Signatures of mutation and selection in the cancer genome

Abstract

The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.

Figure 1. Genomic deletion profile

Deletion patterns in the 746 cancer cell lines across the autosomal chromosomes. The homozygous deletion (red) and small hemizygous deletion (blue) counts are calculated for 100-kb windows across the genome. All homozygous deletion clusters containing six or more homozygous deletions are annotated. Each tick-mark on the vertical axis denotes ten deletions, and the horizontal axis represents each chromosome from p-telomere to q-telomere.

Figure 2. Deletion patterns arising from small and large hemizygous deletions

At any locus each parental chromosome can have one of three deletion states: wild type (W); large deletion (>1 Mb, L); or small deletion (<1 Mb, S). Therefore, in principle, six combinations can exist in a diploid genome: WW, both chromosomes are wild type; WL, one chromosome has a large hemizygous deletion; WS, one chromosome has a small hemizygous deletion; LL, homozygous deletion in which both chromosomes have large overlapping deletions; LS, homozygous deletion in which one chromosome has a large deletion overlapping a small deletion in the other; SS, homozygous deletion in which both chromosomes have small overlapping deletions.

Figure 3. Deletion patterns for clusters of six or more homozygous deletions

Deletion clusters over known fragile sites, over known recessive cancer genes and that are unexplained are shown. The counts for small hemizygous deletions (blue), homozygous deletions arising from two small deletions (orange) and homozygous deletions with at least one large deletion (red) are given for the 100-kb window at the deepest point of each homozygous deletion cluster.