Abstract
Lymph node metastasis, a crucial factor in the spread of gastric cancer (GC), is strongly associated with a negative prognosis for patients. This study aimed to investigate the association of the mesothelin (MSLN) gene polymorphisms (rs3764247, rs3764246, rs12597489, rs1057147, and rs3765319) with the risk of lymph node metastasis of GC patients in a Chinese Han population. The PCR-LDR genotyping was used to detect the genotypes of MSLN polymorphisms in GC patients with lymph node metastasis (n = 610) or without (n = 356). Our research indicates that certain genetic markers, specifically rs3764247, rs3764246, rs12597489, and rs3765319, do not appear to be linked with an increased risk of lymph node metastasis in GC. However, we did observe that patients with the rs1057147 GA genotype exhibited a higher likelihood of lymph node metastasis in GC when compared to those with the GG genotype (OR = 1.33, 95% CI = 1.01 − 1.76, P = 0.045). Patients with rs1057147 GA + AA genotype were found to have a higher likelihood of lymph node involvement (OR = 1.35, 95% CI = 1.03 − 1.77, P = 0.029) when compared to those with GG genotype in the dominant model. The allelic model revealed that the A allele of rs1057147 exhibited a stronger correlation with lymph node metastasis compared to the G allele (OR = 1.28, 95% CI = 1.02 − 1.60, P = 0.031). In addition, we found that rs1057147 polymorphism revealed a poor prognosis for GC patients with lymph node metastasis. Further stratified analysis revealed that the prognostic effect of rs1057147 was more pronounced in patients with GC who had lymph node metastasis and had a tumor size of 4 cm or greater, as well as more than 2 lymph node metastases. Bioinformatics studies showed that the binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. Our study confirmed the important role of MSLN rs1057147 polymorphism locus in GC lymph node metastases and suggested a potential prognostic factor during GC progression.
Key points
• Rs1057147 GA genotype had an increased risk of lymph node metastasis in gastric cancer.
• The A allele of rs1057147 had a stronger association with lymph node metastasis than the G allele.
• The binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The data that support the findings of this study are available on request from the corresponding author LY. The data are not publicly available due to them containing information that could compromise research participant privacy.
References
Abou-El-Naga AM, Abo El-Khair SM, Mahmoud AZ, Hamza M, Elshazli RM (2021) Association of genetic variants in the 3′-untranslated region of the mesothelin (MSLN) gene with ovarian carcinoma. J Biochem Mol Toxicol 35(2):e22637. https://doi.org/10.1002/jbt.22637
Ali Syeda Z, Langden SSS, Munkhzul C, Lee M, Song SJ (2020) Regulatory mechanism of microRNA expression in cancer. Int J Mol Sci 21(5) https://doi.org/10.3390/ijms21051723
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A (2013) NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res 41(D1):D991-5. https://doi.org/10.1093/nar/gks1193
Boffa DJ, Mallin K, Herrin J, Resio B, Salazar MC, Palis B, Facktor M, McCabe R, Nelson H, Shulman LN (2020) Survival after cancer treatment at top-ranked US cancer hospitals vs affiliates of top-ranked cancer hospitals. JAMA Netw Open 3(5):e203942. https://doi.org/10.1001/jamanetworkopen.2020.3942
Bosch F, Todorova R, Link H, Westphalen CB, Boeck S, Heinemann V, Werner J, Kirchner T, Angele MK, Neumann J (2019) Molecular subtyping of gastric cancer with respect to the growth pattern of lymph-node metastases. J Cancer Res Clin Oncol 145(11):2689–2697. https://doi.org/10.1007/s00432-019-03029-4
Cai F, Dong Y, Wang P, Zhang L, Yang Y, Liu Y, Wang X, Zhang R, Liang H, Sun Y, Deng J (2022) Risk assessment of lymph node metastasis in early gastric cancer: establishment and validation of a seven-point scoring model. Surgery 171(5):1273–1280. https://doi.org/10.1016/j.surg.2021.10.049
Carlborg O, Haley CS (2004) Epistasis: too often neglected in complex trait studies? Nat Rev Genet 5(8):618–625. https://doi.org/10.1038/nrg1407
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China. CA Cancer J Clin 66(2):115–132. https://doi.org/10.3322/caac.21338
Dai CL, Yang ZG, Xue LP, Li YM (2013) Application value of multi-slice spiral computed tomography for imaging determination of metastatic lymph nodes of gastric cancer. World J Gastroenterol 19(34):5732–5737. https://doi.org/10.3748/wjg.v19.i34.5732
de Almeida RC, Chagas VS, Castro MAA, Petzl-Erler ML (2018) Integrative analysis identifies genetic variants associated with autoimmune diseases affecting putative microRNA binding sites. Front Genet 9:139. https://doi.org/10.3389/fgene.2018.00139
Deng N, Zhou H, Fan H, Yuan Y (2017) Single nucleotide polymorphisms and cancer susceptibility. Oncotarget 8(66):110635–110649. https://doi.org/10.18632/oncotarget.22372
Di J, Ji H, Ji F, Zhao J, Zhang C, Tang H, Li E, Cao H, Jiang B (2021) Current status and development trends of morbidity and mortality in gastric cancer patients in Xining, 2009–2016. Am J Transl Res 13(11):12431–12439
Fang X, Wei J, He X, An P, Wang H, Jiang L, Shao D, Liang H, Li Y, Wang F, Min J (2015) Landscape of dietary factors associated with risk of gastric cancer: a systematic review and dose-response meta-analysis of prospective cohort studies. Eur J Cancer 51(18):2820–2832. https://doi.org/10.1016/j.ejca.2015.09.010
Fang T, Zhang L, Yin X, Wang Y, Zhang X, Bian X, Jiang X, Yang S, Xue Y (2023) The prognostic marker elastin correlates with epithelial-mesenchymal transition and vimentin-positive fibroblasts in gastric cancer. J Pathol Clin Res 9(1):56–72. https://doi.org/10.1002/cjp2.298
Garritano S, De Santi C, Silvestri R, Melaiu O, Cipollini M, Barone E, Lucchi M, Barale R, Mutti L, Gemignani F, Bonotti A, Foddis R, Cristaudo A, Landi S (2014) A common polymorphism within MSLN affects miR-611 binding site and soluble mesothelin levels in healthy people. J Thorac Oncol 9(11):1662–1668. https://doi.org/10.1097/JTO.0000000000000322
Ge Y, He Y, Jiang M, Luo D, Huan X, Wang W, Zhang D, Yang L, Zhou J (2017) Polymorphisms in lncRNA PTENP1 and the risk of gastric cancer in a Chinese population. Dis Markers 2017:6807452. https://doi.org/10.1155/2017/6807452
Giordano G, Ferioli E, Tafuni A (2022) The role of mesothelin expression in serous ovarian carcinoma: impacts on diagnosis, prognosis, and therapeutic targets. Cancers (Basel) 14(9) https://doi.org/10.3390/cancers14092283
Goldman MJ, Craft B, Hastie M, Repecka K, McDade F, Kamath A, Banerjee A, Luo Y, Rogers D, Brooks AN, Zhu J, Haussler D (2020) Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol 38(6):675–678. https://doi.org/10.1038/s41587-020-0546-8
Goricar K, Kovac V, Dodic-Fikfak M, Dolzan V, Franko A (2020) Evaluation of soluble mesothelin-related peptides and MSLN genetic variability in asbestos-related diseases. Radiol Oncol 54(1):86–95. https://doi.org/10.2478/raon-2020-0011
He C, Tu H, Sun L, Xu Q, Gong Y, Jing J, Dong N, Yuan Y (2015) SNP interactions of Helicobacter pylori-related host genes PGC, PTPN11, IL1B, and TLR4 in susceptibility to gastric carcinogenesis. Oncotarget 6(22):19017–26. https://doi.org/10.18632/oncotarget.4231
He X, Wang L, Riedel H, Wang K, Yang Y, Dinu CZ, Rojanasakul Y (2017) Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. Mol Cancer 16(1):63. https://doi.org/10.1186/s12943-017-0633-8
Hirotsu Y, Hada M, Amemiya K, Oyama T, Mochizuki H, Omata M (2020) Multi-regional sequencing reveals clonal and polyclonal seeding from primary tumor to metastases in advanced gastric cancer. J Gastroenterol 55(5):553–564. https://doi.org/10.1007/s00535-019-01659-6
Hung RJ, Boffetta P, Brennan P, Malaveille C, Gelatti U, Placidi D, Carta A, Hautefeuille A, Porru S (2004) Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis 25(6):973–978. https://doi.org/10.1093/carcin/bgh080
Jia Y, Yan Q, Zheng Y, Li L, Zhang B, Chang Z, Wang Z, Tang H, Qin Y, Guan XY (2022) Long non-coding RNA NEAT1 mediated RPRD1B stability facilitates fatty acid metabolism and lymph node metastasis via c-Jun/c-Fos/SREBP1 axis in gastric cancer. J Exp Clin Cancer Res 41(1):287. https://doi.org/10.1186/s13046-022-02449-4
Joshi SS, Badgwell BD (2021) Current treatment and recent progress in gastric cancer. CA Cancer J Clin 71(3):264–279. https://doi.org/10.3322/caac.21657
Karimzadeh MR, Zarin M, Ehtesham N, Khosravi S, Soosanabadi M, Mosallaei M, Pourdavoud P (2020) MicroRNA binding site polymorphism in inflammatory genes associated with colorectal cancer: literature review and bioinformatics analysis. Cancer Gene Ther 27(10–11):739–753. https://doi.org/10.1038/s41417-020-0172-0
Kong X, Yang S, Liu C, Tang H, Chen Y, Zhang X, Zhou Y, Liang G (2020) Relationship between MEG3 gene polymorphism and risk of gastric cancer in Chinese population with high incidence of gastric cancer. Biosci Rep 40(11) 10.1042/BSR20200305
Kozlov AP (2022) The theory of carcino-evo-devo and its non-trivial predictions. Genes (Basel) 13(12) https://doi.org/10.3390/genes13122347
Lee HH, Kim SY, Jung ES, Yoo J, Kim TM (2019) Mutation heterogeneity between primary gastric cancers and their matched lymph node metastases. Gastric Cancer 22(2):323–334. https://doi.org/10.1007/s10120-018-0870-6
Li W, Ye F, Wang D, Sun X, Tong W, Lian G, Jiang J, Suo J, Zhang DY (2013) Protein predictive signatures for lymph node metastasis of gastric cancer. Int J Cancer 132(8):1851–1859. https://doi.org/10.1002/ijc.27864
Morgan AD, Seely KD, Hagenstein LD, Florey GM, Small JM (2022) Bacterial Involvement in progression and metastasis of adenocarcinoma of the stomach. Cancers (Basel) 14(19) https://doi.org/10.3390/cancers14194886
Nagata K, Shinto E, Shiraishi T, Yamadera M, Kajiwara Y, Mochizuki S, Okamoto K, Einama T, Kishi Y, Ueno H (2021) Mesothelin expression is correlated with chemoresistance in stage IV colorectal cancer. Ann Surg Oncol 28(13):8579–8586. https://doi.org/10.1245/s10434-021-10507-y
Nguyen NT, Dang NT, Dang QH, Tran VC, Vo HL, Yamaguchi M, Ta TV (2021) Polymorphism of MUC1 gene in vietnamese gastric cancer patients: a multicenter case-control study. Front Oncol 11:694977. https://doi.org/10.3389/fonc.2021.694977
Okholm C, Svendsen LB, Achiam MP (2014) Status and prognosis of lymph node metastasis in patients with cardia cancer - a systematic review. Surg Oncol 23(3):140–146. https://doi.org/10.1016/j.suronc.2014.06.001
Raei N, Behrouz B, Zahri S, Latifi-Navid S (2016) Helicobacter pylori infection and dietary factors act synergistically to promote gastric cancer. Asian Pac J Cancer Prev 17(3):917–921. https://doi.org/10.7314/apjcp.2016.17.3.917
Rocken C, Amallraja A, Halske C, Opasic L, Traulsen A, Behrens HM, Kruger S, Liu A, Haag J, Egberts JH, Rosenstiel P, Meissner T (2021) Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine. Genome Med 13(1):177. https://doi.org/10.1186/s13073-021-00975-y
Salaspuro M (2012) Interactions of alcohol and tobacco in gastrointestinal cancer. J Gastroenterol Hepatol 27(Suppl 2):135–139. https://doi.org/10.1111/j.1440-1746.2012.07017.x
Shen K, Liu K, Wang Y, Ni P, Xiao J, Hao F, Zhou X, Xu Z, Yang L (2022) Polymorphisms of an oncogenic gene, mesothelin, predict the risk and prognosis of gastric cancer in a Chinese Han population. Arch Toxicol 96(7):2097–2111. https://doi.org/10.1007/s00204-022-03290-6
Shi Y, Chen X, Xi B, Yu X, Ouyang J, Han C, Qin Y, Wu D, Shen H (2017) SNP rs3202538 in 3′UTR region of ErbB3 regulated by miR-204 and miR-211 promote gastric cancer development in Chinese population. Cancer Cell Int 17:81. https://doi.org/10.1186/s12935-017-0449-z
Shin CM, Park K, Kim N, Won S, Ohn JH, Lee S, Park JH, Kang SJ, Kim JS, Lee DH (2022) rs2671655 single nucleotide polymorphism modulates the risk for gastric cancer in Helicobacter pylori-infected individuals: a genome-wide association study in the Korean population. Gastric Cancer 25(3):573–585. https://doi.org/10.1007/s10120-022-01285-x
Slaby O, Bienertova-Vasku J, Svoboda M, Vyzula R (2012) Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancer. J Cell Mol Med 16(1):8–21. https://doi.org/10.1111/j.1582-4934.2011.01359.x
Song S, Liu B, Zeng X, Wu Y, Chen H, Wu H, Gu J, Gao X, Ruan Y, Wang H (2022) Reticulon 2 promotes gastric cancer metastasis via activating endoplasmic reticulum Ca(2+) efflux-mediated ERK signalling. Cell Death Dis 13(4):349. https://doi.org/10.1038/s41419-022-04757-1
Tian S, Peng P, Li J, Deng H, Zhan N, Zeng Z, Dong W (2020) SERPINH1 regulates EMT and gastric cancer metastasis via the Wnt/beta-catenin signaling pathway. Aging 12(4):3574–3593. https://doi.org/10.18632/aging.102831
Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96(6):434–442. https://doi.org/10.1093/jnci/djh075
Wang M, Yu W, Cao X, Gu H, Huang J, Wu C, Wang L, Sha X, Shen B, Wang T, Yao Y, Zhu W, Huang F (2022) Exosomal CD44 transmits lymph node metastatic capacity between gastric cancer cells via YAP-CPT1A-mediated FAO reprogramming. Front Oncol 12:860175. https://doi.org/10.3389/fonc.2022.860175
Wang H, Gong H, Tang A, Cui Y (2023) Neutrophil/lymphocyte ratio predicts lymph node metastasis in patients with gastric cancer. Am J Transl Res 15(2):1412–1420
Xiao J, Zhu C, Ni P, Chen W, Li Z, Fan H, Ma X, Xu Z, Yang L (2021) Correlations of SNHG5 genetic polymorphisms with susceptibility and prognosis to gastric cancer in a Chinese population. Genomics 113(4):1754–1760. https://doi.org/10.1016/j.ygeno.2021.04.025
Xiao J, Shen K, Liu K, Wang Y, Fan H, Cheng Q, Zhou X, Hu L, Wang G, Xu Z, Yang L (2022) Obesity promotes lipid accumulation in lymph node metastasis of gastric cancer: a retrospective case-control study. Lipids Health Dis 21(1):123. https://doi.org/10.1186/s12944-022-01734-7
Xu Y, Ma H, Yu H, Liu Z, Wang LE, Tan D, Muddasani R, Lu V, Ajani JA, Wang Y, Wei Q (2013) The miR-184 binding-site rs8126 T>C polymorphism in TNFAIP2 is associated with risk of gastric cancer. PLoS One 8(5):e64973. https://doi.org/10.1371/journal.pone.0064973
Yang S, Wang YL, Lyu Y, Jiang Y, Xiang J, Ji S, Kang S, Lyu X, He C, Li P, Liu B, Wu C (2021) mGWAS identification of six novel single nucleotide polymorphism loci with strong correlation to gastric cancer. Cancer Metab 9(1):34. https://doi.org/10.1186/s40170-021-00269-2
Yen EY, Miaw SC, Yu JS, Lai IR (2017) Exosomal TGF-beta1 is correlated with lymphatic metastasis of gastric cancers. Am J Cancer Res 7(11):2199–2208
Zhang T, Li X, He Y, Wang Y, Shen J, Wang S, You Q, Zhai J, Shen L (2022) Cancer-associated fibroblasts-derived HAPLN1 promotes tumour invasion through extracellular matrix remodeling in gastric cancer. Gastric Cancer 25(2):346–359. https://doi.org/10.1007/s10120-021-01259-5
Zhao J, Shi Y, Cao G (2023) The application of single-cell RNA sequencing in the inflammatory tumor microenvironment. Biomolecules 13(2) https://doi.org/10.3390/biom13020344
Zhu H, Yang L, Zhou B, Yu R, Tang N, Wang B (2006) Myeloperoxidase G-463A polymorphism and the risk of gastric cancer: a case-control study. Carcinogenesis 27(12):2491–2496. https://doi.org/10.1093/carcin/bgl121
Acknowledgements
We would like to thank the Core Facility of the First Affiliated Hospital of Nanjing Medical University for its help in the detection of experimental samples.
Funding
This study was financially supported by the National Natural Science Foundation of China (Grant no. 81874219) and Project of Cultivating Innovation in Science and Technology Plan of Liyang City (Grant no.LC2021001).
Author information
Authors and Affiliations
Contributions
KS for study concept and design, analysis and interpretation of data, statistical analysis, and drafting of the manuscript. QC, JX, and XZ for the acquisition of data, analysis, and interpretation of data, and statistical analysis. YW, PN, KL, LH, and HF for technical and material support, acquisition of data, and revision of the manuscript. ZX provided blood and tissue samples for the study. LY for obtaining funding, critical revision of the manuscript for important intellectual content, and study supervision. All authors read and approved the manuscript.
Corresponding author
Ethics declarations
Ethics approval
This study was approved by the ethics committee of the First Affiliated Hospital of Nanjing Medical University and was in accordance with the 1964 Helsinki.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Shen, K., Cheng, Q., Xiao, J. et al. Polymorphism rs1057147 located in mesothelin gene predicts lymph node metastasis in patients with gastric cancer. Appl Microbiol Biotechnol 107, 3637–3651 (2023). https://doi.org/10.1007/s00253-023-12555-8
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s00253-023-12555-8