This may be adequate when a single mutational process generates the majority of mutations in the particular cancer (e.g. UV light is the predominant mutational

process in melanoma [19••]). However, usually multiple mutational processes are operative in a single cancer sample, and combining their mutations generates a mixed composition of the patterns of somatic mutations. In Navitoclax purchase most cases, reporting this jumbled spectrum is uninformative for the diversity of mutational processes operative in a single cancer type or in a single cancer sample [20••]. Moreover, the examined TP53 exons are both under selection and also have a specific nucleotide sequence. This affects the opportunity for Z-VAD-FMK mw observing a somatic mutation and as such the reported spectrum can be a reflection of the processes of selection and/or the nucleotide architecture of the TP53 gene in addition

to the processes of mutation [ 21 and 22]. Two studies tried to overcome some of the single gene limitations by leveraging a targeted capillary sequencing approach of large number of genes. A survey of the 518 protein kinase genes in 25 human breast cancer samples revealed 92 somatic mutations (90 substitutions and 2 indels) in which C > T transitions and C > G transversions preceded by thymine (i.e. C > T and C > G at TpC, mutated base is underlined) occurred with a higher than expected frequency [23]. This survey was later expanded to 210 cancer samples and it revealed more than 1 000 somatic mutations with significant variations in their patterns across the examined twelve cancer types [24]. Only a small fraction of the mutations reported in these screens are likely to be

affected by selection [25], thus indicating that the observed mutational patterns reflect the operative mutational processes in the analyzed samples and not the processes of negative or positive selection. The development of second-generation sequencing technologies allowed examination of cancer exomes (i.e. the combined protein coding exons) and even whole cancer genomes. Sequencing cancer exomes has been generally preferred as the majority of known cancer-causing driver somatic substitutions, Exoribonuclease indels, and copy number changes (although generally not rearrangements) [21] are located in protein coding genes. As the nucleotide sequence of protein coding genes is ∼1% of the whole genome, analysis of exomes is considered an advantageous and cost effective methodology for discovering the genes involved in neoplastic development. As a result, many studies have focused predominantly on the generation and analysis of exome sequences [26]. Early next generation sequencing studies started revealing patterns of somatic substitutions in different cancer types. In 2010, two back-to-back studies in Nature reported the patterns of somatic mutations in a malignant melanoma [ 27•] and small cell lung carcinoma [ 28•].