Somatic mutation profiling of liver and biliary cancer by targeted next generation sequencing

Abstract

Liver and biliary cancers are highly lethal cancer types lacking effective treatments. The somatic mutations, particularly those with low mutant allele frequencies, in Chinese patients with liver and biliary cancer have not been profiled, and the frequency of patients benefiting from targeted therapy has not been studied. The present study evaluated the tumor tissues of 45 Chinese patients with hepatocellular carcinoma (HCC) and 12 Chinese patients with biliary tract cancer (BTC) by targeted next generation sequencing, with an average coverage of 639x, to identify alterations in 372 cancer-related genes. A total of 263 variants were identified in 139 genes, with 85.6% of these variants not previously reported in the Catalogue Of Somatic Mutations In Cancer database, and the mutation profile was different from the current datasets, including The Cancer Genome Atlas dataset and the National Cancer Center Japan (NCC_JP) dataset. Patients with hepatitis B virus (HBV) infection harbored more mutations than those without HBV infection, and the mutations in HBV carriers occurred preferentially in genes involved in vascular endothelial growth factor signaling pathways. Mutations in fibroblast growth factor and RAS signaling pathways were enriched in patients with cirrhosis, and alterations in interleukin and transforming growth factor signaling pathways were more frequently identified in individuals with abnormal bilirubin expression. Of all the patients, 7% exhibited variants in the target of sorafenib, and 42% harbored variants in the targets of drugs that have been approved to treat other types of cancer. These findings indicate diverse HCC/BTC variants patterns in different populations, and that the mutation load and patterns are correlated with clinical features. Further clinical studies are now warranted to evaluate the efficacies of other targeted drugs besides sorafenib in the treatment of patients with liver and biliary cancer.

Keratin 19‐expressing hepatocellular carcinoma and small‐duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features

“…Only one of 12 cases of K19 + HCC associated with HBV infection had a TERT promoter mutation in the present study. CTNNB1 mutations were the second most frequent alterations in HCC (13~35%) . Codons 32–37 encode the β‐Tcrp binding domain, while codons 41 and 45 involve phosphorylation of β‐catenin.…”

Integrative analysis of highly mutated genes in hepatitis B virus‐related hepatic carcinoma

“…Next, a total of 22 significant KEGG pathway terms and 16 significant WIKI pathway terms were identified in upregulated mutated genes (Table S11 and 12). The top 10 enriched KEGG and WIKI pathways of upregulated mutated genes are presented in Figure 4E.…”

“…Accumulation of genetic alterations is a hallmark of HCC, and a great number of mutated genes, including CTNNB1, TSC1/2, PREX2, TP53, TERT, AXIN1, ARID1A, RET, and ARID2, have been identified in HCC, especially, in HBV‐related HCC . Current studies suggest that the mutations of CTNNB1 are associated with low stage HCC .…”

“…Accumulation of genetic alterations is a hallmark of HCC, 8 and a great number of mutated genes, including CTNNB1, TSC1/2, PREX2, TP53, TERT, AXIN1, ARID1A, RET, and ARID2, have been identified in HCC, especially, in HBVrelated HCC. 3,[9][10][11][12][13][14][15] Current studies suggest that the mutations of CTNNB1 are associated with low stage HCC. 16 TERT promoter mutations are more frequently observed in HCC patients with low α-fetoprotein (AFP) levels and advanced ages.…”

High‑level SETD1B gene expression is associated with unfavorable prognosis in hepatocellular carcinoma

“…The mixed lineage leukemia ( MLL ) family of proteins, including MLL1-MLL4, SET1A and SETD1B , specifically methylates Lys4 of histone H3 and serves a vital role in the transcriptional regulation of genes (6). In our previous study, it was identified that SETD1B was the most frequently mutated gene in primary hepatic neuroendocrine tumor, and that one of the three SETD1B mutants, A1054del, promoted cell proliferation, migration and invasion (7). However, the underlying role of SETD1B in liver carcinogenesis was not addressed.…”