TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma

Huigang Li; Zuyuan Lin; Jianyong Zhuo; Modan Yang; Wei Shen; Zhihang Hu; Yichen Ding; Hao Chen; Chiyu He; Xinyu Yang; Siyi Dong; Xuyong Wei; Beicheng Sun; Shusen Zheng; Ren Lang; Di Lu; Xiao Xu

doi:10.21147/j.issn.1000-9604.2023.01.07

TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma

Chin J Cancer Res. 2023 Feb 28;35(1):66-80. doi: 10.21147/j.issn.1000-9604.2023.01.07.

Authors

Huigang Li^{1

2

3

4}, Zuyuan Lin^{1

2

3

4}, Jianyong Zhuo^{1

2

3

4}, Modan Yang^{1

2

3

4}, Wei Shen^{1

2

3

4}, Zhihang Hu^{1

2

3

4}, Yichen Ding¹, Hao Chen^{1

2

3

4}, Chiyu He^{1

2

3

4}, Xinyu Yang^{1

2

3

4}, Siyi Dong⁵, Xuyong Wei^{1

2

3

4}, Beicheng Sun⁶, Shusen Zheng^{4

5

7

8

9}, Ren Lang¹⁰, Di Lu^{1

2

3

4}, Xiao Xu^{1

3

4

5}

Affiliations

¹ Zhejiang University School of Medicine, Hangzhou 310058, China.
² Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
³ The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou 310006, China.
⁴ Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China.
⁵ National Center for Healthcare Quality Management in Liver Transplant, Hangzhou 310003, China.
⁶ Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
⁷ Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
⁸ Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 311112, China.
⁹ NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
¹⁰ Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing 100020, China.

PMID: 36910852
PMCID: PMC9992998
DOI: 10.21147/j.issn.1000-9604.2023.01.07

Abstract

Objective: Lung metastasis is a common and fatal complication of liver transplantation for hepatocellular carcinoma (HCC). The precise prediction of post-transplant lung metastasis in the early phase is of great value.

Methods: The mRNA profiles of primary and paired lung metastatic lesions were analyzed to determine key signaling pathways. We enrolled 241 HCC patients who underwent liver transplantation from three centers. Tissue microarrays were used to evaluate the prognostic capacity of tumor necrosis factor (TNF), tumor necrosis factor receptor 1 (TNFR1), and TNFR2, particularly for post-transplant lung metastasis.

Results: Comparison of primary and lung metastatic lesions revealed that the TNF-dependent signaling pathway was related to lung metastasis of HCC. The expression of TNF was degraded in comparison to that in para-tumor tissues (P<0.001). The expression of key receptors in the TNF-dependent signaling pathway, TNFR1 and TNFR2, was higher in HCC tissues than in para-tumor tissues (P<0.001). TNF and TNFR1 showed no relationship with patients' outcomes, whereas elevated TNFR2 in tumor tissue was significantly associated with worse overall survival (OS) and increased recurrence risk (5-year OS rate: 31.9% vs. 62.5%, P<0.001). Notably, elevated TNFR2 levels were also associated with an increased risk of post-transplant lung metastasis (hazard ratio: 1.146; P<0.001). Cox regression analysis revealed that TNFR2, Hangzhou criteria, age, and hepatitis B surface antigen were independent risk factors for post-transplant lung metastasis, and a novel nomogram was established accordingly. The nomogram achieved excellent prognostic efficiency (area under time-dependent receiver operating characteristic =0.755, concordance-index =0.779) and was superior to conventional models, such as the Milan criteria.

Conclusions: TNFR2 is a potent prognostic biomarker for predicting post-transplant lung metastasis in patients with HCC. A nomogram incorporating TNFR2 deserves to be a helpful prognostic tool in liver transplantation for HCC.

Keywords: Lung metastasis; hepatocellular carcinoma; liver transplantation; nomogram.