A compendium of mutational signatures of environmental agents

It is well known that diverse environmental carcinogens result in distinctly different patterns of genomic responses. Whole-genome sequencing (WGS) of a single malignant melanoma and a single lung cancer cell line in 2010, for example, first illustrated the power of this approach — revealing the characteristic mutational spectra of UV light vs tobacco carcinogens, respectively. Subsequently, WGS of large numbers of other tumors revealed mutational patterns in nearly all tumors that arise from both endogenous (i.e. within the body) and exogenous (outside the body) sources. Global, unbiased depiction provided by WGS has permitted more refined insights into mutational processes of human cancers, facilitating clinical applications of cancer genomics.

Yet, human cancers result from environmental and endogenous exposures that are uncontrolled and in highly variable genetic backgrounds. Although mathematical methods have been applied to deconstruct mutation profiles into individual mutational signatures, these approaches are complex and fraught with issues of interpretation — due to lack of experimental controls. Therefore, an important next step is to examine systematically mutational patterns associated with a broad selection of environmental or therapeutic mutagens, generated under highly-controlled conditions. Authors [see attached article] used a human induced pluripotent stem cell (iPSC) line, having the advantages of being normal, undifferentiated, fast-growing, and easy to clone. Most of the agents tested are classified by the International Agency for Research on Cancer (IARC) as “known, probable, or possible human carcinogens.”

Authors examined mutational signatures in 324 WGS human iPSC lines exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures; some were similar to signatures found in human tumors. In addition, six agents produced double-substitution (altering two base-pairs) signatures, and eight agents produced insertion-deletion (indel) signatures. The mutation patterns included fully functional mismatch- and transcription-coupled repair pathways, resulting in an assortment of signature outcomes — even for a single agent. This compendium of experimentally induced mutational signatures will now permit further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA (when the cells are in a culture dish) is directly vulnerable to environmental agents. [It is known that, in intact pregnant animals, however, stem cell DNA appears to be extremely resistant to such environmental damage.] 🙂


Cell 2 May 2o19; 177: 1–16

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