Absence of GATA3/FOXA1 Co-expression Predicts Poor Prognosis in Upper Tract Urothelial Carcinoma

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Mar 1

PMID 38425344

Authors

Yue Wang

Yunfan Wang

Huiying He

Yan Xiong

Affiliations

Soon will be listed here.

Abstract

Objective: GATA binding protein 3 (GATA3) and forkhead box A1 (FOXA1) have been individually implicated in the progression of upper tract urothelial carcinoma (UTUC). This study aims to evaluate the prognostic value of GATA3/FOXA1 co-expression in UTUC patients.

Methods: We collected 108 UTUC pathological tissue samples with complete follow-up data and 24 normal control urothelial tissues. We created a 132-site microarray and performed immunohistochemistry (IHC) to measure GATA3 and FOXA1 expression levels. Kaplan-Meier survival and Cox regression analyses were conducted to assess UTUC prognosis.

Results: GATA3 expression was positively correlated with FOXA1 (P=0.031). Absence of GATA3/FOXA1 co-expression (GATA3-/FOXA1-) was associated with tumor extensive necrosis (P=0.001) after Bonferroni correction for multiple comparisons. GATA3-/FOXA1- was associated with shorter Disease-Free Survival (DFS) (P=0.001) and Cancer-Specific Survival (CSS) (P<0.001) than other combination groups. Multivariate analyses identified extensive necrosis as an independent prognostic factor for CSS (P=0.030).

Conclusions: Our study revealed a positive correlation between GATA3 and FOXA1 expression in UTUC. GATA3-/FOXA1- is linked to tumor extensive necrosis and poor prognosis in UTUC and may serve as a potential biomarker for UTUC patients.

References

Theodorou V, Stark R, Menon S, Carroll J . GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility. Genome Res. 2012; 23(1):12-22. PMC: 3530671. DOI: 10.1101/gr.139469.112. View

Roupret M, Seisen T, Birtle A, Capoun O, Comperat E, Dominguez-Escrig J . European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur Urol. 2023; 84(1):49-64. DOI: 10.1016/j.eururo.2023.03.013. View

Wang Y, Zhang J, Wang S, Zhang Y, He H . Expression of the epigenetic H3K27me3 modifier genes KDM6A and EZH2 in patients with upper tract urothelial carcinoma. Oncol Lett. 2020; 20(6):349. PMC: 7586283. DOI: 10.3892/ol.2020.12212. View

Kollberg P, Chebil G, Eriksson P, Sjodahl G, Liedberg F . Molecular subtypes applied to a population-based modern cystectomy series do not predict cancer-specific survival. Urol Oncol. 2019; 37(10):791-799. DOI: 10.1016/j.urolonc.2019.04.010. View

Yang B, Zhao X, Wan C, Ma X, Niu S, Guo A . Genomic profiling of Chinese patients with urothelial carcinoma. BMC Cancer. 2021; 21(1):162. PMC: 7885246. DOI: 10.1186/s12885-021-07829-1. View

Detilleux D, Spill Y, Balaramane D, Weber M, Bardet A . Pan-cancer predictions of transcription factors mediating aberrant DNA methylation. Epigenetics Chromatin. 2022; 15(1):10. PMC: 8944071. DOI: 10.1186/s13072-022-00443-w. View

Warrick J, Hu W, Yamashita H, Walter V, Shuman L, Craig J . FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation. Nat Commun. 2022; 13(1):6575. PMC: 9630410. DOI: 10.1038/s41467-022-34251-3. View

Hisamatsu Y, Tokunaga E, Yamashita N, Akiyoshi S, Okada S, Nakashima Y . Impact of GATA-3 and FOXA1 expression in patients with hormone receptor-positive/HER2-negative breast cancer. Breast Cancer. 2014; 22(5):520-8. DOI: 10.1007/s12282-013-0515-x. View

Schrijver W, Schuurman K, van Rossum A, Droog M, Jeronimo C, Salta S . FOXA1 levels are decreased in pleural breast cancer metastases after adjuvant endocrine therapy, and this is associated with poor outcome. Mol Oncol. 2018; 12(11):1884-1894. PMC: 6210032. DOI: 10.1002/1878-0261.12353. View

10.

Martin E, Orlando K, Yokobori K, Wade P . The estrogen receptor/GATA3/FOXA1 transcriptional network: lessons learned from breast cancer. Curr Opin Struct Biol. 2021; 71:65-70. PMC: 8648900. DOI: 10.1016/j.sbi.2021.05.015. View

11.

Warrick J, Walter V, Yamashita H, Chung E, Shuman L, Amponsa V . FOXA1, GATA3 and PPARɣ Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines. Sci Rep. 2016; 6:38531. PMC: 5141480. DOI: 10.1038/srep38531. View

12.

Tang Q, Zuo W, Wan C, Xiong S, Xu C, Yuan C . Comprehensive genomic profiling of upper tract urothelial carcinoma and urothelial carcinoma of the bladder identifies distinct molecular characterizations with potential implications for targeted therapy & immunotherapy. Front Immunol. 2023; 13:1097730. PMC: 9936149. DOI: 10.3389/fimmu.2022.1097730. View

13.

Bontoux C, Rialland T, Cussenot O, Comperat E . A four-antibody immunohistochemical panel can distinguish clinico-pathological clusters of urothelial carcinoma and reveals high concordance between primary tumor and lymph node metastases. Virchows Arch. 2020; 478(4):637-645. DOI: 10.1007/s00428-020-02951-0. View

14.

Wu J, Chen S, Wu X, Mao W, Wang Y, Xu B . Trends of incidence and prognosis of upper tract urothelial carcinoma. Bosn J Basic Med Sci. 2020; 21(5):607-619. PMC: 8381214. DOI: 10.17305/bjbms.2020.5345. View

15.

Raman J, Warrick J, Caruso C, Yang Z, Shuman L, Bruggeman R . Altered Expression of the Transcription Factor Forkhead Box A1 (FOXA1) Is Associated With Poor Prognosis in Urothelial Carcinoma of the Upper Urinary Tract. Urology. 2016; 94:314.e1-7. DOI: 10.1016/j.urology.2016.05.030. View

16.

He Y, Wang L, Wei T, Xiao Y, Sheng H, Su H . FOXA1 overexpression suppresses interferon signaling and immune response in cancer. J Clin Invest. 2021; 131(14). PMC: 8279591. DOI: 10.1172/JCI147025. View

17.

Inoue S, Mizushima T, Fujita K, Meliti A, Ide H, Yamaguchi S . GATA3 immunohistochemistry in urothelial carcinoma of the upper urinary tract as a urothelial marker and a prognosticator. Hum Pathol. 2017; 64:83-90. DOI: 10.1016/j.humpath.2017.04.003. View

18.

Sikic D, Eckstein M, Wirtz R, Jarczyk J, Worst T, Porubsky S . FOXA1 Gene Expression for Defining Molecular Subtypes of Muscle-Invasive Bladder Cancer after Radical Cystectomy. J Clin Med. 2020; 9(4). PMC: 7230662. DOI: 10.3390/jcm9040994. View

19.

Rubin M, Dunn R, Strawderman M, Pienta K . Tissue microarray sampling strategy for prostate cancer biomarker analysis. Am J Surg Pathol. 2002; 26(3):312-9. DOI: 10.1097/00000478-200203000-00004. View

20.

Plage H, Samtleben H, Hofbauer S, Kornienko K, Weinberger S, Bruch P . GATA3 expression loss is linked to stage progression but is unrelated to prognosis in muscle-invasive urothelial carcinoma of the bladder. Hum Pathol. 2022; 130:10-17. DOI: 10.1016/j.humpath.2022.09.004. View