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.
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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)