Are sites with multiple single nucleotide variants in cancer genomes a consequence of drivers, hypermutable sites or sequencing errors?

Thomas C.A Smith,Antony M Carr,Adam C Eyre-Walker

doi:10.7717/peerj.2391

Abstract

Across independent cancer genomes it has been observed that some sites have been recurrently hit by single nucleotide variants (SNVs). Such recurrently hit sites might be either (i) drivers of cancer that are postively selected during oncogenesis, (ii) due to mutation rate variation, or (iii) due to sequencing and assembly errors. We have investigated the cause of recurrently hit sites in a dataset of >3 million SNVs from 507 complete cancer genome sequences. We find evidence that many sites have been hit significantly more often than one would expect by chance, even taking into account the effect of the adjacent nucleotides on the rate of mutation. We find that the density of these recurrently hit sites is higher in non-coding than coding DNA and hence conclude that most of them are unlikely to be drivers. We also find that most of them are found in parts of the genome that are not uniquely mappable and hence are likely to be due to mapping errors. In support of the error hypothesis, we find that recurently hit sites are not randomly distributed across sequences from different laboratories. We fit a model to the data in which the rate of mutation is constant across sites but the rate of error varies. This model suggests that ∼4% of all SNVs are errors in this dataset, but that the rate of error varies by thousands-of-fold between sites.

Highlights

There is currently huge interest in sequencing cancer genomes with a view to identifying the mutations in somatic tissues that lead to cancer, the so-called ‘‘driver’’ mutations
If there is no variation in the density of single nucleotide variants (SNVs) we should find them to be distributed randomly across the genome
Through our analysis of ∼3 million SNVs from whole cancer genomes we have shown that there are many sites at which there is a significant excess of SNVs

Summary

Introduction

There is currently huge interest in sequencing cancer genomes with a view to identifying the mutations in somatic tissues that lead to cancer, the so-called ‘‘driver’’ mutations. Driver mutations are expected to cluster in particular genes or genomic regions, or to recur at particular sites in the genome, because only a limited number of mutations can cause cancer. The driver mutations in the TERT1 promoter were identified because it had independently occurred in multiple cancers (Huang et al, 2013). There are two other processes that can potentially lead to the repeated occurrence of an apparent somatic mutation at a site. How to cite this article Smith et al (2016), Are sites with multiple single nucleotide variants in cancer genomes a consequence of drivers, hypermutable sites or sequencing errors? It is known that the mutation rate varies across the genome at a number of different scales in both the germ-line and soma (Hodgkinson & Eyre-Walker, 2011; Hodgkinson, Chen & Eyre-Walker, 2012; Michaelson et al, 2012; Francioli et al, 2015).

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