How the environment shapes cancer genomes

Abstract

Purpose of review: The mutational patterns of cancer genomes allow conclusions or generation of hypotheses as to what mechanisms or environmental, dietary or occupational exposures might have created the mutations and therefore will have contributed to the formation of the cancer. The arguments for cancer causation are particularly convincing when epidemiological evidence can support the theory that a particular exposure is linked to the cancer and when the mutational process can be recapitulated in experimental systems. In this review, I will summarize recent evidence from cancer genome sequencing studies to exemplify how the environment can modulate tumor genomes.

Recent findings: Mutation data from cancer genomes clearly implicate the ultraviolet B component of sunlight in melanoma skin cancers, tobacco carcinogen-induced DNA damage in lung cancers and aristolochic acid, a chemical compound found in certain herbal medicines, in urothelial carcinomas of exposed populations. However, large-scale sequencing is beginning to unveil other unique mutational spectra in particular cancers, such as A-to-C mutations at 5'AA dinucleotides in esophageal adenocarcinomas and complex mutational patterns in liver cancer. These datasets can form the basis for future studies aimed at identifying the carcinogens at work.

Summary: The findings have substantial implications for our understanding of cancer causation and cancer prevention.

Figure 1. Examples of mutation spectra for human lung cancer, liver cancer and colorectal cancer

Data for base substitution mutations were obtained from the COSMIC database. Note that the data set may be biased to some extent because single gene-specific datasets (e.g. KRAS, CTNNB1) are included, which may be affected by base composition and/or selection for specific mutations.

Figure 2. Use of mutational spectra to deduce the origins of cancer

Cancer genome sequencing provides large datasets that can be used to derive mutational spectra (left). Candidate mutagens can then be tested in experimental systems (right) to determine if their mutational specificity is similar to the spectra observed in human cancer. The spectrum shown is hypothetical.