Modelling Mutation Spectra of Human Carcinogens Using Experimental Systems

Abstract

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...

Experimental and pan-cancer genome analyses reveal widespread contribution of acrylamide exposure to carcinogenesis in humans

“…The majority of the signatures re-main of unknown origin, and additional, yet unrecognized, signatures are likely to be extracted from rapidly accumulating cancer genome data. Well-controlled experimental exposure systems can help identify the causes of the orphan mutational signatures and define new carcinogen-generated patterns (for review, see Hollstein et al 2017;Zhivagui et al 2017).…”

Sequencing Chemically Induced Mutations in the Mutamouse Lacz Reporter Gene Identifies Human Cancer Mutational Signatures

“…In addition, the person’s age at the time of tumour formation will also determine the contribution of “clock-like” signatures, caused by lifetime DNA replication, to the fingerprint of the tumour 22 . There is now compelling evidence that analysis of the spectrum of mutations in a cancer can provide clues to past environmental exposures that contributed to the development of the cancer 23,24 . Implicit in this is that the exposure signature should be present in the normal tissue before the carcinogenic process becomes apparent.…”

Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide

“…However, about 40% of the current signatures remain of unknown origin, and additional, thus far unrecognized, signatures are likely to be defined in rapidly accumulating cancer genome data. Well-controlled experimental exposure systems can thus help identify the underlying causes of known orphan mutational signatures as well as define new patterns generated by candidate carcinogens (reviewed in (3,4)).…”

“…The advent of massively parallel sequencing has created the opportunity to study a large number of mutations in a single sample, thus significantly enhancing the power of mutation analysis in experimental models and enabling reliable identification of specific sequence contexts for the induced alterations. Analogously to human cancer genome projects, genome-scale mutational signatures can be extracted from highly controlled carcinogen exposure experiments using mammalian cell and animal models coupled with advanced mathematical approaches (2,3,37,38).…”

“…Here we report the systematic assessment of acrylamide and glycidamide mutagenicity based on DNA adduct formation and mutation profile analysis using massively parallel sequencing in a cell model amenable to the analysis of carcinogen-induced mutation patterns and their impact on the resulting cell phenotype (3,(37)(38)(39). We identify a specific and robust mutational signature attributable to glycidamide, and by computationally interrogating human cancer genome-wide mutation data, we characterize glycidamide signature-positive tumors, thereby highlighting a potential contribution of acrylamide/glycidamide exposure to carcinogenesis in humans.…”