Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer

Carcinogenesis, Jan 2017

The incidence of liver cancer has increased in recent years. Worldwide, liver cancer is common: more than 600000 related deaths are estimated each year. In the USA, about 27170 deaths due to liver cancer are estimated for 2016. Liver cancer is highly resistant to conventional chemotherapy and radiotherapy. For all stages combined, the 5-year survival rate is 15–17%, leaving much to be desired for liver cancer prevention and therapy. Heterogeneity, which can originate from genomic instability, is one reason for poor outcome. About 80–90% of liver cancers are hepatocellular carcinoma (HCC), and recent cancer genome sequencing studies have revealed frequently mutated genes in HCC. In this review, we discuss the cause of the tumor heterogeneity based on the functions of genes that are frequently mutated in HCC. We overview the functions of the genes that are most frequently mutated (e.g. TP53, CTNNB1, AXIN1, ARID1A and WWP1) that portray major pathways leading to HCC and identify the roles of these genes in preventing genomic instability. Notably, the pathway analysis suggested that oxidative stress management may be critical to prevent accumulation of DNA damage and further mutations. We propose that both chromosome instability (CIN) and microsatellite instability (MIN) are integral to the hepatic carcinogenesis process leading to heterogeneity in HCC and that the pathways leading to heterogeneity may be targeted for prognosis, prevention and treatment.

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Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer

Carcinogenesis Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer Chinthalapally V. Rao 1 Adam S. Asch 0 Hiroshi Y. Yamada 1 0 Stephenson Cancer Center, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC) , Oklahoma City, OK 73104 , USA 1 Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC) , 975 NE 10th Street BRC1207, Oklahoma City, OK 73104 , USA The incidence of liver cancer has increased in recent years. Worldwide, liver cancer is common: more than 60000 related deaths are estimated each year. In the USA, about 27 170 deaths due to liver cancer are estimated for 2016. Liver cancer is highly resistant to conventional chemotherapy and radiotherapy. For all stages combined, the 5-year survival rate is 15-17%, leaving much to be desired for liver cancer prevention and therapy. Heterogeneity, which can originate from genomic instability, is one reason for poor outcome. About 80-90% of liver cancers are hepatocellular carcinoma (HCC), and recent cancer genome sequencing studies have revealed frequently mutated genes in HCC. In this review, we discuss the cause of the tumor heterogeneity based on the functions of genes that are frequently mutated in HCC. We overview the functions of the genes that are most frequently mutated (e.g. TP53, CTNNB1, AXIN1, ARID1A and WWP1) that portray major pathways leading to HCC and identify the roles of these genes in preventing genomic instability. Notably, the pathway analysis suggested that oxidative stress management may be critical to prevent accumulation of DNA damage and further mutations. We propose that both chromosome instability (CIN) and microsatellite instability (MIN) are integral to the hepatic carcinogenesis process leading to heterogeneity in HCC and that the pathways leading to heterogeneity may be targeted for prognosis, prevention and treatment. - Liver cancer is common worldwide, especially in Southeast Asia and sub-Saharan Africa, where hepatitis virus infection is endemic. More than 600 000 deaths from liver cancer are estimated worldwide each year. In contrast to an overall decreasing trend in cancer deaths, the incidence of and deaths by liver cancer in the USA have increased in recent years. Approximately 27 170 deaths are estimated for 2016 ( 1 ). About 90% of liver cancer is hepatocellular carcinoma (HCC); the remaining 10% is cholangiocarcinoma (bile duct cancer). Cirrhosis and nonalcoholic fatty liver disease are prominent risk factors in the USA and are often associated with alcohol abuse and obesity, respectively. In the USA, the overall 5-year survival rate for patients with liver cancer is 15–17% ( 1 ). Surgery is performed at early stages, when the 5-year survival is 31%. However, less than half of all patients with liver cancer are diagnosed at an early stage. Later stage liver cancers are quite resistant to current chemo- and radiotherapies. For patients with later stage cancer, survival rates drop to 11% (regional) and 3% (metastatic). Clinical trials with newer immunotherapies have shown some signs of promise ( 2 ), but more time is needed to assess the results on a larger scale. Thus, better therapies to treat liver cancer, along with diagnostic, prognostic and preventive measures for high-risk groups, such as those with hepatitis virus, cirrhosis or nonalcoholic fatty liver disease, and those who have been exposed to dietary aflatoxin, are desperately needed. Abbreviations Liver cancer is highly heterogeneous in terms of morphology, genome composition and mutated genes ( 3,4 ). Not only is HCC heterogeneous among patients, multiple HCCs that occurred in a patient also showed significant heterogeneity (5) and signs of tumor evolution ( 5–8 ). The heterogeneity of HCCs in a patient may result in difficulty in clinic for designing customized targeted approach for HCCs in such patients. Since 90% of liver cancer is HCC and most studies have been conducted with HCC, in this review, we primarily discuss the results from HCC studies. Risk factors and known causes for HCC include genetic factors (e.g. male gender, metabolic syndrome and diabetes), carcinogens (e.g. aflatoxin), lifestyle/habitual behaviors (e.g. tobacco smoking, alcohol abuse and obesity) and biological factors/infection (e.g. hepatitis virus) ( 1,3,4 ). Exposure to the risk factors depends on environment. Thus, there is much variation among geological regions and time frame in liver cancer etiology. In Africa and Southeast Asia, hepatitis virus and aflatoxin exposure are estimated to be accountable for 70–90% of HCC ( 9 ). Hepatitis virus infection is a leading risk factor for HCC in the USA as well. Among 1500 patients at United States Veterans Administration hospitals who developed HCC from 2005 through 2010, the annual proportion of nonalcoholic stea (...truncated)


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Rao, Chinthalapally V., Asch, Adam S., Yamada, Hiroshi Y.. Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer, Carcinogenesis, 2017, pp. 2-11, Volume 38, Issue 1, DOI: 10.1093/carcin/bgw118