Mutational spectra of human cancer

Abstract

The purpose of this review is to summarize the evidence that can be used to reconstruct the etiology of human cancers from mutations found in tumors. Mutational spectra of the tumor suppressor gene p53 (TP53) are tumor specific. In several cases, these mutational spectra can be linked to exogenous carcinogens, most notably for sunlight-associated skin cancers, tobacco-associated lung cancers, and aristolochic acid-related urothelial tumors. In the TP53 gene, methylated CpG dinucleotides are sequences selectively targeted by endogenous and exogenous mutagenic processes. Recent high-throughput sequencing efforts analyzing a large number of genes in cancer genomes have so far, for the most part, produced mutational spectra similar to those in TP53 but have unveiled a previously unrecognized common G to C transversion mutation signature at GpA dinucleotides in breast cancers and several other cancers. Unraveling the origin of these G to C mutations will be of importance for understanding cancer etiology.

Figure 1. Mutation spectra (A, C, E) and codon distribution (B, D, F) of the TP53 tumor suppressor gene in human non-melanoma skin tumors (basal cell and squamous cell carcinomas), lung tumors of smokers, and breast cancers

A, B. Skin cancer; C, D. Lung cancer of smokers; E, F. Breast cancer. Data were obtained from the TP53 mutation database of the International Agency for Research on Cancer (http://www-p53.iarc.fr/index.html; R13 version). Ins: Insertions; Del: Deletions. Codons containing methylated CpG sequences are indicated by asterisks (*).

Figure 2. Spontaneous and induced mutation spectra of the TP53 tumor suppressor gene in the Hupki mouse model system

A. Mutations in B[a]P-treated Hupki mouse embryonic fibroblasts (n = 36) (data were compiled from (Feldmeyer et al. 2006; Liu et al. 2005; Reinbold et al. 2008). B. Mutations in aristolochic acid-treated Hupki mouse embryonic fibroblasts (n = 36) (data were compiled from (Feldmeyer et al. 2006; Liu et al. 2004; Nedelko et al. 2009; vom Brocke et al. 2006). C. Mutations in 3-nitrobenzanthrone-treated Hupki mouse embryonic fibroblasts (n = 29) (data were obtained from (Vom Brocke et al. 2008). D. Spontaneously derived (control) mutations from Hupki mouse embryonic fibroblasts (n = 58) (data were compiled from refs. (Feldmeyer et al. 2006; Liu et al. 2004; Liu et al. 2005; Luo et al. 2001a; Reinbold et al. 2008; Vom Brocke et al. 2008; vom Brocke et al. 2006).

Figure 3. Mutation spectra of protein kinase genes and other genes of interest in lung, colorectal, and breast cancers

Data for 518 protein kinase-encoding genes were obtained from Greenman et al (Greenman et al. 2007) (panels A, B, C). Data for 623 genes with a known or potential relationship to cancer were obtained from Ding et al (Ding et al. 2008) (panel D).

Figure 4. Mutation spectra of brain, colorectal, and breast cancers derived from large-scale sequencing of cancer genomes

Data from 20,661 protein-coding genes were obtained from Jones et al (Jones et al. 2008).