Discovery and saturation analysis of cancer genes across 21 tumor types

Nature (Impact Factor: 41.46). 01/2014; 505(7484). DOI: 10.1038/nature12912
Source: PubMed


Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics.

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    • "However, not all of these mutations prove to be relevant for malignancy. Melanomas have a median of 13‐17 mutations per Mbp of DNA, the highest frequency among 21 cancer types analyzed (The Cancer Genome Atlas Network, 2015; Hodis et al., 2012; Lawrence et al., 2014), even without considering rearrangements, copy‐number alterations and epigenetic changes. These mutations predominantly carry the signature of ultraviolet light mutagenesis (Hodis et al., 2012). "
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    • "Point mutations are believed to be less contributory in prostate carcinogenesis, with exome sequencing discovering a relatively low mutational frequency of 0.3–5 per Mb (Taylor et al, 2010; Barbieri et al, 2012; Grasso et al, 2012). In a saturation analysis of point mutations, small mutations across multiple tumour types, only four significantly mutated genes were discovered from the prostate cancer data set; SPOP (found in 10.1% of samples), TP53 (3.6%), ATM (2.2%) and MED12 (3.6%; Lawrence et al, 2014). When the prostatic data set was compared with cancer genes from the other 20 cancer types an additional two significantly mutated genes were detected, FOXA1 (2.9%) and COL5A1 (2.2%). "
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