| Abstract: | 肝癌是台灣目前最主要的致死腫瘤之一，在早期並沒有症狀。雖然透過手術切除是最好的治療選擇，但結果的好與壞，全靠發現時的腫瘤個數、大小及癌細胞是否有轉移。肝癌是全世界致死癌症的第二位，也是最常見癌症的第五位，研究指出肝癌在台灣、日本、中國等亞洲國家的發生率較高，反之在西方國家的發生率則相對來的低。而主要造成肝癌的因素大多與B型肝炎、C型肝炎、非酒精性脂肪肝、酒精性肝病以及肝硬化有關。 本研究想全基因體探討肝癌致病機轉及其臨床預後。首先，透過GEO（Gene Expression Omnibus）蒐集五組實驗數據的肝癌病人及正常人肝組織的基因表現圖譜，共計230人，篩選出537個至少兩倍差異表現基因(Differentially Expression Gene，簡稱 DEG)，其中高度表現基因有304個，且近80%基因參與各種metabolic pathways；低度表現有232個基因，其中有20個基因參與cell cycle pathway。值得一提的是上述537個DEGs除了CNIH4，所有基因均呈現一致結果。接著，我們分析這群DEGs是否與臨床預後有關，結果顯示OIT3、CRHBP、MT1M、CDKN2C、MCM7、CDC7、BUB1、CCNA2、CCNE2的基因表現與臨床預後有關且均呈現負面影響。最後，我們用文獻來佐證實驗結果。前人研究顯示CRHBP 表達降低預示著 HCC 的預後不良，此結果與我們不同，推測其原因可能是突變（2.11%）造成。CCNA2 的表現與 HCC 患者的不良分期和預後相關，此結果與本研究相同。我們的研究顯示，CCNA2的低表現其臨床預後較差。文獻說明，在HCC提高MCM7 表現與不利腫瘤特徵和較差的結果相關。但在本研究顯示該基因在低表現時，呈現較差的生存月份，究其原因可能是該基因同時具有3.4%的突變率所致。另外，我們進一步合併CCNA2、CRHBP、MCM7，觀察其預後，結果呈現具加乘效益，亦即原預後生存的狀況就已經是呈現不好的基因，進行加成後導致狀況更差。結論，HCC 組織中 CCNA2 和 MCM7 的低表現以及CRHBP的高表現，均會導致 HCC 患者的總生存期 (OS) 和無病生存期 (DFS) 較差（all log rank P < 0.05）。此外，當 DEG 發生突變時，有可能會干擾其原始的臨床預後存活時間。
Liver cancer is currently one of the most fatal tumors in Taiwan, and there are no symptoms in the early stage. Although surgical resection is the best treatment option, the results depend on the number and size of the tumor at the time of discovery and whether the cancer cells have metastasized. Liver cancer is the second most fatal cancer in the world and the fifth most common cancer. Studies have pointed out that the incidence of liver cancer in Taiwan, Japan, China and other Asian countries is relatively high, while the incidence in Western countries is relatively low. The main factors that cause liver cancer are mostly related to hepatitis B, hepatitis C, non-alcoholic fatty liver, alcoholic liver disease and cirrhosis.In this study, we wanted to explore the pathogenic mechanism of liver cancer and its clinical prognosis with the whole genomic data. A total of 230 gene expression profiles, derived from HCC (Hepatocellular Carcinoma) patients and healthy people from GEO (Gene Expression Omnibus), screened out 537 differential expression genes (DEGs) with at least 2-fold changes. Among them, there are 304 highly expressed genes, and nearly 80% of genes are involved in various metabolic pathways; while 232 under-expression genes, of which 20 genes are involved in the cell cycle pathway. It is worth mentioning that all genes of the above 537 DEGs, except CNIH4, showed consistent results. Next, we analyzed whether this group of DEGs is related to clinical prognosis, and the results showed that the gene expression of OIT3, CRHBP, MT1M, CDKN2C, MCM7, CDC7, BUB1, CCNA2, CCNE2 were related to clinical prognosis and all showed negative effects. Finally, we verified our results by literature. Previous study has shown that decreased CRHBP expression is predictive of poor prognosis in HCC. However, our result indicated that highly-expression of CRHBP with mutation rate of 2.11% is poor survival. Expression of CCNA2 was associated with unfavorable stage and prognosis in individuals with HCC, and this result is the same as ours. In our study, CCNA2 is under-expression with poor survival outcome. MCM7 can significantly inhibit cell proliferation in vitro and HCC tumorigenicity in vivo. The high performance of MCM7 is related to the poorer overall survival rate of HCC patients. However, our result showed that under-expression of MCM7 has a poorer survival month, the reason may be that this gene also has a mutation rate of 3.4%. In addition, we further combined CCNA2, CRHBP, and MCM7 to observe the prognosis, and the results showed an additive benefit.In conclusion, under-expression of CCNA2 and MCM7 while over-expression of CRHBP in HCC tissues accounted for poorer overall survival (OS) and disease-free survival (DFS) in HCC patients (all log rank P < 0.05). Furthermore, when DEGs are mutated, they may interfere with their original clinical prognostic survival time. |
