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Mutation spectra in cancer genomes provide information on the disease aetiology and the causality underlying the evolution and progression of cancer. Genome-wide mutation patterns reflect the effects of mutagenic insults and can thus reveal past carcinogen-specific exposures and inform hypotheses on the causative factors for specific cancer types. To identify mutation profiles in human cancers, single-gene studies were first employed, focusing mainly on the tumour suppressor gene TP53. Furthermore, experimental studies had been developed in model organisms. They allowed the characterization of the mutation patterns specific to known human carcinogens, such as polycyclic aromatic hydrocarbons or ultraviolet light. With the advent of massively parallel sequencing, mutation landscapes become revealed on a large scale, in human primary tumours and in experimental models, enabling deeper investigations of the functional and structural impact of mutations on the genome, including exposurespecific base-change fingerprints known as mutational signatures. These studies can now accelerate the identification of aetiological factors, contribute to carcinogen evaluation and classification and ultimately inform cancer prevention measures.Cancer in humans is characterised by a wide range of somatic mutations that confer a growth advantage on cells, leading to the development of a neoplasm [1,2]. These mutations often result from either endogenous defects in homeostatic biological pathways (e.g. DNA damage repair) or exogenous factors, such as exposures to chemical carcinogens. Various assays have been used to evaluate the genotoxic impact of the studied compounds. The Ames test employs the bacterium Salmonella typhimurium and is commonly used to investigate the mutagenic properties of chemicals. It allows the evaluation of a large number of compounds in a short time, and, depending on the bacterial strain, point or frameshift mutations can be investigated [3]. In eukaryotic cells, comet and micronucleus assays are frequently used to assess the potential of test chemicals to induce DNA breaks. These assays have been instrumental in assessing mechanistic information on compound genotoxicity by programs such as the IARC Monographs. However, these tests rely on prokaryotic systems (Ames), can be laborious (comet, micronucleus) and, most importantly, do not provide insight regarding the specific base changes and other features such as the sequence context. Some mutagenic carcinogens leave specific mutation imprints on the DNA, as exemplified by tobacco smoke carcinogens and ultraviolet (UV) light, causing characteristic mutation patterns in cancers of the lung and skin, respectively [4,5]. Human tumours arise from various causes, and this is reflected in heterogeneous mutation patterns, often a composite result of the action of multiple mutagenic processes throughout the cell lineage life-time. With the advent of massively parallel sequencing, cancer genome studies have accumulated large amounts of mutation data accessibl...

Background: Bisphenol A (BPA), an estrogen-like endocrine disruptor used in plastics, has been associated with development and promotion of breast cancer, so plastic manufacturers shifted towards less-studied analogs, BPF and BPS. Studying the associated DNA methylome-wide mechanisms of these derivatives is timely, particularly in comparison with BPA. Methods: We assessed proliferation, cell cycle, and migration of breast cancer cells (estrogen receptor (ER)-positive: MCF-7 and ER-negative: MDA-MB-231) treated with BPF and BPS ± estrogen receptor inhibitor (ERI) in comparison to BPA ± ERI. RNA expression and activity of DNA (de)methylation enzymes and LINE-1 methylation were quantified. DNA methylome-wide analysis was evaluated in bisphenol-exposed cells and compared to clinical breast cancer data. Results: The three bisphenols caused ER-dependent increased proliferation and migration of MCF-7 but not MDA-MB-231 cells, with BPS being 10 times less potent than BPA and BPF. Although they have similar chemical structures, the three bisphenols induced differential DNA methylation alterations at several genomic clusters of or single CpG sites, with the majority of these being ER-dependent. At equipotent doses, BPA had the strongest effect on the methylome, followed by BPS then BPF. No pathways were enriched for BPF while BPA-and BPS-induced methylome alterations were enriched in focal adhesion, cGMP-PKG, and cancer pathways, which were also dysregulated in methylome-wide alterations comparing ER-positive breast cancer samples to adjacent normal tissues. Conclusions: The three bisphenols have important epigenetic effects in breast cell lines, with those of BPA and BPS overlapping with cancer-related pathways in clinical breast cancer models. Hence, further investigation of their safety is warranted.

Ultraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures previously attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of primary mouse embryonic fibroblasts, human foreskin fibroblasts, and human epidermal keratinocytes.

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