T. Hoki1, E. Katsuta2, L. Yan3, K. Takabe2,4, F. Ito1,4,5 1Roswell Park Cancer Institute,Center For Immunotherapy,Buffalo, NY, USA 2Roswell Park Cancer Institute,Breast Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 3Roswell Park Cancer Institute,Department Of Biostatistics And Bioinformatics,Buffalo, NY, USA 4State University Of New York At Buffalo,Department Of Surgery, University At Buffalo Jacobs School Of Medicine And Biomedical Sciences,Buffalo, NY, USA 5Roswell Park Cancer Institute,Department Of Surgical Oncology,Buffalo, NY, USA
Introduction:
Hepatocellular carcinoma (HCC) is the sixth most common malignancy with poor prognosis worldwide. HCC commonly develops in patients with underlying chronic liver disease. Higher iron accumulation is present in chronic liver disease and is known to be a risk factor in the development of HCC. The divalent metal-ion transporter-1 (DMT1) is a primary importer of non-heme iron, and is ubiquitously expressed throughout the body, with highest expression in the proximal duodenum, which is the main site of iron uptake. We previously reported that mal-regulation of iron metabolism caused by increased DMT1 expression in the duodenum induced hepatocarcinogenesis. Increased expression of DMT1 in tumorous tissue has also been shown to be associated with carcinogenesis and progression in colorectal and esophageal adenocarcinoma. However, the role of DMT1 in liver of HCC patients remains unknown.
Methods:
Clinical and RNA-seq data were obtained from the Cancer Genome Atlas (TCGA). Gene expression level was compared among each AJCC Stage, and each viral infectious status. Patients were divided into two groups based on DMT1 expression level for survival analysis using Kaplan-Meier method followed by Log-rank test. The cut-off value was determined by automated scanning and selecting the threshold yielding the lowest p-value.
Results:
Of 442 HCC patients in the TCGA cohort, tumor RNA-seq data were obtained from 342 patients with overall survival (OS) and etiology data. The prevalence of HBV, HCV, dual HBV-HCV, and non-B non-C were 97(28.4%), 47(13.7%), 6(1.8%), and 192(56.1%), respectively. Clinical stages were available for 327 patients, and the patients number of stage I, II, III, and IV were 165(50.5%), 75(22.9%), 82(25.1%), and 5(1.5%), respectively. The median observation period was 19.3 months (range, 0–120.73m). There was no significant difference in the expression level of DMT1 among each clinical stage (stage I/II/III/IV) and each viral infection status (HBV/HCV/dual HBV-HCV/non-B non-C). To investigate the impact of DMT1 expression on patients’ prognosis, OS was compared between high and low expression groups in the whole cohort as well as in different viral infectious status. Interestingly, high expression of DMT1 showed better survival in non-B non-C patients (5-year OS rate: 65.2% vs 32.7%, p=0.038), HBV patients (5-year OS rate: 78.3% vs 61.9%, p=0.006), and HBV and/or HCV-infected patients (5-year OS rate: 65.7% vs 36.5%, p=0.001) compared to low expression group. Whereas there was no significant difference in OS between high and low expression groups in HCV patients (p=0.193) and the whole cohort (p=0.069).
Conclusion:
HCC with increased expression of DMT1 has better OS for HBV, HBV and/or HCV, and non-B non-C patients. These findings may imply that DMT1 in HCC tumors plays different role among different viral infectious status patients, and play roles to suppress tumor progression other than iron transportation.