Investigating the origins of the mutational signatures in cancer

Abstract

Most of the risk factors associated with chronic and complex diseases, such as cancer, stem from exogenous and endogenous exposures experienced throughout an individual's life, collectively known as the exposome. These exposures can modify DNA, which can subsequently lead to the somatic mutations found in all normal and tumor tissues. Understanding the precise origins of specific somatic mutations has been challenging due to multitude of DNA adducts (i.e. the DNA adductome) and their diverse positions within the genome. Thus far, this limitation has prevented researchers from precisely linking exposures to DNA adducts and DNA adducts to subsequent mutational outcomes. Indeed, many common mutations observed in human cancers appear to originate from error-prone endogenous processes. Consequently, it remains unclear whether these mutations result from exposure-induced DNA adducts, or arise indirectly from endogenous processes or are a combination of both. In this review, we summarize approaches that aim to bridge our understanding of the mechanism by which exposure leads to DNA damage and then to mutation and highlight some of the remaining challenges and shortcomings to fully supporting this paradigm. We emphasize the need to integrate cellular DNA adductomics, long read-based mapping, single-molecule duplex sequencing of native DNA molecules and advanced computational analysis. This proposed holistic approach aims to unveil the causal connections between key DNA modifications and the mutational landscape, whether they originate from external exposures, internal processes or a combination of both, thereby addressing key questions in cancer biology.

Graphical Abstract

Figure 1.

The exposome encompasses the totality of human environmental (both endogenous and exogenous) exposures across the lifespan. The exposome represents a complex mixture of multiple, diverse exposures many of which can directly or indirectly modify, or damage DNA. These DNA modifications can lead to various types of somatic mutations, including SBSs, doublet base substitutions (DBSs), small insertions and deletions (IDs), copy number changes (CNs) and structural variations (SVs). SBSs involve the replacement of one nucleotide with another and are among the most common mutations in cancer. DBSs refer to simultaneous substitutions of two adjacent bases. IDs involve the addition or loss of small DNA segments, potentially disrupting gene function. CN changes involve gains or losses of larger DNA regions, leading to gene amplification or deletion. SVs encompass large-scale genomic alterations, such as deletions, duplications, inversions and translocations, which can disrupt gene structure and regulatory regions, contributing to cancer progression.

Figure 2.

The representative mutational signatures, SBS4 and SBS29, are unique enough to be distinguished from others, associated with a specific exposure and are found in the corresponding tumors. SBS4 (top panel) is associated with tobacco use and found primarily in tumors from tobacco smokers (35), while SBS29 (bottom panel) is associated with chewing tobacco and almost exclusively in oral cancers. Both exposures lead to tumors with predominantly C > A mutations; however, the trinucleotide context profile suggests distinct differences in the mutational signatures, and hence perhaps mechanisms, induced by smoking tobacco compared with those induced by chewing tobacco, which could be elucidated by studying of the DNA adductome.

Figure 3.

Representative mutational signatures, SBS1 and SBS2, are distinct enough to be distinguished from others and are associated with specific endogenous processes. SBS1 (top panel) is thought to result from the spontaneous or enzymatic deamination of 5-Me-Cyt to Thy, while SBS2 (bottom panel) is associated with cytidine deaminase activity, specifically the AID/APOBEC family of cytidine deaminases. Both endogenous processes lead to mutational signatures characterized by C>T mutations; however, each exhibits a unique trinucleotide context profile, suggesting different underlying mechanisms.

Figure 4.

An illustration of the range of DNA adducts and DNA modifications derived from epigenetic remodeling, endogenous and exogenous sources.

Figure 5.

A scheme illustrating a DNA strand, containing a DNA adduct (*) passing through a nanopore and potentially blocking or altering the ion current (dots) at or near the adduct site (A) preceding, (B) at or (C) trailing the DNA adduct.