Abstract
Large cancer genome sequencing initiatives have led to the identification of cancer driver genes based on signals of positive selection in somatic mutation data. Additionally, the identification of purifying (negative) selection has the potential to identify essential genes that may be of therapeutic interest. The most widely used way of quantifying selection pressures in protein-coding genes is the dN/dS metric, which compares non-synonymous to synonymous substitution rates. In this study, we examine whether and how this metric is influenced by the mutational processes that have been active during tumor evolution. We use exome sequencing data from six different cancer types from The Cancer Genome Atlas (TCGA) and demonstrate that dN/dS in its basic form, where uniform base substitution probabilities are assumed, is in fact strongly biased by these mutational processes. This is particularly true in malignant melanoma, where the mutational signature is characterized by a high amount of UV-induced cytosine to thymine mutations at dipyrimidine dinucleotides. This increases the likelihood of random synonymous mutations occurring in hydrophobic amino acid codons, leading to reduced dN/dS ratios in genes encoding membrane proteins and falsely suggesting purifying selection in these genes. When this effect is corrected for by taking mutational signature-derived substitution probabilities into account, purifying selection was found to be limited and similar in all cancer types studied. Our results demonstrate that it is crucial to take mutational signatures into account when applying the dN/dS metric to cancer somatic mutation data.
Highlights
Carcinogenesis is an evolutionary process resulting from the accumulation of somatic mutations in cancer genes (Vogelstein et al, 2013)
In addition to positive selection, there are indications that the genomic constitution of a tumor is further shaped by negative selection forces in which detrimental mutations in essential genes are selected out during tumor evolution (Lohr et al, 2012; Ostrow et al, 2014; Pyatnitskiy et al, 2015; Van den Eynden et al, 2016), these signals appear to be less prominent. It has become obvious from large cancer genome initiatives like The Cancer Genome Atlas (TCGA) that the overall mutational patterns observed in tumors are strongly influenced by heterogeneous mutational processes underlying their development, and that cancer types are characterized by different mutational signatures (Alexandrov et al, 2013; Kandoth et al, 2013; Lawrence et al, 2013)
Eighteen (1,211 out of 6,643) percent of all genes that were analyzed in this cancer had dN/dS ratios that were significantly lower than 1, which was higher than any other cancer studied (Figure 1C)
Summary
Carcinogenesis is an evolutionary process resulting from the accumulation of somatic mutations in cancer genes (Vogelstein et al, 2013). In addition to positive selection, there are indications that the genomic constitution of a tumor is further shaped by negative (or purifying) selection forces in which detrimental mutations in essential genes are selected out during tumor evolution (Lohr et al, 2012; Ostrow et al, 2014; Pyatnitskiy et al, 2015; Van den Eynden et al, 2016), these signals appear to be less prominent In recent years, it has become obvious from large cancer genome initiatives like The Cancer Genome Atlas (TCGA) that the overall mutational patterns observed in tumors are strongly influenced by heterogeneous mutational processes underlying their development, and that cancer types are characterized by different mutational signatures (Alexandrov et al, 2013; Kandoth et al, 2013; Lawrence et al, 2013). These signatures are determined by the proportion of the six main substitution classes (i.e., C>A, C>G, C>T, T>A, T>C, T>G; note that the pyrimidine of the mutated base pair is always used as a reference) and the adjacent up- and down-stream base pairs, resulting in 96 possible mutation types (6 substitution classes and 16 different combinations of up- and down-stream nucleotides)
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