الفهرس 
Hepatocellular carcinomaOnly 14 pages are availabe for public view
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Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver that usually develops in the setting of chronic liver disease. It is now sixth most commonly-diagnosed cancer and the fourth leading cause of cancer-related death worldwide. In Egypt, it ranks as the first malignancy in males and the second in female with being the first leading cause of cancer-related mortality and morbidity according to the according to National Population-Based Cancer Registry Program. With limitation of patients’ number eligible for surgical resection, limited efficacy of sorafenib targeted therapy and high mortality and recurrence rates, there is an urgent need to investigate for novel genes involved in HCC initiation and progression that could have diagnostic and therapeutic potentials.
SET oncoprotein is a potent inhibitor of PP2A tumor suppressor protein leading to upregulation of many kinases-driven oncogenic pathways as AKT, MAPK and BCR-ABL. SET overexpression has been reported in many solid cancers like Wilms’ tumor, leukemia, breast cancer, pancreatic cancer, colon cancer, non-small cell lung cancer and gastric cancer where it enhances cell proliferation, survival, drug resistance, invasion and metastasis suggesting its crucial role in carcinogenesis and poor prognostic value. The use of SET antagonist targeted therapy to reactivate PP2A activity has been suggested.
Therefore, the present study aimed to assess the expression level of SET protein in hepatocellular carcinoma in Egyptian population compared to normal tissues and also its correlation with the clinicopathological parameters to identify its clinical significance and prognostic value.
This was a retrospective study included 100 liver surgical specimens from patients presented with hepatocellular carcinoma with paired samples collected from the tumor tissue and the adjacent non-tumorous liver tissue.
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Most of HCC cases (63%) were <60-year-old with a male predominance (76%). Ninety-eight (98%) of cases were positive for hepatitis viral infection and 78.7% of cases had an AFP level <500ng/ml. Seventy-nine (79%) of cases presented by a solitary focal lesion with 74% of cases with tumor size ≤ 5cm. All our cases (100%) were of classic HCC type with prevalence of low tumor grade (73%) and low pathologic stage (92%). Fourty-five (45%) of cases exhibited microscopic vascular invasion. Adjacent liver tissue showed cirrhotic changes in 86% of cases.
The current study revealed overexpression of SET protein in HCC with 54% of cases showing high-SET expression (H-score ≥200) and 46% of cases showing low-SET expression (H-score <200). There was also a significantly higher mean value of H-score of SET oncoprotein in HCC tissues (206.5) than in the adjacent non-tumorous liver tissue (137) (P<0.0001). Furthermore, almost every studied case had a significantly higher SET expression in the tumor tissue than its adjacent non-tumorous tissue with an average tumor/paired non-tumor ratio of 1.74.
In comparison of SET expression with the relevant clinicopathological data of HCC cases, SET oncoprotein overexpression in tumor tissues significantly correlated with larger tumor size (>5cm) and positive lymphovascular invasion.
There was no significant correlation between SET expression and other clinicopathological parameters (age, gender, etiology, AFP level, tumor focality, tumor pattern, tumor grade or pathologic stage).
Kaplan-Meier univariate survival analysis revealed that high AFP level (>500ng/ml) (P=0.019), large tumor size (>5cm) (P=0.003), advanced tumor stage (T3, T4) (P= 0.010) and high value of SET protein expression level (H-score ≥200) (P<0.001) significantly correlated with shorter overall survival.
The Kaplan-Meier multivariate survival analysis revealed that SET expression in tumor tissues is the most independent factor to affect the overall survival for the studied Egyptian HCC patients after surgical resection. SET overexpression significantly correlates with shorter overall survival (HR: 4.41; 95% CI: 1.96-10.35; p < 0.001). The second most independent factor that
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significantly affects the overall survival was the advanced pathological stage; pT3,4 (HR: 4.04; 95% CI: 1.48-11.01; p=0.006).