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Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma

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Abstract

Penile squamous cell carcinoma (PSCC) with a poor prognosis lacks reliable biomarkers for stratifying patients. Fas-associated death domain (FADD) could regulate cell proliferation and has shown promising diagnostic and prognostic significance in multiple cancers. However, researchers have not determined how FADD exerts its effect on PSCC. In this study, we set out to investigate the clinical features of FADD and the prognostic impact of PSCC. Additionally, we also assessed the role of affecting the immune environment in PSCC. Immunohistochemistry was carried out to evaluate the protein expression of FADD. The difference between FADDhigh and FADDlow was explored by RNA sequencing from available cases. The immune environment evaluation of CD4, CD8, and Foxp3 was performed by immunohistochemical. In this study, we found that FADD was overexpressed in 19.6 (39/199) patients, and the overexpression of FADD was associated with phimosis (p=0.007), N stage (p<0.001), clinical stage (p=0.001), and histologic grade (p=0.005). The overexpression of FADD was an independent prognostic factor for both PFS (HR 3.976, 95% CI 2.413–6.553, p<0.001) and OS (HR 4.134, 95% CI 2.358–7.247, p<0.001). In addition, overexpression of FADD was mainly linked to T cell activation and PD-L1 expression combined with PD-L1 checkpoint in cancer. Further validation demonstrated that overexpression of FADD was positively correlated with the infiltration of Foxp3 in PSCC (p=0.0142). It is the first time to show that overexpression of FADD is an adjunct biomarker with poor prognosis in PSCC and could also serve as a tumor immune environment regulator.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Cheng-Chao Shen for his kind help in pathological assistance and sample collection.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81772755) during the conduct of study.

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Author notes

  1. Ting Xue and Ru Yan contributed equally to this work and shared the first authorship.

Authors and Affiliations

  1. Department of Urology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, 510060, China

    Ting Xue, Ru Yan, Shengjie Guo, Lijuan Jiang, Tingyu Liu, Lichao Wei, Longbin Xiong, Fangjian Zhou, Kai Yao, Ranyi Liu & Hui Han

  2. Department of Medical Oncology, Guizhou Provincial People’s Hospital, Guiyang, China

    Ru Yan

  3. Department of Urology, Shenzhen People’s Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518060, China

    Zaishang Li

  4. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Xiao Xiao & Jietian Jin

  5. Department of Radiology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Huali Ma

  6. Department of General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Chong Wu

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  1. Ting Xue
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Contributions

Study conception and design: R Yan, T Xue, and H Han; acquisition of data: R Yan, SJ Guo, ZS Li, Chong Wu, and Tingyu Liu; performed the experiments and analysis: X X, JJ Jin, LC Wei, LB Xiong, R Yan, and T Xue; analysis and interpretation of data: T Xue, LJ Jiang, and HL Ma; funding acquisition: H Han; drafting of the manuscript: R Yan, T Xue; collection  and integration of data: critical revision of the manuscript for important intellectual content: FJ Zhou, K Yao, RY Liu, H Han; statistical analysis: R Yan, T Xue, and RY Liu; administrative, technical, or material support: RY Liu and H Han; supervision: RY Liu and H Han.

Corresponding authors

Correspondence to Ranyi Liu or Hui Han.

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The Institutional Review Board of Sun Yat-Sen University Cancer Center approved this study.

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Supplementary Information

Figure S1.

The mRNA level of FADD in FADDlow and FADDhigh group. P values were calculated with the use of the Student’s t-test. (PNG 56 kb)

High Resolution Image (TIF 75468 kb)

Figure S2.

Difference analysis of FADDlow and FADDhigh group DEGs in PSCC. a Volcano plot of DEGs between samples in PSCC with FADDlow and FADDhigh group; b Heatmap between FADDlow and FADDhigh group DEGs by clustering analysis. (PNG 2145 kb)

High Resolution Image (TIF 4717 kb)

Figure S3.

Representative micrographs of the staining of Foxp3 (a), CD8+ (b) and CD4+ (c) T cells by immunohistochemistry assay. The upper image shows immunohistochemistry for FADD at low magnification (100×). A lower image in each image shows the high magnification in the upper ones (400×). (PNG 2658 kb)

High Resolution Image (TIF 2200 kb)

Table S1

RIIN value of RNA samples used for RNA sequencing. (DOCX 17 kb)

Table S2

The DEGs of FADDlow and FADDhigh group. (XLS 42 kb)

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Xue, T., Yan, R., Li, Z. et al. Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma. Virchows Arch 482, 869–878 (2023). https://doi.org/10.1007/s00428-023-03514-9

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