Abstract
DNA damage in somatic cells originates from both environmental and endogenous sources, giving rise to mutations through multiple mechanisms. When these mutations affect the function of critical genes, cancer may ensue. Although identifying genomic subsets of mutated genes may inform therapeutic options, a systematic survey of tumor mutational spectra is required to improve our understanding of the underlying mechanisms of mutagenesis involved in cancer etiology. Recent studies have presented genome-wide sets of somatic mutations as a 96-element vector, a procedure that only captures the immediate neighbors of the mutated nucleotide. Herein, we present a 32 × 12 mutation matrix that captures the nucleotide pattern two nucleotides upstream and downstream of the mutation. A somatic autosomal mutation matrix (SAMM) was constructed from tumor-specific mutations derived from each of 909 individual cancer genomes harboring a total of 10,681,843 single-base substitutions. In addition, mechanistic template mutation matrices (MTMMs) representing oxidative DNA damage, ultraviolet-induced DNA damage, 5mCpG deamination, and APOBEC-mediated cytosine mutation, are presented. MTMMs were mapped to the individual tumor SAMMs to determine the maximum contribution of each mutational mechanism to the overall mutation pattern. A Manhattan distance across all SAMM elements between any two tumor genomes was used to determine their relative distance. Employing this metric, 89.5 % of all tumor genomes were found to have a nearest neighbor from the same tissue of origin. When a distance-dependent 6-nearest neighbor classifier was used, 86.9 % of all SAMMs were assigned to the correct tissue of origin. Thus, although tumors from different tissues may have similar mutation patterns, their SAMMs often display signatures that are characteristic of specific tissues.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1566-1) contains supplementary material, which is available to authorized users.
Highlights
Cancer is promoted by a diverse set of genetic and epigenetic alterations in the soma, including single-base substitutions (SBSs), insertions and deletions, chromosome and DNA segment copy number variations (CNV), as well as chromosomal translocations and rearrangements
The rationale for applying vertical ionization potential (VIP) values to address the issue of SBSs in cancer genomes is based on a large number of theoretical and experimental studies performed during the past 30 years on short DNA oligomers (Kanvah et al 2010; Saito et al 1998; Yoshioka et al 2003)
This composite work has led to the conclusion that chemical reactivity of DNA bases to attacking oxidants is influenced by the energy required to abstract an electron from the DNA, and that the values of this energy are strongly sequence context dependent, being influenced by the differential ability of electrons to fastly migrate from one base to another based on the types of the DNA bases
Summary
Cancer is promoted by a diverse set of genetic and epigenetic alterations in the soma, including single-base substitutions (SBSs), insertions and deletions, chromosome and DNA segment copy number variations (CNV), as well as chromosomal translocations and rearrangements. Whereas “driver” mutations enable positive selection, “passenger” mutations are, by definition, tolerated and provide no proliferative advantage or disadvantage to tumor cells (Stratton et al 2009; Vogelstein et al 2013); the molecular mechanisms leading to the generation of driver and passenger mutations are expected to be similar. Mutational patterns are in turn determined by chemical reactions, with respect to initial base modification by chemical or enzymatic activity (e.g., cytosine deamination) and through subsequent interactions with DNA repair mechanisms, as well as long-range interactions at both intermolecular and atomic levels, such that these patterns may be heavily influenced by the local nucleotide sequence context (Holmquist and Gao 1997; Pfeifer et al 2005). Sequence-specific mutational biases in germline mutational spectra (Cooper et al 2011), and in genes implicated in tumorigenesis (Ivanov et al 2011), have been shown to be consequent to the basic properties of a range of different mutational mechanisms (Bacolla et al 2014; Helleday et al 2014)
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