The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time

Abstract

During life, the DNA of our cells is continuously exposed to external damaging processes. Despite the activity of various repair mechanisms, DNA damage eventually results in the accumulation of mutations in the genomes of our cells. Oncogenic mutations are at the root of carcinogenesis, and carcinogenic agents are often highly mutagenic. Over the past decade, whole genome sequencing data of healthy and tumor tissues have revealed how cells in our body gradually accumulate mutations because of exposure to various mutagenic processes. Dissection of mutation profiles based on the type and context specificities of the altered bases has revealed a variety of signatures that reflect past exposure to environmental mutagens, ranging from chemotherapeutic drugs to genotoxic gut bacteria. In this review, we discuss the latest knowledge on somatic mutation accumulation in human cells, and how environmental mutagenic factors further shape the mutation landscapes of tissues. In addition, not all carcinogenic agents induce mutations, which may point to alternative tumor-promoting mechanisms, such as altered clonal selection dynamics. In short, we provide an overview of how environmental factors induce mutations in the DNA of our healthy cells and how this contributes to carcinogenesis. A better understanding of how environmental mutagens shape the genomes of our cells can help to identify potential preventable causes of cancer.

Keywords: cancer; environmental carcinogens; genomics; mutagens; mutational signatures.

FIGURE 1

Mutational signatures over time. (A) Presence of clonal mutations in normal cells, premalignant clones and cancer. Blue mutations present in the non-malignant normal cell. These mutations are retained in the premalignant clone and cancer, along with additional mutations acquired during tumorigenesis. Subclonal mutations are independently acquired by each cell, and can become clonal when selective sweeps favor expansion of a subclonal cell population. (B) Number of discovered mutational signatures catalogued in the COSMIC database, version indicated on top. Signature associations determined as in Supplementary Table S1. *signatures from Nik-Zainal et al., 2012. (C) Depiction of mutational signature extraction using tumor cells, normal cells and in vitro exposed cells as input source. Signatures can be extracted from the mutation catalogues using non-negative matrix factorization. This results in both signatures, and their relative contribution in each tumor type.

FIGURE 2

Mechanisms underlying topographical differences in mutation accumulation. Left column: Molecular mechanism of mutation induction. Right column: Typical readout of these processes in mutation data catalogues. (A) Transcriptional strand bias. Mutations indicated in green are preferentially repaired by TC-NER on the transcribed strand. (B) Incorporation of mutations opposite of DNA-adducts during replication results in the asymmetric division of mutations on either the Watson or Crick strand. (C) Preferential binding of DNA-damaging agents to specific contexts, resulting in the extended-context biases of mutations.

FIGURE 3

Influence of environmental genotoxins in the development of cancer. Schematic depicting multiple possible mechanisms responsible for an increased risk on developing cancer. (A) Aging drives a general mutation accumulation, inducing early driver mutations, which drive clonal expansions. These age-related clonal expansions induce an increasing, but relatively low risk on developing cancer during aging. (B) Early mutagenesis induces additional clones containing driver mutations in the tissue. An increased number of driver-containing clonal expansions increases the chance of acquiring additional driver mutations resulting in malignant cancer (red). (C) Late mutagenesis by environmental factors induces additional mutations in pre-existing oncogenic clones resulting in malignancies (red). (D) Exposure to the environmental factor results in preferential selection of driver-containing clones. The enhanced size of the clones increases the chance of acquiring additional driver mutations, resulting in malignancy.