Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment

Abstract

BackgroundThe APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment.ResultsWe used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs. Among the five genes, APOBEC3B expression levels were bimodally distributed, whereas expression of APOBEC3A, REV1, UNG, and FHIT was unimodally distributed. The majority of the cell lines had low levels of APOBEC3A expression. The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A. Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types.ConclusionsWe observed correlations of expression levels of the five candidate genes in cell line models with sensitivity to cancer drug treatment. We also noted suggestive correlations between measures of abundance of APOBEC-like sequence motifs with drug sensitivity in small samples of cell lines from individual cancer categories, which require further validation in larger datasets. Molecular mechanisms underlying the links between the activities of the products of each of the five genes, the resulting mutagenic processes, and sensitivity to each category of antitumor agents require further investigation.

Distribution and difference of APOBEC‐induced mutations in the TpCpW context of HBV DNA between HCC and non‐HCC

“…The result suggested that APOBECs might act strongly in this region of the minus‐strand in HCC cells. This phenomenon may be attributable to the high expression of APOBECs during the development and progression of HCC cells, so that more APOBECs in cancer cells would be packaged into the viral capsid, which exerts a stronger effect on HBV minus‐strand DNA. In view of the above characteristics of HCC‐derived HBV DNA, it may be possible to identify HCC by APOBEC‐induced mutation pattern of HBV DNA.…”

<p>Berzosertib (VE-822) inhibits gastric cancer cell proliferation via base excision repair system</p>

“…Activation-induced cytidine deaminase required class switch recombination and somatic hypermutation; during the process, UNG promotes the former one and suppresses the latter one 11–13. Moreover, there was also a negative correlation between UNG expression and APOBEC3B (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) in mature B-cell lymphoma cells 13. An important carcinogenic factor is a viral infection which may be caused by up-regulation of APOBEC3B 13.…”

“…Moreover, there was also a negative correlation between UNG expression and APOBEC3B (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) in mature B-cell lymphoma cells 13. An important carcinogenic factor is a viral infection which may be caused by up-regulation of APOBEC3B 13. APOBEC3B gene up-regulation increased cancer risk with 5–10% up-regulated in lower end spectrum tumors and nearly 90–95% up-regulated in higher end spectrum tumors 14–16.…”

“…APOBEC3B gene up-regulation increased cancer risk with 5–10% up-regulated in lower end spectrum tumors and nearly 90–95% up-regulated in higher end spectrum tumors 14–16. UNG plays a reverse role against APOBEC3B by affecting its mutagenesis 13. In accordance with previous studies, our KM plotter results also showed only high UNG expression was associated with high overall survival probability in gastric cancer patients that suggested UNG may take a major role in BER-related DNA damage repair.…”

Insights into the Structures and Multimeric Status of APOBEC Proteins Involved in Viral Restriction and Other Cellular Functions

“…The A3A is thought to play a role in restricting foreign infectious DNA viruses [ 96 , 97 , 98 , 99 , 100 ] and in restricting internal retroelements [ 101 , 102 , 103 ]. However, elevated expression or/and defective regulation of A3A can also lead to mutations of genomic DNA and contribute to various diseases, including cancer [ 100 , 104 , 105 , 106 ]. More recently, A3A is also shown to deaminate RNA substrates bearing specific structural features [ 107 , 108 ], and editing of RNA by A3A is shown to occur in tumor cells [ 109 ].…”