Statistical analysis of pathogenicity of somatic mutations in cancer.
Recent large-scale sequencing studies have revealed that cancer genomes contain variable numbers of somatic point mutations distributed across many genes. These somatic mutations most likely include passenger mutations that are not cancer causing and pathogenic driver mutations in cancer genes. Establishing a significant presence of driver mutations in such data sets is of biological interest. Whereas current techniques from phylogeny are applicable to large data sets composed of singly mutated samples, recently exemplified with a p53 mutation database, methods for smaller data sets containing individual samples with multiple mutations need to be developed. By constructing distinct models of both the mutation process and selection pressure upon the cancer samples, exact statistical tests to examine this problem are devised. Tests to examine the significance of selection toward missense, nonsense, and splice site mutations are derived, along with tests assessing variation in selection between functional domains. Maximum-likelihood methods facilitate parameter estimation, including levels of selection pressure and minimum numbers of pathogenic mutations. These methods are illustrated with 25 breast cancers screened across the coding sequences of 518 kinase genes, revealing 90 base substitutions in 71 genes. Significant selection pressure upon truncating mutations was established. Furthermore, an estimated minimum of 29.8 mutations were pathogenic.
Greenman
Chris
C
Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, United Kingdom. cdg@sanger.ac.uk
Wooster
Richard
R
Futreal
P Andrew
PA
Stratton
Michael R
MR
Easton
Douglas F
DF
D000595:Amino Acid Sequence / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D030541:Databases, Genetic; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53