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Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma.

ABSTRACT: High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis. Tumor and paired tumor-free liver (TFL) tissues of HCC-patients and healthy tissues were assessed for mRNA expression of 49 CTAs by RT-qPCR and protein expression of five CTAs by immunohistochemistry. Twelve CTA-mRNAs were expressed in ≥10% of HCC-tumors and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA-expression in TFL was an independent negative prognostic factor for post-resection HCC-recurrence and survival. We established a panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients. The increased risk of HCC-recurrence in patients with CTA expression in TFL, suggests that CTA-expressing (pre-)malignant cells may be a source of HCC-recurrence, reflecting the relevance of targeting these to prevent HCC-recurrence.

SUBMITTER: Noordam L

PROVIDER: S-EPMC8160719 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatic resection remains the treatment of choice for patients with early-stage HCC with preserved liver function. Unfortunately, however, the majority of patients develop tumor recurrence. While several clinical factors were found to be associated with tumor recurrence, HCC pathogenesis is a complex process of accumulation of somatic genomic alterations, which leads to a huge molecular heterogeneity that has not been completely understood. The aim of this study is to complement potentially predictive clinical and pathological factors with next-generation sequencing genomic profiling and loss of heterozygosity analysis.Methods124 HCC patients, who underwent a primary hepatic resection from January 2016 to December 2019, were recruited for this study. Next-generation sequencing (NGS) analysis and allelic imbalance assessment in a case-control subgroup analysis were performed. A time-to-recurrence analysis was performed as well by means of Kaplan-Meier estimators.ResultsCumulative number of HCC recurrences were 26 (21%) and 32 (26%), respectively, one and two years after surgery. Kaplan-Meier estimates for the probability of recurrence amounted to 37% (95% C.I.: 24-47) and to 51% (95% C.I.: 35-62), after one and two years, respectively. Multivariable analysis identified as independent predictors of HCC recurrence: hepatitis C virus (HCV) infection (HR: 1.96, 95%C.I.: 0.91-4.24, p = 0.085), serum bilirubin levels (HR: 5.32, 95%C.I.: 2.07-13.69, p = 0.001), number of nodules (HR: 1.63, 95%C.I.: 1.12-2.38, p = 0.011) and size of the larger nodule (HR: 1.11, 95%C.I.: 1.03-1.18, p = 0.004). Time-to-recurrence analysis showed that loss of heterozygosity in the PTEN loci (involved in the PI3K/AKT/mTOR signaling pathway) was significantly associated with a lower risk of HCC recurrence (HR: 0.35, 95%C.I.: 0.13-0.93, p = 0.036).Conclusionsmultiple alterations of cancer genes are associated with HCC progression. In particular, the evidence of a specific AI mutation presented in 20 patients seemed to have a protective effect on the risk of HCC recurrence.

Project description:Background and aims Liver transplantation (LT) can be offered to patients with Hepatocellular carcinoma (HCC) beyond Milan criteria. However, there are currently limited molecular markers on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to derive a combined proteomic/transcriptomic signature on HCC explant predictive of recurrence post-transplant using unbiased, high-throughput approaches. Methods Patients who received a LT for HCC beyond Milan criteria in the context of hepatitis B cirrhosis were identified. Tumor explants from patients with post-transplant HCC recurrence (N = 7) versus those without recurrence (N = 4) were analyzed by mass spectrometry and gene expression array. Univariate analysis was used to generate a combined proteomic/transcriptomic signature linked to recurrence. Significantly predictive genes and proteins were verified and internally validated by immunoblotting and immunohistochemistry. Results Seventy-nine proteins and 636 genes were significantly differentially expressed in HCC tumors with subsequent recurrence (p < 0.05). Univariate survival analysis identified Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) gene (HR = 0.084, 95%CI 0.01–0.68, p = 0.0152), ALDH1A1 protein (HR = 0.039, 95%CI 0.16–0.91, p = 0.03), Galectin 3 Binding Protein (LGALS3BP) gene (HR = 7.14, 95%CI 1.20–432.96, p = 0.03), LGALS3BP protein (HR = 2.6, 95%CI 1.1–6.1, p = 0.036), Galectin 3 (LGALS3) gene (HR = 2.89, 95%CI 1.01–8.3, p = 0.049) and LGALS3 protein (HR = 2.6, 95%CI 1.2–5.5, p = 0.015) as key dysregulated analytes in recurrent HCC. In concordance with our proteome findings, HCC recurrence was linked to decreased ALDH1A1 and increased LGALS3 protein expression by Western Blot. LGALS3BP protein expression was validated in 29 independent HCC samples. Conclusions Significantly increased LGALS3 and LGALS3BP gene and protein expression on explant were associated with post-transplant recurrence, whereas increased ALDH1A1 was associated with absence of recurrence in patients transplanted for HCC beyond Milan criteria. This combined proteomic/transcriptomic signature could help in predicting HCC recurrence risk and guide post-transplant surveillance. Supplementary Information The online version contains supplementary material available at 10.1186/s12014-021-09333-x.

Project description:ImportanceThe remnant liver after hepatectomy may have inadequate blood supply, especially following nonanatomical resection or vascular damage.ObjectiveTo evaluate whether remnant liver ischemia (RLI) may have an adverse effect on long-term survival and morbidity after liver resection in patients with hepatocellular carcinoma.Design, setting, and participantsThis study was a retrospective analysis at Seoul National University Bundang Hospital. Remnant liver ischemia was graded on postoperative computed tomographic scans in 328 patients who underwent hepatectomy for hepatocellular carcinoma between January 1, 2004, and December 31, 2013.Main outcomes and measuresRemnant liver ischemia was defined as reduced or absent contrast enhancement during the venous phase. Remnant liver ischemia was classified as minimal (none or marginal) or severe (partial, segmental, or necrotic).ResultsAmong 328 patients (252 male and 76 female; age range, 26-83 years [mean age, 58.2 years]), radiologic signs of severe RLI were found in 98 patients (29.9%), of whom 63, 16, and 19 had partial, segmental, or necrotic RLI, respectively. These patients experienced more complications and longer hospital stay than patients with minimal RLI. Preoperative history of transarterial embolization (odds ratio [OR], 1.77; 95% CI, 1.02-3.03; P = .04), use of the Pringle maneuver (OR, 1.96; 95% CI, 1.08-3.58; P = .03), and longer operative time (OR, 1.003; 95% CI, 1.002-1.005; P < .001) were independent risk factors for severe RLI. Early recurrence rates within 6 (60.2% vs 9.6%) or 12 (79.6% vs 18.7%) months after hepatectomy were higher in patients with severe RLI than in patients without RLI (P < .001). Severe remnant liver ischemia was an independent risk factor for overall survival (OR, 6.98; 95% CI, 4.27-11.43; P < .001) and disease-free survival (OR, 5.15; 95% CI, 3.62-7.35; P < .001).Conclusions and relevancePreventive management and technical refinements in hepatectomy are important to decrease the risk of RLI and to improve survival of patients with hepatocellular carcinoma.

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Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma.

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