing cellular senescence8. Additionally, FBXW7 likely functions as a tumor suppressor in esophageal squamous carcinoma by regulating cellular senescence and DNA damage repair, among other mec.

例如，EZH2和TOP2A敲低通过诱导细胞衰老来抑制肝癌发生7。IL-1是SASP的关键成分，可促进口腔前体病变的恶性转化7。SOX6通过诱导细胞衰老来抑制宫颈细胞增殖8。此外，FBXW7可能通过调节细胞衰老和DNA损伤修复等mec在食管鳞状细胞癌中发挥抑癌作用。

Data availability

数据可用性

All data used in this study are publicly available. Supplementary Table 2 provides detailed information on the source, sample size and ethnic composition of all data used.

本研究中使用的所有数据均可公开获得。补充表2提供了有关所用所有数据的来源，样本量和种族组成的详细信息。

Code availability

代码可用性

The main R packages used for analysis in this study include the TwoSampleMR R package (version 0.5.6) and the coloc R package (version 5.2.2), and some software and online websites were also used, such as: the Linux version 1.3.1 SMR software, AutoDockTools 1.5.6 software, the GEPIA database, the STRING database, etc., as described in the Methods section.

本研究中用于分析的主要R包包括TwoSampleMR R包（版本0.5.6）和coloc R包（版本5.2.2），还使用了一些软件和在线网站，例如：Linux版本1.3.1 SMR软件，AutoDockTools 1.5.6软件，GEPIA数据库，字符串数据库等，如方法部分所述。

No custom algorithms or code were used in this study. For more information about the analysis scripts or any specific code used in our study, please contact the corresponding author upon request..

本研究未使用自定义算法或代码。有关我们研究中使用的分析脚本或任何特定代码的更多信息，请根据要求联系相应的作者。。

ReferencesLee, S. & Schmitt, C. A. The dynamic nature of senescence in cancer. Nat. Cell Biol. 21, 94–101 (2019).Article

参考Lee，S。＆Schmitt，C.A。癌症衰老的动态性质。自然细胞生物学。21,94-101（2019）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Gorgoulis, V. et al. Cellular Senescence: Defining a Path Forward. Cell 179, 813–827 (2019).Article

Gorgoulis，V。等人，《细胞衰老：定义前进的道路》。细胞179813-827（2019）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Shmulevich, R. & Krizhanovsky, V. Cell Senescence, DNA Damage, and Metabolism. Antioxid. Redox Signal. 34, 324–334 (2021).Article

Shmulevich，R。＆Krizhanovsky，V。细胞衰老，DNA损伤和代谢。抗氧化剂。氧化还原信号。34324-334（2021）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Hanahan, D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 12, 31–46 (2022).Article

Hanahan，D。癌症的标志：新的维度。癌症发现。12，31–46（2022）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

He, S. & Sharpless, N. E. Senescence in Health and Disease. Cell 169, 1000–1011 (2017).Article

He，S。＆Sharpless，N.E。健康和疾病中的衰老。细胞1691000-1011（2017）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Campisi, J. Aging, cellular senescence, and cancer. Annu Rev. Physiol. 75, 685–705 (2013).Article

Campisi，J。衰老，细胞衰老和癌症。Annu Rev.Physiol。75685-705（2013）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Wang, K. et al. EZH2-H3K27me3-mediated silencing of mir-139-5p inhibits cellular senescence in hepatocellular carcinoma by activating TOP2A. J. Exp. Clin. Cancer Res. 42, 320 (2023).Article

Wang，K。等人。EZH2-H3K27me3介导的mir-139-5p沉默通过激活TOP2A抑制肝细胞癌中的细胞衰老。J、实验临床。癌症研究42320（2023）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zheng, H. et al. MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer. Mol. Oncol. https://doi.org/10.1002/1878-0261.13613 (2024).Bi, Y. et al. FBXW7 inhibits the progression of ESCC by directly inhibiting the stemness of tumor cells.

Zheng，H。等人。MAP4K4和WT1通过协同激活宫颈癌中的ATF2-TGFβ2-Smad2/3信号通路来介导SOX6诱导的细胞衰老。。https://doi.org/10.1002/1878-0261.13613（2024年）。Bi，Y。等人，FBXW7通过直接抑制肿瘤细胞的干性来抑制ESCC的进展。

Neoplasma 70, 733–746 (2023).Article .

肿瘤70733-746（2023）。。

CAS

中科院

PubMed

Google Scholar

谷歌学者

Thanassoulis, G. & O’Donnell, C. J. Mendelian randomization: nature’s randomized trial in the post-genome era. JAMA 301, 2386–2388 (2009).Article

Thanassoulis，G。＆O'Donnell，C.J。孟德尔随机化：后基因组时代的自然随机试验。JAMA 3012386-2388（2009）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Burgess, S., Timpson, N. J., Ebrahim, S. & Davey Smith, G. Mendelian randomization: where are we now and where are we going. Int. J. Epidemiol. 44, 379–388 (2015).Article

Burgess，S.，Timpson，N.J.，Ebrahim，S。和Davey Smith，G。孟德尔随机化：我们现在在哪里，我们要去哪里。国际流行病学杂志。44379-388（2015）。文章

PubMed

Google Scholar

谷歌学者

Davey Smith, G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23, R89–R98 (2014).Article

Davey Smith，G。＆Hemani，G。孟德尔随机化：流行病学研究中因果推断的遗传锚。嗯，摩尔·吉内特。23，R89–R98（2014）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Davies, N. M., Holmes, M. V. & Davey Smith, G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362, k601 (2018).Article

Davies，N.M.，Holmes，M.V。和Davey Smith，G。阅读孟德尔随机研究：临床医生指南，词汇表和清单。BMJ 362，k601（2018）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Jones, H. J. et al. Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study. lancet Psychiatry 8, 1062–1070 (2021).Article

Jones，H.J.等人，《血浆脂肪酸浓度与精神分裂症之间的关联：双样本孟德尔随机研究》。柳叶刀精神病学81062-1070（2021）。文章

PubMed

Google Scholar

谷歌学者

Higbee, D. H., Granell, R., Sanderson, E., Davey Smith, G. & Dodd, J. W. Lung function and cardiovascular disease: a two-sample Mendelian randomisation study. Eur. Respir. J. 58, https://doi.org/10.1183/13993003.03196-2020 (2021).Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets.

Higbee，D.H.，Granell，R.，Sanderson，E.，Davey Smith，G。＆Dodd，J.W。肺功能和心血管疾病：一项双样本孟德尔随机研究。欧元呼吸。J、 58岁，https://doi.org/10.1183/13993003.03196-2020（2021年）。Zhu，Z.等人。GWAS和eQTL研究总结数据的整合预测了复杂的性状基因靶标。

Nat. Genet 48, 481–487 (2016).Article .

《自然遗传学》48481-487（2016）。第[UNK]条。

CAS

中科院

PubMed

Google Scholar

谷歌学者

Liu, Y. et al. Mendelian Randomization Integrating GWAS, eQTL, and mQTL Data Identified Genes Pleiotropically Associated With Atrial Fibrillation. Front. Cardiovasc. Med. 8, 745757 (2021).Article

Liu，Y。等人。整合GWAS，eQTL和mQTL数据的孟德尔随机化鉴定了与心房颤动多效性相关的基因。正面。心血管。医学杂志8745757（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhou, D. Y. et al. Decreased CNNM2 expression in prefrontal cortex affects sensorimotor gating function, cognition, dendritic spine morphogenesis and risk of schizophrenia. Neuropsychopharmacology, https://doi.org/10.1038/s41386-023-01732-y (2023).Lin, J., Zhou, J. & Xu, Y. Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis.

Zhou，D.Y.等人，前额叶皮层中CNNM2表达的降低会影响感觉运动门控功能，认知，树突棘形态发生和精神分裂症的风险。神经精神药理学，https://doi.org/10.1038/s41386-023-01732-y（2023年）。Lin，J.，Zhou，J。＆Xu，Y。通过孟德尔随机分析确定了多发性硬化症的潜在药物靶标。

Brain 146, 3364–3372 (2023).Article .

大脑1463364-3372（2023）。。

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Skrivankova, V. W. et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA 326, 1614–1621 (2021).Article

Skrivankova，V.W.等人。使用孟德尔随机化加强流行病学观察性研究的报告：STROBE-MR声明。JAMA 3261614-1621（2021）。文章

PubMed

Google Scholar

谷歌学者

Skrivankova, V. W. et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ 375, n2233 (2021).Article

Skrivankova，V.W.等人。使用孟德尔随机化（STROBE-MR）加强流行病学观察性研究的报告：解释和阐述。BMJ 375，n2233（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Galamb, O. et al. Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma. World J. Gastroenterol. 22, 10325–10340 (2016).Article

Galamb，O。等人。衰老相关甲基化影响结直肠癌和腺瘤中关键控制基因的基因表达。世界J.胃肠病学。2210325-10340（2016）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Song, P. et al. CNOT6: A Novel Regulator of DNA Mismatch Repair. Cells 11, https://doi.org/10.3390/cells11030521 (2022).Maragozidis, P. et al. Poly(A)-specific ribonuclease and Nocturnin in squamous cell lung cancer: prognostic value and impact on gene expression. Mol. Cancer 14, 187 (2015).Article .

Song，P。等人。CNOT6：DNA错配修复的新型调节剂。单元格11，https://doi.org/10.3390/cells11030521（2022年）。Maragozidis，P。等。鳞状细胞肺癌中的聚（A）特异性核糖核酸酶和夜尿素：预后价值和对基因表达的影响。Mol.Cancer 14187（2015）。。

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhou, F. et al. Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs. Mol. Carcinogenesis 56, 1227–1238 (2017).Article

Zhou，F。等人。CNOT6在一般mRNA降解途径中的易感基因座与肺癌风险-对8个GWAS的重新分析。分子致癌561227-1238（2017）。文章

CAS

中科院

Google Scholar

谷歌学者

McKinstry, R. et al. Inhibitors of MEK1/2 interact with UCN-01 to induce apoptosis and reduce colony formation in mammary and prostate carcinoma cells. Cancer Biol. Ther. 1, 243–253 (2002).Article

McKinstry，R。等人。MEK1/2抑制剂与UCN-01相互作用，诱导乳腺癌和前列腺癌细胞凋亡并减少集落形成。癌症生物学。他们。1243-253（2002）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Sun, Y. et al. Apoptosis induction in human prostate cancer cells related to the fatty acid metabolism by wogonin-mediated regulation of the AKT-SREBP1-FASN signaling network. Food Chem. Toxicol. 169, 113450 (2022).Article

Sun，Y。等人。汉黄芩素介导的AKT-SREBP1-FASN信号网络调控与脂肪酸代谢相关的人前列腺癌细胞凋亡诱导。食品化学。毒理学。169113450（2022）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Karsli-Ceppioglu, S. et al. Genome-wide DNA methylation modified by soy phytoestrogens: role for epigenetic therapeutics in prostate cancer. OMICS 19, 209–219 (2015).Article

Karsli Ceppioglu，S.等。大豆植物雌激素修饰的全基因组DNA甲基化：表观遗传治疗在前列腺癌中的作用。组学19209-219（2015）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Ma, L. et al. The essential roles of m(6)A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma. J. Exp. Clin. Cancer Res. 41, 36 (2022).Article

Ma，L。等人。m（6）A RNA修饰在肺腺癌中刺激ENO1依赖性糖酵解和肿瘤发生的重要作用。J、实验临床。癌症研究41,36（2022）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liu, W., Xie, A., Tu, C. & Liu, W. REX-1 Represses RASSF1a and Activates the MEK/ERK Pathway to Promote Tumorigenesis in Prostate Cancer. Mol. Cancer Res. 19, 1666–1675 (2021).Article

Liu，W.，Xie，A.，Tu，C。＆Liu，W。REX-1抑制RASSF1a并激活MEK/ERK途径以促进前列腺癌的肿瘤发生。Mol.Cancer Res.191666–1675（2021）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Zhu, A. et al. DNMT1 and DNMT3B regulate tumorigenicity of human prostate cancer cells by controlling RAD9 expression through targeted methylation. Carcinogenesis 42, 220–231 (2021).Article

Zhu，A。等人。DNMT1和DNMT3B通过靶向甲基化控制RAD9表达来调节人前列腺癌细胞的致瘤性。致癌作用42220-231（2021）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Farah, E. et al. Targeting DNMTs to Overcome Enzalutamide Resistance in Prostate Cancer. Mol. Cancer Ther. 21, 193–205 (2022).Article

Farah，E.等人靶向DNMT以克服前列腺癌中的Enzalutamide耐药性。分子癌症治疗。21193-205（2022）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Tzelepi, V. et al. Epigenetics and prostate cancer: defining the timing of DNA methyltransferase deregulation during prostate cancer progression. Pathology 52, 218–227 (2020).Article

Tzelepi，V。等。表观遗传学和前列腺癌：定义前列腺癌进展过程中DNA甲基转移酶失调的时间。病理学52218-227（2020）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Yang, Y. et al. Targeting LAYN inhibits colorectal cancer metastasis and tumor-associated macrophage infiltration induced by hyaluronan oligosaccharides. Matrix Biol. J. Int. Soc. Matrix Biol. 117, 15–30 (2023).Article

Yang，Y。等人。靶向LAYN抑制透明质酸寡糖诱导的结直肠癌转移和肿瘤相关巨噬细胞浸润。矩阵生物学。J、。117，15-30（2023）。文章

CAS

中科院

Google Scholar

谷歌学者

Cao, L., Zhu, L. & Cheng, L. ncRNA-Regulated LAYN Serves as a Prognostic Biomarker and Correlates with Immune Cell Infiltration in Hepatocellular Carcinoma: A Bioinformatics Analysis. Biomed. Res. Int. 2022, 5357114 (2022).Article

Cao，L.，Zhu，L。＆Cheng，L。ncRNA调节的LAYN可作为预后生物标志物，并与肝细胞癌中的免疫细胞浸润相关：生物信息学分析。生物医学。《国际研究》20225357114（2022年）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lokeshwar, V. B. et al. Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Res. 70, 2613–2623 (2010).Article

Lokeshwar，V.B.等人。透明质酸合成抑制剂4-甲基伞形酮在前列腺癌细胞中的抗肿瘤活性。癌症研究702613-2623（2010）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Benitez, A. et al. Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells. Cancer Res. 71, 4085–4095 (2011).Article

Benitez，A。等人。靶向透明质酸酶用于癌症治疗：硫酸化透明质酸在前列腺癌细胞中的抗肿瘤活性。癌症研究714085-4095（2011）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lee, J. S. et al. Clinical Practice Guideline for Blood-based Circulating Tumor DNA Assays. Ann. Lab. Med. 44, 195–209 (2024).Article

Lee，J.S.等人，《基于血液的循环肿瘤DNA测定的临床实践指南》。《安实验室医学》44195-209（2024）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liu, Y. et al. Significance of circulating tumor cells detection in tumor diagnosis and monitoring. BMC Cancer 23, 1195 (2023).Article

Liu，Y.等。循环肿瘤细胞检测在肿瘤诊断和监测中的意义。BMC Cancer 231195（2023）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Church, T. R. et al. Prospective evaluation of methylatedSEPT9in plasma for detection of asymptomatic colorectal cancer. Gut 63, 317–325 (2014).Article

Church，T.R.等人。血浆中甲基化SEPT9检测无症状结直肠癌的前瞻性评估。肠道63317-325（2014）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Hammarström, S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin. Cancer Biol. 9, 67–81 (1999).Article

Hammarström，S。癌胚抗原（CEA）家族：结构，在正常和恶性组织中的功能和表达。塞米。癌症生物学。9，67-81（1999）。文章

PubMed

Google Scholar

谷歌学者

Avelar, R. A. et al. A multidimensional systems biology analysis of cellular senescence in aging and disease. Genome Biol. 21, 91 (2020).Article

Avelar，R.A.等人。衰老和疾病中细胞衰老的多维系统生物学分析。基因组生物学。21，91（2020）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Võsa, U. et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat. Genet 53, 1300–1310 (2021).Article

Võsa，U。等人。大规模的顺式和反式eQTL分析确定了数千个调节血液基因表达的遗传基因座和多基因评分。《国家遗传学》531300–1310（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

McRae, A. F. et al. Identification of 55,000 Replicated DNA Methylation QTL. Sci. Rep. 8, 17605 (2018).Article

McRae，A.F.等人鉴定了55000个复制的DNA甲基化QTL。科学。代表817605（2018）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ferkingstad, E. et al. Large-scale integration of the plasma proteome with genetics and disease. Nat. Genet 53, 1712–1721 (2021).Article

Ferkingstad，E.等人。血浆蛋白质组与遗传学和疾病的大规模整合。《国家遗传学》531712-1721（2021）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Hemani, G. et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife 7, https://doi.org/10.7554/eLife.34408 (2018).Nie, D. et al. Association between green tea intake and digestive system cancer risk in European and East Asian populations: a Mendelian randomization study.

Hemani，G。等人。MR基础平台支持跨人类表型的系统因果推断。Elife 7，https://doi.org/10.7554/eLife.34408（2018年）。Nie，D.等人。欧洲和东亚人群摄入绿茶与消化系统癌症风险之间的关联：孟德尔随机研究。

Eur. J. Nutr. 63, 1103–1111 (2024).Article .

CAS

中科院

PubMed

Google Scholar

谷歌学者

Bowden, J. et al. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat. Med. 36, 1783–1802 (2017).Article

Bowden，J.等人。双样本汇总数据孟德尔随机化中多效性研究的框架。《统计医学》361783-1802（2017）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rasooly, D., Peloso, G. M. & Giambartolomei, C. Bayesian Genetic Colocalization Test of Two Traits Using coloc. Curr. Protoc. 2, e627 (2022).Article

Rasooly，D.，Peloso，G.M。和Giambartolomei，C。使用coloc对两个性状进行贝叶斯遗传共定位测试。。普罗托克。2，e627（2022）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Wishart, D. S. et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 46, D1074–D1082 (2018).Article

Wishart，D.S.等人，《DrugBank 5.0：2018年DrugBank数据库的重大更新》。核酸研究46，D1074–D1082（2018）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Zdrazil, B. et al. The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods. Nucleic Acids Res., https://doi.org/10.1093/nar/gkad1004 (2023).Kim, S. et al. PubChem 2023 update. Nucleic Acids Res. 51, D1373–D1380 (2023).Article

Zdrazil，B。等人。2023年的ChEMBL数据库：跨越多种生物活性数据类型和时间段的药物发现平台。核酸研究。，https://doi.org/10.1093/nar/gkad1004（2023年）。Kim，S.等人，《PubChem 2023更新》。核酸研究51，D1373–D1380（2023）。文章

PubMed

Google Scholar

谷歌学者

Burley, S. K. et al. RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning. Nucleic Acids Res. 51, D488–D508 (2023).Article

Burley，S.K.等人，RCSB蛋白质数据库（RCSB.org）：提供实验确定的PDB结构以及来自人工智能/机器学习的100万个蛋白质计算结构模型。核酸研究51，D488–D508（2023）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Forli, S. et al. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat. Protoc. 11, 905–919 (2016).Article

Forli，S.等人。使用AutoDock套件进行计算蛋白质-配体对接和虚拟药物筛选。自然协议。11905-919（2016）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Adasme, M. F. et al. PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA. Nucleic Acids Res. 49, W530–W534 (2021).Article

Adasme，M.F.等人，《PLIP 2021：将蛋白质-配体相互作用分析仪的范围扩展到DNA和RNA》，《核酸研究》49，W530–W534（2021）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Tang, Z. et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98–W102 (2017).Article

Tang，Z。等人。GEPIA：用于癌症和正常基因表达谱分析和交互分析的网络服务器。。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yu, G., Wang, L. G., Han, Y. & He, Q. Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012).Article

Yu，G.，Wang，L.G.，Han，Y。＆He，Q.Y。clusterProfiler：用于比较基因簇之间生物学主题的R包。组学16284-287（2012）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yuan, H. et al. CancerSEA: a cancer single-cell state atlas. Nucleic Acids Res. 47, D900–D908 (2019).Article

袁，H。等。癌症：癌症单细胞状态图谱。核酸研究47，D900–D908（2019）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Szklarczyk, D. et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, D447–D452 (2015).Article

Szklarczyk，D。等。STRING v10：蛋白质-蛋白质相互作用网络，整合在生命树上。核酸研究43，D447–D452（2015）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Download referencesAcknowledgementsThis work was supported by the National Natural Science Foundation of China (Award No.81970501) and the Science and Technology Plan of Shenyang (Grant 22-321-32-03).Author informationAuthor notesThese authors contributed equally: Xunan Qiu, Rui Guo.Authors and AffiliationsTumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, 110001, ChinaXunan Qiu, Rui Guo, Yingying Wang, Shuwen Zheng, Bengang Wang & Yuehua GongKey Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, 110001, ChinaXunan Qiu, Rui Guo, Yingying Wang, Shuwen Zheng, Bengang Wang & Yuehua GongKey Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, ChinaXunan Qiu, Rui Guo, Yingying Wang, Shuwen Zheng, Bengang Wang & Yuehua GongAuthorsXunan QiuView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了国家自然科学基金（奖项编号81970501）和沈阳市科学技术计划（拨款22-321-32-03）的支持。作者信息作者注意到这些作者做出了同样的贡献：徐楠秋，郭睿。作者和单位中国医科大学第一医院肿瘤研究所和普外科肿瘤病因学与筛查科，沈阳，110001，邱旭南，郭睿，王英英，郑淑文，王本刚，王跃华辽宁省教育部肿瘤病因学与预防重点实验室，中国医科大学第一医院，沈阳，110001，邱旭南，郭睿，王英英，郑淑文，王本刚，王跃华辽宁省胃肠道肿瘤病因学与预防重点实验室，中国医科大学第一医院，沈阳，110001，邱旭南，王瑞国，王英英，郑淑文，王本刚，王跃华作者徐楠·邱维作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarRui GuoView author publicationsYou can also search for this author in

PubMed Google ScholarRui GuoView作者出版物您也可以在

PubMed Google ScholarYingying WangView author publicationsYou can also search for this author in

PubMed Google ScholarYingying WangView作者出版物您也可以在

PubMed Google ScholarShuwen ZhengView author publicationsYou can also search for this author in

PubMed Google ScholarShuwen ZhengView作者出版物您也可以在

PubMed Google ScholarBengang WangView author publicationsYou can also search for this author in

PubMed Google ScholarBengang WangView作者出版物您也可以在

PubMed Google ScholarYuehua GongView author publicationsYou can also search for this author in

PubMed Google ScholarYuehua GongView作者出版物您也可以在

PubMed Google ScholarContributionsY.H.-G., B.G.-W., X.N.-Q., and R.-G. conceived the study. X.N.-Q. drafted the manuscript. X.N.-Q. and R.-G. performed the analyses. Y.Y.-W. and S.W.-Z. participated in manuscript drafting and interpreting data. X.N.-Q., R.-G., Y.H.-G., and B.G.-W.

PubMed谷歌学术贡献。H、 -G.，B.G.-W.，X.N.-Q。和R.G.构思了这项研究。十、 N.-Q.起草了手稿。十、 N.-Q.和R.-G.进行了分析。Y、 Y.-W.和S.W.-Z.参与了手稿的起草和解释数据。十、 N.-Q.，R.-G.，Y.H.-G。和B.G.-W。

revised the manuscript and sorted out key points. All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

修改稿件并整理要点。所有作者都阅读并批准了最终稿件。通讯作者通讯。

Bengang Wang or Yuehua Gong.Ethics declarations

王本刚或龚月华。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval

道德认可

This study did not contain clinical studies or patient data and was based on large-scale summary GWAS datasets rather than individual-level data. In all corresponding original studies, all participants gave informed consent and no additional ethical approvals applied.

这项研究不包含临床研究或患者数据，而是基于大规模的GWAS汇总数据集，而不是个人层面的数据。在所有相应的原始研究中，所有参与者都给出了知情同意书，没有额外的道德批准。

Peer review

同行评审

Peer review information

同行评审信息

Communications biology thanks Diptavo Dutta, Evangelina López de Maturana and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Tobias Goris. A peer review file is available.

通信生物学感谢Diptavo Dutta，Evangelina López de Maturana和另一位匿名审稿人对这项工作的同行评审所做的贡献。主要处理编辑：Tobias Goris。可以获得同行评审文件。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationPeer review fileSupplementary InformationReporting SummaryRights and permissions

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息同行评审文件补充信息报告摘要权限

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

开放获取本文是根据知识共享署名非商业性NoDerivatives 4.0国际许可证授权的，该许可证允许以任何媒介或格式进行任何非商业性使用，共享，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出您是否修改了许可材料。

You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by-nc-nd/4.0/..

Reprints and permissionsAbout this articleCite this articleQiu, X., Guo, R., Wang, Y. et al. Mendelian randomization reveals potential causal relationships between cellular senescence-related genes and multiple cancer risks.

转载和许可本文引用本文Qiu，X.，Guo，R.，Wang，Y。等人。孟德尔随机化揭示了细胞衰老相关基因与多种癌症风险之间的潜在因果关系。

Commun Biol 7, 1069 (2024). https://doi.org/10.1038/s42003-024-06755-9Download citationReceived: 16 March 2024Accepted: 20 August 2024Published: 31 August 2024DOI: https://doi.org/10.1038/s42003-024-06755-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Commun Biol 71069（2024）。https://doi.org/10.1038/s42003-024-06755-9Download引文接收日期：2024年3月16日接受日期：2024年8月20日发布日期：2024年8月31日OI：https://doi.org/10.1038/s42003-024-06755-9Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供

CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

评论通过提交评论，您同意遵守我们的条款和社区指南。。

全球产业链接平台

重庆市渝北区金星科技大厦A区5楼512室

联系电话：023-67139735（重庆）

关于我们

产品服务