APOBEC3B Upregulation and Genomic Mutation Patterns in Serous Ovarian Carcinoma

Abstract

Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here we report wide variation in expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in a majority of ovarian cancer cell lines (3 standard deviations above the mean of normal ovarian surface epithelial cells) and high grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′TC dinucleotide motifs in early-stage high grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA ‘repair’ enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability.

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…The mechanistic details of these events following deamination by A3s remain uncharacterized, but working models have been proposed based upon what is known about AID-dependent SHM [5,[20][21][22]. As summarized in Figure 1, replication prior to removal of dU can result in C>T transitions due to incorporation of dA into the daughter strand through Watson-Crick base pairing.…”

“…This may be because epithelia are a front-line barrier to viruses, and hence the innate immune response, including A3 viral restriction, is more primed or active in these cells. A3B is highly expressed in tumor types with enrichment of A3 mutation signatures [37,38], and its expression correlates with prevalence of A3 signatures in breast and ovarian cancers [22,35]. Much attention therefore, has focused on A3B as an agent for genomic mutations.…”

“…However even within and between different breast cancer samples a mixed presentation of A3-like mutations within large rearrangement-associated kataegis macroclusters, or sporadically throughout the genome, or with varying proportions of transition or transversion can be observed [32]. Indeed, a recent analysis of ovarian cancer has linked C>A transversions to A3B activity, with the implication that a different TLS polymerase may act on abasic sites caused by cytosine deamination in these tumors [22] (Figure 1). This suggests that many of the proposed models of A3-mediated mutagenesis maybe valid, and that together with increased A3A or A3B expression (as occurs during HPV infection, for example) there are multiple points of failure in DSB repair, replication or transcription that might potentiate A3 off-target activity, even within cancers arising in the same tissue.…”

APOBEC3B: Pathological consequences of an innate immune DNA mutator

“…Biochemical assays in vitro demonstrated that APO-BEC3B prefers substrate cytosines in 5"TCA and 5"TCG contexts. [9,11] Mutation data from three independent primary breast tumor genome datasets clearly indicated that mutations at these sites are significantly enriched. [9] Moreover, APOBEC3B expression levels correlated positively with both cytosine mutation and overall mutation loads.…”

“…Some of these sources are well known, such as oxidation of guanine and hydrolytic deamination of cytosine, but many others are poorly defined. [3,8] However, much headway has been made recently in understanding additional endogenous sources of DNA damage, with our group [9][10][11][12] and others [2,3,13,14] implicating APOBEC3B, a member of the APOBEC family of single-stranded DNA (ssDNA) polynucleotide cytosine deaminases, in cancer genome mutagenesis [ Figure 1]. …”