Impact of CDH1 Mutation Status on Gene Expression and Co-Expression Networks in Stomach Adenocarcinoma
DOI:
https://doi.org/10.37609/srinmed.51Anahtar Kelimeler:
CDH1- Correlation network- Gene expression- Stomach adenocarcinomaÖz
Objective: This study aims to explore how cadherin 1 (CDH1) mutation status influences gene expression and co-expression networks in Stomach Adenocarcinoma (STAD). By examining frequently mutated genes, we assess transcriptomic alterations and potential molecular rewiring associated with CDH1 mutations.
Method: Somatic mutation profiles and RNA-seq data for STAD patients were obtained from The Cancer Genome Atlas (TCGA). The 20 most frequently mutated genes were identified. Samples were stratified into CDH1-mutated (CDH1+) and non-mutated (CDH1-) groups. Gene expression differences were analyzed using the Wilcoxon rank-sum test. Spearman’s correlation was used to construct gene co-expression networks for each group, with significance defined as FDR-adjusted P≤0.05 and |ρ| > 0.5.
Results: Seven genes showed significant differential expression between CDH1+ and CDH1- tumors. Among these, FAT3, SYNE1, ZFHX4, FAT4, and HMCN1 were upregulated in CDH1+ cases, while PCLO and DNAH5 were downregulated. Co-expression network analysis revealed 47 significant gene-pair correlations in CDH1+ tumors versus 19 in CDH1-.
Conclusion: CDH1 mutation status in STAD is associated with distinct gene expression profiles and co-expression patterns, particularly involving genes related to cell adhesion and cytoskeletal organization. These findings highlight the broader impact of CDH1 alterations beyond E-cadherin loss and suggest candidate genes and pathways that may serve as biomarkers or therapeutic targets in CDH1-mutant gastric cancer.
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Referanslar
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, So-erjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. https://doi.org/10.3322/ caac.21834
Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56. https://doi. org/10.1038/nm.3850
Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9. https://doi. org/10.1038/nature13480
Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46(6):573–82. https://doi. org/10.1038/ng.2983
Sohn BH, Hwang JE, Jang HJ, Lee HS, Oh SC, Shim JJ, et al. Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project. Clin Cancer Res. 2017;23(15):4441–49. https://doi.org/10.1158/1078-0432.CCR-16-2211
Gall TM, Frampton AE. Gene of the month: E-cadherin (CDH1). J Clin Pathol. 2013;66(11):928–32. https:// doi.org/10.1136/jclinpath-2013-201768
Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015;1(1):23–32. https://doi.org/10.1001/jamaon-col.2014.168
Barber M, Murrell A, Ito Y, Maia AT, Hyland S, Oliveira C, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol. 2008;216(3):295–306. https://doi.org/10.1002/ path.2426
Carneiro P, Fernandes MS, Figueiredo J, Caldeira J, Carvalho J, Pinheiro H, et al. E-cadherin dysfunction in gastric cancer--cellular consequences, clinical applications and open questions. FEBS Lett. 2012;586(18):2981–9. https://doi.org/10.1016/j.febs-let.2012.07.045
Graziano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol. 2003;14(12):1705–13. https://doi. org/10.1093/annonc/mdg486
Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2016;44(8):e71. https://doi.org/10.1093/ nar/gkv1507
Wickham H. ggplot2 : Elegant Graphics for Data Analysis. Cham: Springer International Publishing : Imprint: Springer,; 2016.
Csardi G, Nepusz T. The igraph software package for complex network research. InterJournal. 2006;Comp-lex Systems:1695.
Busuttil RA, Zapparoli GV, Haupt S, Fennell C, Wong SQ, Pang JM, et al. Role of p53 in the progression of gastric cancer. Oncotarget. 2014;5(23):12016–26. https://doi.org/10.18632/oncotarget.2434
Haridas D, Ponnusamy MP, Chugh S, Lakshmanan I, Seshacharyulu P, Batra SK. MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB J. 2014;28(10):4183–99. https://doi.org/10.1096/fj.14-257352
Huang YJ, Cao ZF, Wang J, Yang J, Wei YJ, Tang YC, et al. Why MUC16 mutations lead to a better prognosis: A study based on The Cancer Genome Atlas gastric cancer cohort. World J Clin Cases. 2021;9(17):4143– 58. https://doi.org/10.12998/wjcc.v9.i17.4143
Wang K, Kan J, Yuen ST, Shi ST, Chu KM, Law S, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011;43(12):1219–23. https://doi.org/10.1038/ ng.982
Tabouret E, Labussiere M, Alentorn A, Schmitt Y, Marie Y, Sanson M. LRP1B deletion is associated with poor outcome for glioblastoma patients. J Neurol Sci. 2015;358(1-2):440–3. https://doi.org/10.1016/j. jns.2015.09.345
Katoh M. Function and cancer genomics of FAT family genes (review). Int J Oncol. 2012;41(6):1913–8. https://doi.org/10.3892/ijo.2012.1669
Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan S, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013;45(3):253–61. https://doi.org/10.1038/ng.2538
Cai J, Feng D, Hu L, Chen H, Yang G, Cai Q, et al. FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/beta-catenin signalling. Br J Cancer. 2015;113(12):1720–9. https://doi.org/10.1038/ bjc.2015.367
Fontana P, Ginevrino M, Bejo K, Cantalupo G, Ciava-rella M, Lombardi C, et al. A ZFHX4 mutation associated with a recognizable neuropsychological and facial phenotype. Eur J Med Genet. 2021;64(11):104321. https://doi.org/10.1016/j.ejmg.2021.104321
Harbin LM, Lin N, Ueland FR, Kolesar JM. SYNE1 Mutation Is Associated with Increased Tumor Mutation Burden and Immune Cell Infiltration in Ovarian Cancer. Int J Mol Sci. 2023;24(18). https://doi. org/10.3390/ijms241814212
Li X, Tang Z, Li Z, Li Z, Zhao P, Song Y, et al. Somatic mutations that affect early genetic progression and immune microenvironment in gastric carcinoma. Pathol Res Pract. 2024;257:155310. https://doi.org/10.1016/j. prp.2024.155310
Lee SH, Je EM, Yoo NJ, Lee SH. HMCN1, a cell polarity-related gene, is somatically mutated in gastric and colorectal cancers. Pathol Oncol Res. 2015;21(3):847– 8. https://doi.org/10.1007/s12253-014-9809-3
Zhu C, Yang Q, Xu J, Zhao W, Zhang Z, Xu D, et al. Somatic mutation of DNAH genes implicated higher chemotherapy response rate in gastric adenocarcinoma patients. J Transl Med. 2019;17(1):109. https://doi. org/10.1186/s12967-019-1867-6
Bernhardt M, Behrens HM, Kruger S, Rocken C. Exploration of the Tumour Biological Significance of PCLO in Gastric Cancer: Results from a Large Central European Cohort. Pathobiology. 2024;91(3):187–95. https://doi.org/10.1159/000534889
Cai HQ, Zhang LY, Fu LM, Xu B, Jiao Y. Mutational landscape of TP53 and CDH1 in gastric cancer. World J Gastrointest Surg. 2024;16(2):276–83. https://doi. org/10.4240/wjgs.v16.i2.276
Lopez MJ, Carbajal J, Alfaro AL, Saravia LG, Za-nabria D, Araujo JM, et al. Characteristics of gastric cancer around the world. Crit Rev Oncol Hematol. 2023;181:103841. https://doi.org/10.1016/j.critre-vonc.2022.103841
Pinheiro H, Bordeira-Carrico R, Seixas S, Carvalho J, Senz J, Oliveira P, et al. Allele-specific CDH1 downregulation and hereditary diffuse gastric cancer. Hum Mol Genet. 2010;19(5):943–52. https://doi. org/10.1093/hmg/ddp537
Gamble LA, Heller T, Davis JL. Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1: A Review. JAMA Surg. 2021;156(4):387–92. https://doi.org/10.1001/jamasurg.2020.6155
Aguiar KEC, Oliveira IS, Cohen-Paes AN, Coelho RCC, Vinagre L, Rodrigues JCG, et al. Molecular Profile of Variants in CDH1, TP53, PSCA, PRKAA1, and TTN Genes Related to Gastric Cancer Susceptibility in Amazonian Indigenous Populations. J Pers Med. 2023;13(9). https://doi.org/10.3390/jpm13091364
33. Wang H, Shen L, Li Y, Lv J. Integrated characterisation of cancer genes identifies key molecular biomarkers in stomach adenocarcinoma. J Clin Pathol. 2020;73(9):579–86. https://doi.org/10.1136/jclinpath-2019-206400
Jinawath N, Shiao MS, Chanpanitkitchote P, Svasti J, Furukawa Y, Nakamura Y. Enhancement of Migration and Invasion of Gastric Cancer Cells by IQGAP3. Biomolecules. 2020;10(8). https://doi.org/10.3390/ biom10081194
Shenoy S. CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management. Cancer Manag Res. 2019;11:10477–86. https://doi.org/10.2147/CMAR. S208818
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