A comprehensive catalogue of somatic mutations from a human cancer genome

Abstract

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.

Figure 1. The catalogue of somatic mutations in COLO-829

Chromosome ideograms are shown around the outer ring and are oriented pter–qter in a clockwise direction with centromeres indicated in red. Other tracks contain somatic alterations (from outside to inside): validated insertions (light-green rectangles); validated deletions (dark-green rectangles); heterozygous (light-orange bars) and homozygous (dark-orange bars) substitutions shown by density per 10 megabases; coding substitutions (coloured squares: silent in grey, missense in purple, nonsense in red and splice site in black); copy number (blue lines); regions of LOH (red lines); validated intrachromosomal rearrangements (green lines); validated interchromosomal rearrangements (purple lines).

Figure 2. Patterns of somatic substitution

a, Mutation spectrum. b, Mutation sequence context compared to random T bases and C bases (top two panels). c, Mutation counts by transcribed (T) and untranscribed (UT) strands. d, Effect of gene expression on mutation prevalence. Lines are parametrically fitted curves to the data. Mutation prevalence is expressed as the number of mutations per Mb of each class. T, transcribed strands; UT, untranscribed strands. e, Effect of distance along the transcript on mutation prevalence. Each dot represents a 5-kb bin along gene footprints, from transcription start sites to 200 kb. The y axis shows the fraction of genes in each bin carrying a somatic mutation.