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Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Endometrial Cancer | Primary research

Identification of the prognostic value of a 2-gene signature of the WNT gene family in UCEC using bioinformatics and real-world data

Authors: Yuexin Hu, Mingjun Zheng, Dandan Zhang, Rui Gou, Ouxuan Liu, Shuang Wang, Bei Lin

Published in: Cancer Cell International | Issue 1/2021

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Abstract

Background

The WNT gene family plays an important role in the occurrence and development of malignant tumors, but its involvement has not been systematically analyzed in uterine corpus endometrial carcinoma (UCEC). This study aimed to evaluate the prognostic value of the WNT gene family in UCEC.

Methods

Pan-cancer transcriptome data of the UCSC Xena database and Genotype-Tissue Expression (GTEx) normal tissue data were downloaded to analyze the expression and prognosis of 19 WNT family genes in UCEC. A cohort from The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) was used to analyze the expression of the WNT gene family in different immune subtypes and clinical subgroups. The STRING database was used to analyze the interaction of the WNT gene family and its biological function. Univariate Cox regression analysis and Lasso cox analysis were used to identify the genes associated with significant prognosis and to construct multi signature prognosis model. An immunohistochemical assay was used to verify the predictive ability of the model. Risk score and the related clinical features were used to construct a nomogram.

Results

The expression levels of WNT2, WNT3, WNT3A, WNT5A, WNT7A, and WNT10A were significantly different among different immune subtypes and correlated with TP53 mutation. According to the WNT family genes related to the prognosis of UCEC, UCEC was classified into two subtypes (C1, C2). The prognosis of subtype C1 was significantly better than that of subtype C2. A 2-gene signature (WNT2 and WNT10A) was constructed and the two significantly prognostic groups can be divided based on median Risk score. These results were verified using real-world data, and the nomogram constructed using clinical features and Risk score had good prognostic ability.

Conclusions

The 2-gene signature including WNT2 and WNT10A can be used to predict the prognosis of patients with UCEC, which is important for clinical decision-making and individualized therapy for patients with UCEC.
Literature
1.
go back to reference Global Burden of Disease, Cancer C, Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2018;4:1553–68.CrossRef Global Burden of Disease, Cancer C, Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2018;4:1553–68.CrossRef
2.
go back to reference Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics. CA Cancer J Clin. 2021;71:7–33.CrossRef Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics. CA Cancer J Clin. 2021;71:7–33.CrossRef
3.
go back to reference Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet. 2016;387:1094–108.CrossRef Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet. 2016;387:1094–108.CrossRef
4.
go back to reference Bell DW, Ellenson LH. Molecular genetics of endometrial carcinoma. Annu Rev Pathol. 2019;14:339–67.CrossRef Bell DW, Ellenson LH. Molecular genetics of endometrial carcinoma. Annu Rev Pathol. 2019;14:339–67.CrossRef
5.
go back to reference Akalay I, Tan TZ, Kumar P, Janji B, Mami-Chouaib F, Charpy C, et al. Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene. 2015;34:2261–71.CrossRef Akalay I, Tan TZ, Kumar P, Janji B, Mami-Chouaib F, Charpy C, et al. Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene. 2015;34:2261–71.CrossRef
6.
go back to reference Dale TC. Signal transduction by the Wnt family of ligands. Biochem J. 1998;329(Pt 2):209–23.CrossRef Dale TC. Signal transduction by the Wnt family of ligands. Biochem J. 1998;329(Pt 2):209–23.CrossRef
7.
go back to reference Yong X, Tang B, Xiao YF, Xie R, Qin Y, Luo G, et al. Helicobacter pylori upregulates Nanog and Oct4 via Wnt/beta-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett. 2016;374:292–303.CrossRef Yong X, Tang B, Xiao YF, Xie R, Qin Y, Luo G, et al. Helicobacter pylori upregulates Nanog and Oct4 via Wnt/beta-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett. 2016;374:292–303.CrossRef
8.
go back to reference Monteleone E, Orecchia V, Corrieri P, Schiavone D, Avalle L, Moiso E, et al. SP1 and STAT3 functionally synergize to induce the RhoU small GTPase and a subclass of non-canonical WNT responsive genes correlating with poor prognosis in breast cancer. Cancers (Basel). 2019;11:101.CrossRef Monteleone E, Orecchia V, Corrieri P, Schiavone D, Avalle L, Moiso E, et al. SP1 and STAT3 functionally synergize to induce the RhoU small GTPase and a subclass of non-canonical WNT responsive genes correlating with poor prognosis in breast cancer. Cancers (Basel). 2019;11:101.CrossRef
9.
go back to reference Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 2001;61:6050–4.PubMed Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 2001;61:6050–4.PubMed
10.
go back to reference Cheng Y, Li X, Dai Y, Dong Y, Yang X, Wang J. Identification of an immune-related risk signature and nomogram predicting the overall survival in patients with endometrial cancer. J Gynecol Oncol. 2021;32:e30.CrossRef Cheng Y, Li X, Dai Y, Dong Y, Yang X, Wang J. Identification of an immune-related risk signature and nomogram predicting the overall survival in patients with endometrial cancer. J Gynecol Oncol. 2021;32:e30.CrossRef
11.
go back to reference Zhang J, Wang Z, Zhao R, An L, Zhou X, Zhao Y, et al. An integrated autophagy-related gene signature predicts prognosis in human endometrial Cancer. BMC Cancer. 2020;20:1030.CrossRef Zhang J, Wang Z, Zhao R, An L, Zhou X, Zhao Y, et al. An integrated autophagy-related gene signature predicts prognosis in human endometrial Cancer. BMC Cancer. 2020;20:1030.CrossRef
12.
go back to reference Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.CrossRef Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.CrossRef
13.
go back to reference Tibshirani R. Regression shrinkage and selection via the lasso: a retrospective. 1996; 58. Tibshirani R. Regression shrinkage and selection via the lasso: a retrospective. 1996; 58.
14.
go back to reference Balachandran VP, Gonen M, Smith JJ, Dematteo RP. Nomograms in oncology: more than meets the eye. Lancet Oncol. 2015;16:e173–80.CrossRef Balachandran VP, Gonen M, Smith JJ, Dematteo RP. Nomograms in oncology: more than meets the eye. Lancet Oncol. 2015;16:e173–80.CrossRef
15.
go back to reference Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity. 2018;48:812–830.e14.CrossRef Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity. 2018;48:812–830.e14.CrossRef
16.
go back to reference Bur ME, Perlman C, Edelmann L, Fey E, Rose PG. p53 expression in neoplasms of the uterine corpus. Am J Clin Pathol. 1992;98:81–7.CrossRef Bur ME, Perlman C, Edelmann L, Fey E, Rose PG. p53 expression in neoplasms of the uterine corpus. Am J Clin Pathol. 1992;98:81–7.CrossRef
17.
go back to reference Jia L, Liu Y, Yi X, Miron A, Crum CP, Kong B, et al. Endometrial glandular dysplasia with frequent p53 gene mutation: a genetic evidence supporting its precancer nature for endometrial serous carcinoma. Clin Cancer Res. 2008;14:2263–9.CrossRef Jia L, Liu Y, Yi X, Miron A, Crum CP, Kong B, et al. Endometrial glandular dysplasia with frequent p53 gene mutation: a genetic evidence supporting its precancer nature for endometrial serous carcinoma. Clin Cancer Res. 2008;14:2263–9.CrossRef
18.
go back to reference Catasus L, Gallardo A, Cuatrecasas M, Prat J. Concomitant PI3K-AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol. 2009;22:522–9.CrossRef Catasus L, Gallardo A, Cuatrecasas M, Prat J. Concomitant PI3K-AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol. 2009;22:522–9.CrossRef
19.
go back to reference Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15:10–7.CrossRef Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15:10–7.CrossRef
20.
go back to reference Hussein YR, Soslow RA. Molecular insights into the classification of high-grade endometrial carcinoma. Pathology. 2018;50:151–61.CrossRef Hussein YR, Soslow RA. Molecular insights into the classification of high-grade endometrial carcinoma. Pathology. 2018;50:151–61.CrossRef
21.
go back to reference Carlson JW, Nastic D. High-grade endometrial carcinomas: classification with molecular insights. Surg Pathol Clin. 2019;12:343–62.CrossRef Carlson JW, Nastic D. High-grade endometrial carcinomas: classification with molecular insights. Surg Pathol Clin. 2019;12:343–62.CrossRef
22.
go back to reference McAlpine JN, Temkin SM, Mackay HJ. Endometrial cancer: not your grandmother’s cancer. Cancer. 2016;122:2787–98.CrossRef McAlpine JN, Temkin SM, Mackay HJ. Endometrial cancer: not your grandmother’s cancer. Cancer. 2016;122:2787–98.CrossRef
23.
go back to reference Urick ME, Bell DW. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer. 2019;19:510–21.CrossRef Urick ME, Bell DW. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer. 2019;19:510–21.CrossRef
24.
go back to reference Talhouk A, McAlpine JN. New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016;3:14.CrossRef Talhouk A, McAlpine JN. New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016;3:14.CrossRef
25.
go back to reference McMellen A, Woodruff ER, Corr BR, Bitler BG, Moroney MR. Wnt signaling in gynecologic malignancies. Int J Mol Sci. 2020;21:4272.CrossRef McMellen A, Woodruff ER, Corr BR, Bitler BG, Moroney MR. Wnt signaling in gynecologic malignancies. Int J Mol Sci. 2020;21:4272.CrossRef
26.
go back to reference Coopes A, Henry CE, Llamosas E, Ford CE. An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target. Endocr Relat Cancer. 2018;25:647.CrossRef Coopes A, Henry CE, Llamosas E, Ford CE. An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target. Endocr Relat Cancer. 2018;25:647.CrossRef
27.
go back to reference Kramer N, Schmollerl J, Unger C, Nivarthi H, Rudisch A, Unterleuthner D, et al. Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene. 2017;36:5460–72.CrossRef Kramer N, Schmollerl J, Unger C, Nivarthi H, Rudisch A, Unterleuthner D, et al. Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene. 2017;36:5460–72.CrossRef
28.
go back to reference Han Q, Wang X, Liao X, Han C, Yu T, Yang C, et al. Diagnostic and prognostic value of WNT family gene expression in hepatitis B virusrelated hepatocellular carcinoma. Oncol Rep. 2019;42:895–910.PubMedPubMedCentral Han Q, Wang X, Liao X, Han C, Yu T, Yang C, et al. Diagnostic and prognostic value of WNT family gene expression in hepatitis B virusrelated hepatocellular carcinoma. Oncol Rep. 2019;42:895–910.PubMedPubMedCentral
29.
go back to reference Pan LH, Yao M, Cai Y, Gu JJ, Yang XL, Wang L, et al. Oncogenic Wnt3a expression as an estimable prognostic marker for hepatocellular carcinoma. World J Gastroenterol. 2016;22:3829–36.CrossRef Pan LH, Yao M, Cai Y, Gu JJ, Yang XL, Wang L, et al. Oncogenic Wnt3a expression as an estimable prognostic marker for hepatocellular carcinoma. World J Gastroenterol. 2016;22:3829–36.CrossRef
30.
go back to reference Oguma J, Ozawa S, Kazuno A, Nitta M, Ninomiya Y, Kajiwara H. Wnt3a expression is associated with poor prognosis of esophageal squamous cell carcinoma. Oncol Lett. 2018;15:3100–8.PubMed Oguma J, Ozawa S, Kazuno A, Nitta M, Ninomiya Y, Kajiwara H. Wnt3a expression is associated with poor prognosis of esophageal squamous cell carcinoma. Oncol Lett. 2018;15:3100–8.PubMed
31.
go back to reference Liu J, Li S, Feng G, Meng H, Nie S, Sun R, et al. Nine glycolysis-related gene signature predicting the survival of patients with endometrial adenocarcinoma. Cancer Cell Int. 2020;20:183.CrossRef Liu J, Li S, Feng G, Meng H, Nie S, Sun R, et al. Nine glycolysis-related gene signature predicting the survival of patients with endometrial adenocarcinoma. Cancer Cell Int. 2020;20:183.CrossRef
32.
go back to reference Jiang P, Sun W, Shen N, Huang X, Fu S. Identification of a metabolism-related gene expression prognostic model in endometrial carcinoma patients. BMC Cancer. 2020;20:864.CrossRef Jiang P, Sun W, Shen N, Huang X, Fu S. Identification of a metabolism-related gene expression prognostic model in endometrial carcinoma patients. BMC Cancer. 2020;20:864.CrossRef
33.
go back to reference Ali I, Medegan B, Braun DP. Wnt9A induction linked to suppression of human colorectal cancer cell proliferation. Int J Mol Sci. 2016;17:495.CrossRef Ali I, Medegan B, Braun DP. Wnt9A induction linked to suppression of human colorectal cancer cell proliferation. Int J Mol Sci. 2016;17:495.CrossRef
34.
go back to reference Augustin I, Dewi DL, Hundshammer J, Rempel E, Brunk F, Boutros M. Immune cell recruitment in teratomas is impaired by increased Wnt secretion. Stem Cell Res. 2016;17:607–15.CrossRef Augustin I, Dewi DL, Hundshammer J, Rempel E, Brunk F, Boutros M. Immune cell recruitment in teratomas is impaired by increased Wnt secretion. Stem Cell Res. 2016;17:607–15.CrossRef
35.
go back to reference Liu X, Lu R, Wu S, Zhang YG, Xia Y, Sartor RB, et al. Wnt2 inhibits enteric bacterial-induced inflammation in intestinal epithelial cells. Inflamm Bowel Dis. 2012;18:418–29.CrossRef Liu X, Lu R, Wu S, Zhang YG, Xia Y, Sartor RB, et al. Wnt2 inhibits enteric bacterial-induced inflammation in intestinal epithelial cells. Inflamm Bowel Dis. 2012;18:418–29.CrossRef
36.
go back to reference Lopez-Bergami P, Barbero G. The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment. Cancer Metastasis Rev. 2020;39:933–52.CrossRef Lopez-Bergami P, Barbero G. The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment. Cancer Metastasis Rev. 2020;39:933–52.CrossRef
37.
go back to reference Liu Y, Meng F, Xu Y, Yang S, Xiao M, Chen X, et al. Overexpression of Wnt7a is associated with tumor progression and unfavorable prognosis in endometrial cancer. Int J Gynecol Cancer. 2013;23:304–11.CrossRef Liu Y, Meng F, Xu Y, Yang S, Xiao M, Chen X, et al. Overexpression of Wnt7a is associated with tumor progression and unfavorable prognosis in endometrial cancer. Int J Gynecol Cancer. 2013;23:304–11.CrossRef
38.
go back to reference Hu M, Xie J, Liu Z, Wang X, Liu M, Wang J. Comprehensive analysis identifying Wnt ligands gene family for biochemical recurrence in prostate adenocarcinoma and construction of a nomogram. J Comput Biol. 2020;27:1656–67.CrossRef Hu M, Xie J, Liu Z, Wang X, Liu M, Wang J. Comprehensive analysis identifying Wnt ligands gene family for biochemical recurrence in prostate adenocarcinoma and construction of a nomogram. J Comput Biol. 2020;27:1656–67.CrossRef
39.
go back to reference Cai L, Hu C, Yu S, Liu L, Zhao J, Zhao Y, et al. Identification of EMT-related gene signatures to predict the prognosis of patients with endometrial cancer. Front Genet. 2020;11:582274.CrossRef Cai L, Hu C, Yu S, Liu L, Zhao J, Zhao Y, et al. Identification of EMT-related gene signatures to predict the prognosis of patients with endometrial cancer. Front Genet. 2020;11:582274.CrossRef
40.
go back to reference Liu J, Jiang P, Chen X, Shen Y, Cui G, Ma Z, et al. Construction of a nine DNA repair-related gene prognostic classifier to predict prognosis in patients with endometrial carcinoma. BMC Cancer. 2021;21:29.CrossRef Liu J, Jiang P, Chen X, Shen Y, Cui G, Ma Z, et al. Construction of a nine DNA repair-related gene prognostic classifier to predict prognosis in patients with endometrial carcinoma. BMC Cancer. 2021;21:29.CrossRef
Metadata
Title
Identification of the prognostic value of a 2-gene signature of the WNT gene family in UCEC using bioinformatics and real-world data
Authors
Yuexin Hu
Mingjun Zheng
Dandan Zhang
Rui Gou
Ouxuan Liu
Shuang Wang
Bei Lin
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02215-0

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